Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH2:14][CH2:13][C:12](=[O:15])[NH:11][C:10]2=[O:16])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[C:10]([C:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)([CH2:14][CH2:13][C:12]([N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:15])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:16])[NH2:11]
Reactant: C1CCNCC1
Reactant: O=C(O)CCC1(c2ccc(Cl)c(Cl)c2)CCC(=O)NC1=O
Product: NC(=O)C(CCC(=O)O)(CCC(=O)N1CCCCC1)c1ccc(Cl)c(Cl)c1

Procedure:
0.3 g of 3-[3-(3,4-dichlorophenyl)-2,6-dioxopiperidin-3-yl]propionic acid of S configuration is treated with piperidine as described in Preparation 3 to give 0.3 g of the expected compound.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:11])=[CH:6][C:7]=1[C:8]([OH:10])=[O:9].[OH-:12].[Na+]>>[Cl:11][C:5]1[N:4]=[N:3][C:2]([OH:12])=[C:7]([C:8]([OH:10])=[O:9])[CH:6]=1
Reactant: O=C(O)c1cc(Cl)nnc1Cl
Reactant: [OH-]
Agent: [Na+]
Product: O=C(O)c1cc(Cl)nnc1O

Procedure:
2 mmol of 3,6-Dichloropyridazine-4-carboxylic acid are treated with 8 ml of aqueous 2N NaOH and refluxed for 1 h. The reaction mixture was acidified to pH=1. The resulting white solid was filtered off and dried under vacuum. MS(ISO): 173.2 (M−H+)
Reaction SMILES: [F:1][C:2]([F:21])([C:17]([F:20])([F:19])[F:18])[C:3]([F:16])([F:15])[C:4]1[NH:9][C:8](=[O:10])[C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:5]=1.[Cl:22]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:22][C:5]1[CH:6]=[C:7]([C:11]([O:13][CH3:14])=[O:12])[C:8](=[O:10])[NH:9][C:4]=1[C:3]([F:15])([F:16])[C:2]([F:1])([F:21])[C:17]([F:19])([F:18])[F:20]
Reactant: COC(=O)c1ccc(C(F)(F)C(F)(F)C(F)(F)F)[nH]c1=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)c(C(F)(F)C(F)(F)C(F)(F)F)[nH]c1=O
Temperature: 50 °C
Reaction time: 3 h

Procedure:
16.7 g (52 mmol) of methyl 6-(heptafluoropropyl)-2-oxo-1,2-dihydropyridine-3-carboxylate were dissolved in 160 ml of N,N-dimethylformamide, and 7.08 g (52 mmol) of N-chlorosuccinimide were added at room temperature. After 3 hours of stirring at 50° C., the reaction mixture was added to water and extracted repeatedly with ethyl acetate. The organic phase was then separated off, washed with water and dried. The resulting crude product was then purified by preparative RP-HPLC. This gave 10.1 g (54% of theory) of the product as a colorless powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11](=[O:13])C)[CH:5]=[C:6]2[C:10]=1[CH2:9][CH2:8][CH2:7]2.[O-]Cl.[Na+].[OH-].[Na+].S(S([O-])=O)([O-])(=O)=[O:20].[Na+].[Na+]>C(COC)OC.O>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:20])[CH:5]=[C:6]2[C:10]=1[CH2:9][CH2:8][CH2:7]2
Reactant: CC(=O)c1cc(Br)c2c(c1)CCC2
Reactant: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: O=C(O)c1cc(Br)c2c(c1)CCC2
Temperature: 50 °C
Yield: 98.2 %

Procedure:
1-(7-bromo-2,3-dihydro-1H-inden-5-yl)ethanone (8.6 g, 36 mmol) was dissolved in dimethoxyethane (100 mL) and to the solution were added NaClO aq (200 mL 1M, 200 mmol) and NaOH aq (20 mL 10 M, 200 mmol). The mixture was heated to 50° C. for 1 h and then diluted with water (200 mL). Sodium pyrosulfite (5.7 g, 30 mmol) was added. The mixture was washed with ether, acidified with concentrated HCl and then extracted twice with ether (150 mL). The organic solution was washed with brine, dried and then the solvent was evaporated. The solid residue was treated with cold CH2Cl2 (−40° C.), then filtered off and dried. There was obtained 7.1 g (82%) of 7-bromoindane-5-carboxylic acid as a solid material. 1H NMR (300 MHz, CD3OD): 2.0-2.2 (q, 2H), 2.9 (t, 2H), 3.1 (t, 2H), 7.8 (s, 1H), 7.9 (s, 1H).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][CH:10]([CH2:13]O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[C:24]([O:26][CH3:27])=[O:25])[CH:17]=[CH:16]1.C(P(=CC#N)(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[C:1]1([N:7]2[CH2:8][CH2:9][CH:10]([CH2:13][N:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][C:22]=4[C:24]([O:26][CH3:27])=[O:25])[CH:17]=[CH:16]3)[CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cccc2cc[nH]c12
Reactant: OCC1CCN(c2ccccc2)CC1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc2ccn(CC3CCN(c4ccccc4)CC3)c12
Temperature: 100 °C
Reaction time: 24 h
Yield: 13.9 %

Procedure:
To a mixture of (1-phenylpiperidin-4-yl)methanol (958 mg), methyl 1H-indole-7-carboxylate (590 mg), and toluene (20 mL) was added (tributylphosphoranylidene)acetonitrile (1.0 g) at room temperature. The mixture was stirred at 100° C. for 1 day. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain methyl 1-[(1-phenylpiperidin-4-yl)methyl]-1H-indole-7-carboxylate (163 mg).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][NH:6][C:7](=[O:29])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:21][C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:10][CH:9]=1.Br[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>>[CH2:32]([O:28][C:25]1[CH:24]=[CH:23][C:22]([O:21][CH:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:30])=[O:29])=[CH:9][CH:10]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:27][CH:26]=1)[CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCBr
Reactant: CCCCCCC(Oc1ccc(O)cc1)c1ccc(C(=O)NCCC(=O)OC)cc1
Product: CCCCCCC(Oc1ccc(OCCCCC)cc1)c1ccc(C(=O)NCCC(=O)O)cc1

Procedure:
The title compound is prepared in a manner substantially similar to Example 92 starting from 3-{4-[1-(4-hydroxy-phenoxy)-heptyl]-benzoylamino}-propionic acid methyl ester and 1-bromo-pentane. MS: 468.2 [M−H]−.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:3](O)=[O:4].C(Cl)(=O)C([Cl:14])=O>>[CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:3]([Cl:14])=[O:4]
Reactant: CCCCCC(C)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Product: CCCCCC(C)C(=O)Cl

Procedure:
Employing 5 g. of 2-methylheptanoic acid and 7.6 ml. of oxalyl chloride and using the procedure of Preparation A2, 3.3 g. of the desired product was obtained, b.p. 32°-34 ° C./0.6 torr.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([S:12]([OH:15])(=[O:14])=O)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.C[N:21]([CH3:24])[CH:22]=O>>[Cl:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([S:12]([N:10]2[CH2:9][CH2:8][CH2:24][NH:21][CH2:22][CH2:11]2)(=[O:14])=[O:15])=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)c1ccc(Cl)c2ncccc12
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=S(=O)(c1ccc(Cl)c2ncccc12)N1CCCNCC1
Reaction time: 2 h
Yield: 54 %

Procedure:
To 14.2 g of 8-chloro-5-quinolinesulfonic acid were added 142 ml of thionyl chloride and 1.42 ml of dimethylformamide, followed by heating under reflux for 3 hours. Then, the thionyl chloride was removed under reduced pressure and the resultant residue was dissolved in 100 ml of ice water. The pH of the resultant solution was adjusted at 6 with a saturated aqueous sodium hydrogencarbonate solution. The solution was subjected to extraction with 100 ml of dichloromethane. The resultant dichloromethane layer was added dropwise to 100 ml of a dichloromethane solution containing 5.81 g of homopiperazine and 5.6 g of triethylamine over a period of 30 minutes while cooling with ice. The mixture was stirred at a temperature of 15° C. to 20° C. for 2 hours, washed with a 200 ml of water, and dried over anhydrous magnesium sulfate. Then, the solvent was removed under reduced pressure to obtain a residue. The thus obtained residue was subjected to purification by means of a chromatography column packed with 500 g of silica gel (Wacogel C-200, manufactured by Wako Pure Chemicals Industries, Ltd., Japan) and using, as a solvent, a mixture of methanol and chloroform (5% methanol), to thereby obtain 10.2 g of 1-(8-chloro-5-quinolinesulfonyl)homopiperazine (54) (yield: 54%).
Reaction SMILES: [C:1]([NH:4][C@@H:5]([CH3:30])[CH2:6][O:7][C:8]1[N:13]=[CH:12][C:11]([NH:14][C:15](=[O:28])[C:16]2[CH:21]=[C:20]([F:22])[C:19]([O:23][CH2:24][CH:25]3[CH2:27][CH2:26]3)=[N:18][CH:17]=2)=[C:10](Cl)[CH:9]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.[Cu]I>[CH:25]1([CH2:24][O:23][C:19]2[N:18]=[CH:17][C:16]([C:15]3[O:28][C:10]4[CH:9]=[C:8]([O:7][CH2:6][C@@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH3:30])[N:13]=[CH:12][C:11]=4[N:14]=3)=[CH:21][C:20]=2[F:22])[CH2:27][CH2:26]1
Reactant: CC(=O)N[C@@H](C)COc1cc(Cl)c(NC(=O)c2cnc(OCC3CC3)c(F)c2)cn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H](C)COc1cc2oc(-c3cnc(OCC4CC4)c(F)c3)nc2cn1
Temperature: 160 °C
Reaction time: 3 h
Yield: 5 %

Procedure:
A suspension of N-(6-(((2S)-2-acetamidopropyl)oxy)-4-chloropyridin-3-yl)-6-(cyclopropylmethoxy)-5-fluoronicotinamide (860 mg), potassium carbonate (544 mg) and copper(I) iodide (37.5 mg) in DMF (10 mL) was stirred at 160° C. for 3 hr under microwave irradiation. To the reaction mixture was added water, and the obtained mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and subjected to silica gel column chromatography (NH, ethyl acetate). The solvent was evaporated, and the obtained solid was washed with ethyl acetate/hexane to give the title compound (39.8 mg).
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:9]=[C:10]([OH:15])[CH:11]=[CH:12][C:13]=1[Cl:14].CS([C:20]1[C:25]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:24][CH:23]=[CH:22][N:21]=1)(=O)=O>C1COCC1>[Cl:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][C:13]=1[Cl:14])[O:15][C:20]1[C:25]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:24][CH:23]=[CH:22][N:21]=1
Reactant: CS(=O)(=O)c1cccnc1S(C)(=O)=O
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cccnc1Oc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Potassium t-butoxide (2.47 g) was dissolved in 30 ml of THF and then 3.46 g of 3,4-dichlorophenol dissolved in THF was added. A solution of 5.00 g of 2,3-bis(methylsulfonyl)pyridine in 20 ml THF/20 ml DMSO was added dropwise. The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was poured onto ice-water which resulted in the formation of an oil which solidified on standing. The product was collected by filtration and dried in a vacuum oven and 5.33 g of material obtained. Recrystallization from CH2Cl2 /hexane gave purified 2-(3,4-dichlorophenoxy)-3-(methylsulfonyl)pyridine, m.p. 95°-96° C.
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[CH:10][C:9]([S:13]([OH:16])(=[O:15])=[O:14])=[CH:8][C:3]=1[C:4](OC)=[O:5].[K].[NH2:18][NH2:19]>CO>[OH:1][C:2]1[C:11]([OH:12])=[CH:10][C:9]([S:13]([OH:16])(=[O:15])=[O:14])=[CH:8][C:3]=1[C:4]([NH:18][NH2:19])=[O:5]
Reactant: COC(=O)c1cc(S(=O)(=O)O)cc(O)c1O
Reactant: NN
Agent: [K]
Solvent: CO
Product: NNC(=O)c1cc(S(=O)(=O)O)cc(O)c1O

Procedure:
2,3-Dihydroxy-5-sulfobenzoic acid, methyl ester, monopotassium salt (2.7 g, 9.4 mmole) and neat hydrazine (0.88 ml, 28 mmoles) in 100 ml of methanol were refluxed for 48 hours. The resulting white precipitate was filtered, dried, and dissolved in water (10 ml). Acidification to pH=2.5 with 2N hydrochloric acid, filtering and drying gave 940 mg of the title compound as a solid.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1Cl)=[O:13])[CH2:8]2.[NH:24]1[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26][CH2:25]1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1[N:24]1[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26][CH2:25]1)=[O:13])[CH2:8]2
Reactant: OC1CCNCC1
Reactant: CC(C)(C)n1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1Cl
Product: CC(C)(C)n1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1N1CCC(O)CC1

Procedure:
Heating a mixture of 1-tert-butyl-5-chloro-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Example 36, 101 mg; 0.30 mmol) and piperidin-4-ol (303 mg; 3.0 mmol) under microwave irradiation according to the procedure described in Example 37, Step 5 provided after purification by reverse phase HPLC, 1-tert-butyl-5-(4-hydroxy-piperidin-1-yl)-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (14 mg, 12%) as an off-white powder. ES-HRMS m/e calcd for C23H37N4O2 (M+H+) 357.2649, found 357.2650.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:5]=1[C:6]([C:8]1[N:12]([CH3:13])[C:11]([CH2:14][C:15]([O:17]CC)=[O:16])=[CH:10][C:9]=1[CH3:20])=[O:7]>>[Cl:3][C:4]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:5]=1[C:6]([C:8]1[N:12]([CH3:13])[C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][C:9]=1[CH3:20])=[O:7]
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc(Cl)cc2Cl)n1C
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(CC(=O)O)n(C)c1C(=O)c1ccc(Cl)cc1Cl
Yield: 89.1 %

Procedure:
A solution of 2.38 mL (1.1 eq) of 1N NaOH was added dropwise to a refluxing solution of 76.89 g (0.217 mole) of ethyl 5-(2,4-dichlorobenzoyl)-1,4-dimethyl-1H-pyrrole-2-acetat (3)in 750 mL absolute ethanol. The mixture was heated under reflux for 20 minutes. The reaction was poured into 3N HCl/ice and extracted three times with diethyl ether. The organics were washed with water (twice), brine, and dried (MgSO4). Evaporation of the solvent in vacuo gave a tan oil which was crystallized from acetonitrile to give 63.05 g of product: mp 140°-143° C.; mass spectrum (Cl--CH4) m/z=326 (M+1); NMR 300 MHz (Me2SO-d6) d 7.8 (s, 1H); 7.6 (m, 1H); 7.4 (m, 1H); 6.0 (s, 1H); 3.8 (s, 3H); 3.75 (s, 2H); 1.45 (s, 3H). Anal Calcd for C15H13Cl2NO3 : C, 55.24; H, 4.02; N, 4.29. Found: C, 55.47; H, 3.84; N, 4.29.
Reaction SMILES: [Cl:1][C:2]1[O:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[Na].[CH2:10]([O:12][C:13](=[O:18])[CH2:14][N:15]=[N+]=[N-])[CH3:11]>C(O)C>[CH2:10]([O:12][C:13]([C:14]1[NH:15][C:4]2[CH:3]=[C:2]([Cl:1])[O:6][C:5]=2[CH:7]=1)=[O:18])[CH3:11]
Reactant: O=Cc1ccc(Cl)o1
Reactant: CCOC(=O)CN=[N+]=[N-]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1cc2oc(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Chloro-furan-2-carbaldehyde (Snyder, H. R., Jr.; Seehausen, P. H., J. Heterocycl. Chem., 10: 385-6 (1973)) was annulated according to Procedure H (8 equiv sodium; aldehyde and azido-acetic acid ethyl ester added as ethanol solution (0.9 M of ester); condensation reaction mixture allowed to warm to room temperature, stirred for 1 h, quenched at −40° C., diluted with water, and extracted with ether; acrylate not purified; crude furanopyrrole filtered before concentration).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[OH:7][C@H:8]1[CH2:12][CH2:11][NH:10][C@@H:9]1[C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[S:22][CH:23]=[C:24]([C:26]3[CH:35]=[CH:34][C:33]4[C:32]([CH3:37])([CH3:36])[CH2:31][CH2:30][C:29]([CH3:39])([CH3:38])[C:28]=4[CH:27]=3)[N:25]=2)[CH2:17][CH2:16]1)=O>C1COCC1>[CH3:36][C:32]1([CH3:37])[CH2:31][CH2:30][C:29]([CH3:38])([CH3:39])[C:28]2[CH:27]=[C:26]([C:24]3[N:25]=[C:21]([CH:18]4[CH2:17][CH2:16][N:15]([CH2:13][C@@H:9]5[C@@H:8]([OH:7])[CH2:12][CH2:11][NH:10]5)[CH2:20][CH2:19]4)[S:22][CH:23]=3)[CH:35]=[CH:34][C:33]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(C4CCN(C(=O)[C@H]5NCC[C@@H]5O)CC4)n3)ccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(C4CCN(C[C@H]5NCC[C@@H]5O)CC4)n3)ccc21

Procedure:
The preparation was carried out as already described using a 2N lithium aluminium hydride solution in THF starting from 30 mg (0.06 mmol) of ((2S,3S)-3-hydroxypyrrolidin-2-yl)-{4-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidin-1-yl}methanone. The product was purified by means of preparative HPLC and is in the form of the hydrochloride.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][NH2:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:12]1[N:13]=[N+:14]([O-:26])[C:15]2[CH:25]=[C:24]3[C:19]([CH2:20][CH2:21][CH2:22][CH2:23]3)=[CH:18][C:16]=2[N:17]=1>COCCOC>[N:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:12]2[N:13]=[N+:14]([O-:26])[C:15]3[CH:25]=[C:24]4[C:19]([CH2:20][CH2:21][CH2:22][CH2:23]4)=[CH:18][C:16]=3[N:17]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: [O-][n+]1nc(Cl)nc2cc3c(cc21)CCCC3
Reactant: NCCCN1CCOCC1
Solvent: COCCOC
Product: [O-][n+]1nc(NCCCN2CCOCC2)nc2cc3c(cc21)CCCC3
Yield: 99.7 %

Procedure:
3-(4-Morpholinyl)propylamine (314 mg, 2.18 mmol) was added to a stirred solution of chloride 176 (171 mg, 0.73 mmol) in DME (8 mL) and the solution stirred at reflux temperature for 30 min. The solution was cooled and partitioned in between EtOAc and aqueous Na2CO3 solution. The organic fraction was washed with water, dried and the solvent evaporated to give 1-oxide 179 (250 mg, 100%) as an orange solid: mp (EtOAc) 115-116° C.; 1H NMR δ 7.97 (s, 1H, H-10), 7.29 (s, 1H, H-5), 6.14 (br s, 1H, NH), 3.75 (t, J=4.6 Hz, 4H, 2×CH2O), 3.60 (q, J=6.2 Hz, 2H, CH2N), 2.86-2.95 (m, 4H, H-6, H-9), 2.45-2.56 (m, 6H, 3×CH2N), 1.80-1.88 (m, 6H, H-7, H-8, CH2); 13C NMR δ 158.7, 147.5 147.0, 136.0, 129.1, 124.9, 119.0, 67.0 (2), 57.3, 53.8 (2), 40.8, 30.0, 29.3, 25.3, 22.7, 22.5. Anal. calcd for C18H25N5O2: C, 63.0; H, 7.3; N, 20.4. Found: C, 62.8; H, 7.4; N, 20.3%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[CH3:11][O-:12].[Na+].Cl>CO>[Cl:1][C:2]1[CH:7]=[C:6]([O:12][CH3:11])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1
Reactant: CSc1nc(Cl)cc(Cl)n1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1cc(Cl)nc(SC)n1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
4,6-Dichloro-2-(methylthio)pyrimidine (40 g, 205 mmol) was dissolved in methanol (1025 mL) and cooled to 0° C. Sodium methoxide (55.4 g, 1025 mmol) was added slowly and the mixture was stirred at room temperature for 18 h. 300 mL of 3 M HCl was added and the methanol was evaporated. Additional water (500 mL) was added and the mixture was filtered, washed with water and dried to give the title compound as a white solid. 1H NMR (CDCl3) δ 6.41 (s, 1H), 3.97 (s, 3H), 2.55 (s, 3H); LCMS 2.40 min, 191 (M+H).
Reaction SMILES: C[Si](C)(C(C)(C)C)[O:3][C@@H:4]([CH2:16][NH2:17])[CH2:5][O:6][C:7]1[C:15]2[NH:14][CH:13]=[N:12][C:11]=2[CH:10]=[CH:9][CH:8]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:3][C@@H:4]([CH2:16][NH2:17])[CH2:5][O:6][C:7]1[C:15]2[NH:14][CH:13]=[N:12][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN)COc1cccc2nc[nH]c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: NC[C@H](O)COc1cccc2nc[nH]c12
Temperature: 0 °C
Reaction time: 4 h

Procedure:
(S)-4-[2-(Dimethyl tert-butylsilyl)oxy-3-aminopropoxy]benzimidazole (10 mg, 31 mmol) was dissolved in THF (1 mL) and the mixture cooled to 0° C. Tetrabutylammonium fluoride (1 mL, 1.0 M solution in THF) was added. The reaction stirred at this temperature for 4 hours. The reaction was quenched by addition of water. Evaporation of the aqueous layer provided the desired alcohol. NMR. MS.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][C:7]1[N+:8]([O-])=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[O:10][C:11]=1[CH3:12]>ClCCl>[Cl:3][CH2:6][C:7]1[N:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[O:10][C:11]=1[CH3:12]
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)[n+]([O-])c1C
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1CCl
Temperature: 25 °C
Yield: 11.2 %

Procedure:
Phosphorous oxychloride (0.72 mL, 7.8 mmol) was added dropwise to an oven-dried 100 mL pear-shaped flask charged with 18.1 (1.8 g, 7.00 mmol) and dichloromethane (20 mL). The reaction was refluxed under nitrogen atmosphere for 30 minutes and then cooled to room temperature. The reaction was washed with water (2×250 mL) and the combined aqueous layers were back extracted with DCM (2×25 mL). The combined organic layers were washed with brine and dried (Na2SO4). The solvent was removed under reduced pressure and the resulting residue was purified via radial chromatography (15% diethyl ether in hexanes) to yield 216 mg (15%) of 4-chloromethyl-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole as a white solid. LC/MSD m/e: 276.0 (M+H); 1H NMR (400 MHz) (CDCl3) δ 8.15 (2H, d, J=8.0 Hz), 7.73 (2H, d, J=8.0 Hz), 4.59 (2H, s), 2.48 (2H, s).
Reaction SMILES: [C:1]([NH:4][C:5]([C@@H:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)([CH2:13][CH2:14][CH:15]=[CH2:16])[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:3])[CH3:2].[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1.C(O)(=O)C.C(Cl)Cl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[C:1]([NH:4][C:5]([C@@H:17]1[CH2:21][CH2:20][N:19]([CH2:27][C:26]2[CH:29]=[CH:30][C:23]([F:22])=[CH:24][CH:25]=2)[CH2:18]1)([CH2:13][CH2:14][CH:15]=[CH2:16])[C:6]([NH:8][C:9]([CH3:11])([CH3:12])[CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: C=CCCC(NC(C)=O)(C(=O)NC(C)(C)C)[C@@H]1CCNC1
Reactant: O=Cc1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: C=CCCC(NC(C)=O)(C(=O)NC(C)(C)C)[C@@H]1CCN(Cc2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
A solution of 2-acetamido-N-tert-butyl-2-[(3R)-pyrrolidin-3-yl]hex-5-enamide (315 mg, 1.07 mmol), 4-fluorobenzaldehyde (140 uL, 1.3 mmol) and acetic acid (60 uL, 1 mmol) in methylene chloride (10 mL, 200 mmol) was stirred for 10 minutes prior to the addition of sodium triacetoxyborohydride (377 mg, 1.78 mmol) in a single portion. After stirring at room temperature overnight, the reaction was quenched with 1 N NaOH (10 mL). The organic layer thus obtained was separated and the aqueous layer further extracted with DCM (3×10 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated to give 2-acetamido-N-tert-butyl-2-((R)-1-(4-fluorobenzyl)pyrrolidin-3-yl)hex-5-enamide (0.387 g, 89.9%) as an oil. The oil was used in the next step without purification. ESI MS found for C23H34FN3O2 m/z 404.3 (M+H)+.
Reaction SMILES: [CH:1]1[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.C1C(=O)N([Br:24])C(=O)C1>C(Cl)(Cl)Cl>[Br:24][C:8]1[C:7]2[C:16]3=[C:15]4[C:4](=[CH:5][CH:6]=2)[CH:3]=[CH:2][CH:1]=[C:14]4[CH:13]=[CH:12][C:11]3=[CH:10][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1cc2ccc3cccc4ccc(c1)c2c34
Solvent: ClC(Cl)Cl
Product: Brc1ccc2ccc3cccc4ccc1c2c34
Temperature: 65 °C
Yield: 71.9 %

Procedure:
Pyrene (2 g, 9.9 mmol), NBS (1.78 g, 10 mmol) were dissolved in 20 mL of CHCl3 under dry nitrogen topped with a reflux condenser. The reaction was stirred at 65° C. and monitored by GC-MS until complete. After evaporation of the solvent the crude product was further purified by chromatography on silica gel using 20:1 petroleum ether 60-80: EtOAc as eluent to afford a yellow solid (2 gr, 72%). 1H-NMR (500 MHz, CD2Cl2): δ 8.02-8.11 (m, 4H), 8.17-8.24 (m, 4H), 8.41 (d, J=9.2 Hz, 1H). 13C-NMR (125 MHz, CD2Cl2): δ 120.2, 124.4, 125.4, 126.1, 126.2, 126.3, 127.1, 127.6, 128.2, 129.5, 130.0, 130.5, 131.1, 131.2, 131.4, 131.7. EI-MS: m/z M+ Calculated 280.0, found 280.0.