Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH2:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[C:18]#[N:19]>C(Cl)Cl.[N-]=C=O>[C:18]([C:17]1[CH:16]=[C:15]([NH:14][C:12](=[O:13])[NH:11][C:8]2[CH:7]=[CH:6][C:5]([S:2]([Cl:1])(=[O:4])=[O:3])=[CH:10][CH:9]=2)[CH:22]=[CH:21][CH:20]=1)#[N:19]
Reactant: O=C=Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#Cc1cccc(N)c1
Agent: [N-]=C=O
Solvent: ClCCl
Product: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)Cl)cc2)c1
Reaction time: 8 h
Yield: 94.8 %

Procedure:
A solution of 5.00 g (1 eq.) of 4-chlorosulfonylphenylisocyanate in anhydrous DCM (40 ml) was added to a solution of 3-aminobenzonitrile (2.71 g, 1 eq.) in anhydrous isocyanate (60 ml) at rt under inert atmosphere and the mixture was stirred overnight. The precipitate was filtered off to yield 7.3 g (95%) of 4-[3-(3-cyanophenyl)-ureido]-benzenesulfonyl chloride.
Reaction SMILES: [C:1]1(=[O:21])[N:5]([CH2:6][CH2:7][CH2:8][S:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[C:4](=[O:16])[C:3]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:2]12.[BH4-].[Na+]>C(O)C>[OH:21][CH:1]1[C:2]2[C:3](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:4](=[O:16])[N:5]1[CH2:6][CH2:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCSc1ccncc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=C1c2ccccc2C(O)N1CCCSc1ccncc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 54.4 %

Procedure:
To a solution of 5.97 g (20.0 mmol) of 4-(3-phthalimidopropylthio)pyridine in 300 ml of ethanol, 1.51 9 (40 mmol) of sodium borohydride was added, and the mixture was stirred at room temperature for 5 hours. The solvent was distilled off and saturated saline was added to the residue. The mixture was extracted with chloroform and the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by column chromatography (eluent: ethanol/ethyl acetate=1:10) to give 3.27 g of the desired compound (54.4% yield, colorless crystals), mp. 132°-134° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7])#[N:2].C1C=CC2N(O)N=[N:18]C=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH2:18])=[O:7])#[N:2]
Reactant: On1nnc2ccccc21
Reactant: N#Cc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1cccc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Cyano-benzoic acid (1.2 eq), the amine derivative (1 eq), HOBt (1.2 eq), DIEA (1.2 eq) and EDCI.HCl (1.2 eq) were dissolved in dry DMF (0.15 M), under argon. The mixture was stirred at room temperature overnight. DMF is evaporated and saturated NaHCO3 solution was added. Product was extracted with EtOAc, dried over Na2SO4, filtered and evaporated. The crude was purified on reverse phase (H2O 1% TFA/MeCN 1% TFA 100/0, 0/100). MeCN was evaporated. The product was suspended in H2O and basified with saturated NaHCO3 solution until pH=8-9. The aqueous layer was extracted three times with AcOEt. The organic layer was evaporated to give the final compound.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([OH:16])=O)=[CH:5][CH:4]=1.[CH2:19]([CH:21]1[CH2:26][NH:25][CH:24]([CH3:27])[CH2:23][CH2:22]1)[CH3:20]>>[CH2:19]([CH:21]1[CH2:26][N:25]([C:14]([C:10]2[CH:11]=[N:12][O:13][C:9]=2[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:18])[F:17])=[CH:8][CH:7]=2)=[O:16])[CH:24]([CH3:27])[CH2:23][CH2:22]1)[CH3:20]
Reactant: CCC1CCC(C)NC1
Reactant: O=C(O)c1cnoc1-c1ccc(C(F)(F)F)cc1
Product: CCC1CCC(C)N(C(=O)c2cnoc2-c2ccc(C(F)(F)F)cc2)C1

Procedure:
The title compound was prepared from 5-(4-trifluoromethylphenyl)isoxazole-4-carboxylic acid (12.9 mg, 0.050 mmol) and 5-ethyl-2-methylpiperidine (7.6 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (5.3 mg). Calcd for C19H21F3N2O2: 366.1555, found 366.1552.
Reaction SMILES: [C:1]([O:9]CC)(=O)[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[CH3:14][O:15][C:16]1[CH:34]=[CH:33][C:19]([CH2:20][N:21]2[C:26]3[N:27]=[CH:28][CH:29]=[CH:30][C:25]=3[C:24](=O)[O:23]C2=O)=[CH:18][CH:17]=1.Cl>CC(N(C)C)=O>[CH2:6]([O:5][C:3]([C:2]1[C:1](=[O:9])[N:21]([CH2:20][C:19]2[CH:18]=[CH:17][C:16]([O:15][CH3:14])=[CH:34][CH:33]=2)[C:26]2[C:25]([C:24]=1[OH:23])=[CH:30][CH:29]=[CH:28][N:27]=2)=[O:4])[CH3:7]
Reactant: COc1ccc(Cn2c(=O)oc(=O)c3cccnc32)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1c(O)c2cccnc2n(Cc2ccc(OC)cc2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.7 %

Procedure:
Diethyl malonate (2.37 mL, 15.61 mmol) was added slowly to a suspension of NaH (60% in mineral oil, 0.62 g, 15.61 mmol) in dimethylacetamide (40 mL) and stirred at room temperature for 0.5 h under inert atmosphere. 1-(4-Methoxy-benzyl)-1H-pyrido[2,3-d][1,3]oxazine-2,4-dione (12) (4.47 g, 15.61 mmol) was added to the solution and heated at 110° C. for 3 h (TLC control). The solution was cooled and poured into ice water. The pH of the solution was adjusted to 3 by cold 10% HCl. The solids formed were filtered, washed by excess water, and dried in a vacuum oven. The crude product was recrystallized by ethylacetate to yield 1.2 g (21%) of 4-hydroxy-1-(4-methoxy-benzyl)-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (13) as white solids. MP: 153° C.; 1H-NMR (DMSO-d6): δ 1.31 (t, J=7.0 Hz, 3H), 3.68 (s, 3H), 4.32 (q, J=7.0 Hz, 2H), 5.47 (s, 2H), 6.81 (d, J=7.7 Hz, 2H), 7.21 (d, J=7.6 Hz, 2H), 7.36 (d, J=7.6 Hz, 1H), 8.42 (dd, J=1.5, 7.5 Hz, 1H), 8.73 (dd, J=1.5, 7.5 Hz, 1H), 13.00 (S, 1H); EIMS: 355 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[C:24](O)(=[O:34])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][C:24](=[O:34])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: CCCCCCCCCC(=O)O
Product: CCCCCCCCCC(=O)O[C@@]1(C#Cc2cccc(C)c2)CCC[C@@H]2[C@H]1CCN2C(=O)OC

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and decanoic acid to yield (3aR,4S,7aR)-4-decanoyloxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. MS [M+H] 296 (ester elimination ion); RT1.70 min; UPLC Method I
Reaction SMILES: [O:1]=[C:2]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:24]3[NH:28][N:27]=[N:26][N:25]=3)[CH:22]=2)[O:17][C:4]2([CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]2)[CH2:3]1>Cl.O1CCOCC1>[NH:28]1[C:24]([C:21]2[CH:22]=[C:23]3[C:18](=[CH:19][CH:20]=2)[O:17][C:4]2([CH2:9][CH2:8][NH:7][CH2:6][CH2:5]2)[CH2:3][C:2]3=[O:1])=[N:25][N:26]=[N:27]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(-c3nnn[nH]3)ccc1O2
Agent: Cl
Solvent: C1COCCO1
Product: O=C1CC2(CCNCC2)Oc2ccc(-c3nnn[nH]3)cc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4 N HCl-1,4-dioxane (200 mL) was added to 40.6 g tert-butyl 4-oxo-6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidine]-1′-carboxylate produced in Reference Example 6, and stirred at room temperature for 5 hours. The reaction mixture was concentrated, and the residue was triturated with methanol. The insoluble solid was collected through filtration, and dried under reduced pressure to obtain 6-(1H-tetrazol-5-yl)-spiro[chroman-2,4′-piperidine]-4-one as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C@:8]2([CH3:20])[CH2:13][O:12][C@@:11]([CH3:18])([C:14]([F:17])([F:16])[F:15])[C:10]([NH2:19])=[N:9]2)[C:5]([F:21])=[CH:4][CH:3]=1.[C:22](Cl)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:31]1[CH:38]=[CH:37][C:34]([O:35][CH3:36])=[CH:33][CH:32]=1)[C:23]1[CH:30]=[CH:29][C:26]([O:27][CH3:28])=[CH:25][CH:24]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:36][O:35][C:34]1[CH:33]=[CH:32][C:31]([C:22]([NH:19][C:10]2[C@:11]([CH3:18])([C:14]([F:15])([F:17])[F:16])[O:12][CH2:13][C@:8]([C:6]3[C:5]([F:21])=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=3)([CH3:20])[N:9]=2)([C:23]2[CH:24]=[CH:25][C:26]([O:27][CH3:28])=[CH:29][CH:30]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:38][CH:37]=1
Reactant: C[C@@]1(c2nc(Br)ccc2F)CO[C@@](C)(C(F)(F)F)C(N)=N1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(NC2=N[C@](C)(c3nc(Br)ccc3F)CO[C@@]2(C)C(F)(F)F)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (2R,5R)-5-(6-bromo-3-fluoro-pyridin-2-yl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine (500 mg, 1.35 mmol, CAS registry 1387561-18-3, WO 2012/095469) in DCM (13.5 ml) was added DMTr-Cl (0.481 g, 1.418 mmol) and triethylamine (0.374 ml, 2.70 mmol), the reaction mixture was stirred under argon at rt for 18 h. The reaction mixture was washed with NaHCO3 saturated aqueous solution and brine. The organic layers were backextracted with DCM. The combined organic layer were dried with Na2SO4. The residue was purified by chromatography (eluent: CyHex/EtOAc gradient) to afford the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:4]=1.[C-:20]#[N:21].[K+].O>CS(C)=O>[C:8]1([N:7]2[C:3]([CH2:2][C:20]#[N:21])=[N:4][C:5]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:6]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: [C-]#N
Reactant: BrCc1nc(-c2ccccc2)nn1-c1ccccc1
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCc1nc(-c2ccccc2)nn1-c1ccccc1
Temperature: 60 °C
Yield: 114.4 %

Procedure:
A mixture of 5-(bromomethyl)-1,3-diphenyl-1H-1,2,4-triazole (265 mg, 843 μmol) and potassium cyanide (62.3 mg, 928 μmol) in DMSO (5 mL) was heated at 60° C. for 1.5 h. The reaction mixture was cooled to RT, poured into water (25 mL) and extracted with ethyl acetate (2×50 mL). The organic phases were washed with water (2×25 mL) and brine (1×25 mL), and the combined organic layer was dried over MgSO4 and concentrated in vacuo to give 251 mg of crude product. The product was obtained after purification by flash chromatography (using silica gel and an ethyl acetate/heptane gradient) as light yellow waxy solid (120 mg, 461 μmol, 54.7%).
Reaction SMILES: C(OC([N:6]1[CH:10]=[C:9]([C:11]2[N:16]=[N:15][C:14]([NH2:17])=[N:13][CH:12]=2)[CH:8]=[N:7]1)C)C.Cl[CH:19]([CH2:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[CH:28][CH:27]=[CH:26]2)[CH:20]=O.Cl>C(O)(C)C>[NH:7]1[CH:8]=[C:9]([C:11]2[CH:12]=[N:13][C:14]3[N:15]([C:19]([CH2:22][C:23]4[CH:24]=[C:25]5[C:30](=[CH:31][CH:32]=4)[N:29]=[CH:28][CH:27]=[CH:26]5)=[CH:20][N:17]=3)[N:16]=2)[CH:10]=[N:6]1
Reactant: O=CC(Cl)Cc1ccc2ncccc2c1
Reactant: CCOC(C)n1cc(-c2cnc(N)nn2)cn1
Agent: Cl
Solvent: CC(C)O
Product: c1cnc2ccc(Cc3cnc4ncc(-c5cn[nH]c5)nn34)cc2c1
Temperature: 110 °C
Yield: 64.2 %

Procedure:
A mixture of 6-[1-(1-ethoxyethyl)-1H-pyrazol-4-yl]-1,2,4-triazin-3-amine (390.0 mg, 1.665 mmol) and 2-chloro-3-quinolin-6-ylpropanal (480 mg, 2.2 mmol) in isopropyl alcohol (20 mL) was heated at 110° C. for 2 days. After cooling to RT, 0.2 mL of concentrated HCl was added and stirred until completely deprotected. The solid formed was collected by filtration to give the desired product (0.35 g, 64%). LCMS: (M+H)=328.3.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:5]=3[C:4]=2[CH:3]=1.[H-].[Na+].[CH2:18](I)[CH3:19]>CN(C=O)C>[CH2:18]([N:7]1[C:8]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][C:4]=2[C:5]2[C:14](=[O:15])[NH:13][CH2:12][CH2:11][C:6]1=2)[CH3:19]
Reactant: CCI
Reactant: O=C1NCCc2[nH]c3ccc(F)cc3c21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c2c(c3cc(F)ccc31)C(=O)NCC2
Yield: 21.2 %

Procedure:
8-Fluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one (I-59f: 500 mg, 2.44 mmol) in DMF (200 mL) was reacted with 60% NaH (196 mg, 8.16 mmol) and ethyl iodide (456 mg, 2.92 mmol) to afford the crude product. The reaction mass was quenched with chilled water and extracted with ethyl acetate. The organic layer was washed with water, brine solution, dried over Na2SO4 and concentrated to afford the crude product. Purification by column chromatography on silica gel (1% methanol in DCM) afforded 120 mg of the product (21.2% yield).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17]Cl)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[CH2:19]([NH:22][CH2:23][CH2:24][CH3:25])[CH2:20][CH3:21]>>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:22]([CH2:23][CH2:24][CH3:25])[CH2:19][CH2:20][CH3:21])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CCCNCCC
Reactant: CC(=O)O[C@H]1CC[C@H](c2ccc(CCl)cc2)CC1
Product: CCCN(CCC)Cc1ccc([C@H]2CC[C@H](OC(C)=O)CC2)cc1

Procedure:
from trans-O-acetyl-4-(4-chloromethylphenyl)-cyclohexanol and dipropylamine. Colourless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.Cl.[C:13](Cl)(Cl)=[O:14]>ClC1C=CC=CC=1>[CH3:11][O:10][C:4]1[CH:3]=[C:2]([N:1]=[C:13]=[O:14])[CH:7]=[CH:6][C:5]=1[O:8][CH3:9]
Reactant: O=C(Cl)Cl
Reactant: COc1ccc(N)cc1OC
Agent: Cl
Solvent: Clc1ccccc1
Product: COc1ccc(N=C=O)cc1OC

Procedure:
A solution of 0.163 m of 4-aminoveratrole in 250 ml of chlorobenzene was treated with excess HCl gas resulting in a heavy precipitate. The mixture was refluxed and treated with a stream of phosgene for 1/2 hr (50 g, 0.49 m). After refluxing an additional 1/2 hr chlorobenzene was evaporated in vacuo. Distillation of the residue afforded 23 g (79%) b.p. 145°-150° C, 17-18 mm.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.[H-].[Na+].C1(C)C=CC(S(O[CH:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)(=O)=O)=CC=1.O>C1COCC1>[F:12][C:2]([F:1])([F:11])[O:3][C:4]1[CH:5]=[CH:6][C:7]([S:10][CH:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)=[CH:8][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: FC(F)(F)Oc1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Sc2ccc(OC(F)(F)F)cc2)CC1
Reaction time: 0.5 h
Yield: 80.3 %

Procedure:
4-(Trifluoromethoxy)thiophenol (2.0 g, 10.3 mmol) was dissolved in THF (30 ml), and this solution was cooled in an ice-bath. To which sodium hydride (453 mg, 11.3 mmol) was added, and the mixture was stirred for 30 minutes. To which tert-butyl 4-(toluene-4-sulfonyloxy)piperidine-1-carboxylate (3.66 g, 10.3 mmol) prepared in Reference Example 137 was added, and the resulting mixture was stirred at room temperature for 30 minutes, and then heated under reflux for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride. The extract was dried over magnesium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl chloride=20/1) to afford tert-butyl 4-(4-trifluoromethoxyphenylsulfanyl)piperidine-1-carboxylate (3.12 g, yield 80%) as a colorless oil.
Reaction SMILES: [N:1]([O-:3])=[O:2].[Na+].Br[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].O>CN(C)C=O>[N+:1]([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH3:6])([O-:3])=[O:2]
Reactant: CCCCCCCCCCCCCBr
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCC[N+](=O)[O-]
Reaction time: 6 h

Procedure:
To a stirred, room temperature suspension of sodium nitrite (227 g, 3.29 mol) in dimethylformamide (3.8 L) was added 1-bromotridecane (514.51 g, 1.95435 mol), and the mixture was stirred for 6 hours. The mixture was poured into cold water (8 L) and extracted with petroleum ether (2×2 L). The organic layer was washed with water (2 n), saturated sodium chloride, dried (MgSO4), and rotoevaporated to a yellow oil. The oil was distilled in vacuo to give another oil; yield 171.9 g, bp 101°-120° C. (0.2 mm Hg). The oil was chromatographed on silica gel (3.0 kg, 230-400 mesh) using ether/ethyl acetate (100:1, 4×2 L; 80:1, 4×2 L; 50:1, 7×2 L) to give a clear colorless oil; yield 109.8 g (24.5%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=[O:12].C(Cl)CCl.O[N:19]1[C:23](=[O:24])[CH2:22][CH2:21][C:20]1=[O:25].C([O-])(O)=O.[Na+]>CN(C=O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([O:13][N:19]1[C:23](=[O:24])[CH2:22][CH2:21][C:20]1=[O:25])=[O:12]
Reactant: O=C(O)c1ccc2ccccc2n1
Reactant: O=C1CCC(=O)N1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(ON1C(=O)CCC1=O)c1ccc2ccccc2n1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of 2-quinoline carboxylic acid (1.2 eq.) in DMF at 0° C. was treated with EDC (1.4 eq.). The mixture was stirred at 0° C. for 1 to 2 h and then N-hydroxysuccinimide (1.0 eq.) was added. After stirring at RT for more than 3 h, the reaction mixture was poured into 60% sat. NaHCO3 and the product filtered: 1H NMR (CDCl3, 300 MHz, ppm) 8.35 (d, 1H), 8.27 (d, 1H), 8.19 (d, 1H), 7.87 (d, 1H), 7.80 (m, 1H), 7.68 (m, 1H), 2.91 (s, 4H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[O:7][CH2:8][C:9]1[N:10]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:12][CH:13]=1)([O-])=O.O.C(=O)(O)[O-].[Na+]>C(O)C>[C:14]1([C:11]2[S:12][CH:13]=[C:9]([CH2:8][O:7][C:6]3[CH:5]=[C:4]([NH2:1])[CH:22]=[CH:21][CH:20]=3)[N:10]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=[N+]([O-])c1cccc(OCc2csc(-c3ccccc3)n2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1cccc(OCc2csc(-c3ccccc3)n2)c1
Yield: 85 %

Procedure:
A solution of 16.0 g (0.05 mol) of 4-[(3-nitrophenoxy)methyl-2-phenylthiazole and 56.5 g (0.25 mol) of stannous chloride dihydrate in 300 ml of absolute ethanol is heated to reflux for 20 hours. The mixture is poured into 2 L of water and made alkaline by the addition of solid sodium bicarbonate. The mixture is extracted twice with 1 L of ethyl acetate. The combined ethyl acetate layers are washed twice with dilute aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain 12.0 g (85%) of an oil, which solidifies. The crystals, m.p. 75°-80° C., MS (CI) 283 (M+H), are used without further purification in subsequent reactions.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH2:15])[N:12]=2)=[CH:4][CH:3]=1.[F:18][C:19]([F:35])([F:34])[C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:26]=[N:27][CH:28]=[C:29]([CH:33]=2)[C:30](O)=[O:31])[N:21]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH:15][C:30](=[O:31])[C:29]3[CH:33]=[C:25]([C:22]4[N:21]=[C:20]([C:19]([F:35])([F:34])[F:18])[O:24][N:23]=4)[CH:26]=[N:27][CH:28]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cncc(-c2noc(C(F)(F)F)n2)c1
Reactant: CC(C)(CN)c1coc(-c2ccc(F)cc2)n1
Product: CC(C)(CNC(=O)c1cncc(-c2noc(C(F)(F)F)n2)c1)c1coc(-c2ccc(F)cc2)n1
Yield: 13 %

Procedure:
This compound was synthesized from 2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropan-1-amine and 5-(5-trifluoromethyl-[1,2,4]oxadiazol-3-yl)-nicotinic acid as described in example 8 step 6 (19 mg, yield 13%). 1H NMR (400 MHz, MeOD) δ 9.38 (d, J=1.5 Hz, 1H), 9.17 (d, J=1.8 Hz, 1H), 8.84 (d, J=1.8 Hz, 1H), 8.09-8.05 (m, 2H), 7.78 (s, 1H), 7.25-7.20 (m, 2H), 3.68 (s, 2H), 1.42 (s, 6H). MS (ESI) m/z: Calculated for C22H17F4N5O3: 475.13. found: 476.2 (M+H)+.
Reaction SMILES: [CH:1]([CH:4]1[C:8]2[C:9]([NH2:13])=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([CH3:15])([CH3:14])[O:5]1)([CH3:3])[CH3:2].C(N(CC)CC)C.[F:23][C:24]1[N:28]([CH3:29])[N:27]=[C:26]([CH:30]([F:32])[F:31])[C:25]=1[C:33](Cl)=[O:34]>C(Cl)Cl>[F:32][CH:30]([F:31])[C:26]1[C:25]([C:33]([NH:13][C:9]2[C:8]3[CH:4]([CH:1]([CH3:3])[CH3:2])[O:5][C:6]([CH3:15])([CH3:14])[C:7]=3[CH:12]=[CH:11][CH:10]=2)=[O:34])=[C:24]([F:23])[N:28]([CH3:29])[N:27]=1
Reactant: Cn1nc(C(F)F)c(C(=O)Cl)c1F
Reactant: CC(C)C1OC(C)(C)c2cccc(N)c21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C1OC(C)(C)c2cccc(NC(=O)c3c(C(F)F)nn(C)c3F)c21
Reaction time: 4 h
Yield: 78 %

Procedure:
In a 25 ml round bottom flask, a solution of 3-isopropyl-1,1-dimethyl-1,3-dihydro-2-benzofuran-4-amine (62 mg, 0.301 mmol, 1 eq) in 5 ml of DCM is cooled to 0° C. and triethylamine (0.05 ml, 0.361 mmol, 1.2 eq) is added. A solution of 5-fluoro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride (70 mg, 0.331 mmol, 1.1 eq) in 1 ml of DCM is added dropwise. Stirring is allowed for 4 h at r.t. The reaction is quenched with 1N aq. HCl, and diluted with EtOAc. The aqueous layer was separated and extracted with EtOAc. The organics were combined, washed with NaOH 1N, dried over MgSO4 and concentrated. The crude material was purified by chromatography on silica gel to give pure material (78%)
Reaction SMILES: [C:1]([C:9]1[N:10]=[C:11]([CH2:16][CH2:17][CH2:18][CH3:19])[NH:12][C:13]=1[C:14]#[N:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[C:29]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[C:1]([C:9]1[N:10]=[C:11]([CH2:16][CH2:17][CH2:18][CH3:19])[N:12]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:24][CH:23]=2)[C:13]=1[C:14]#[N:15])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCc1nc(C(=O)c2ccccc2)c(C#N)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCCCc1nc(C(=O)c2ccccc2)c(C#N)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Yield: 80.7 %

Procedure:
Following a procedure similar to that described in Example 11(a), but using 1.27 g of 4-benzoyl-2-butyl-5-cyanoimidazole (prepared as described in Preparation 6), 1.74 g of t-butyl 4'-bromomethylbiphenyl-2-carboxylate, 0.69 of potassium carbonate and 20 ml of N,N-dimethylacetamide, and then purifying the product by column chromatography through silica gel, using a 2:1 by volume mixture of hexane and ethyl acetate as the eluent, 2.1 g of the title compound were obtained.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[C:3]1[CH:17]=CC1C=CC=CC=1.I([O-])(=O)(=O)=[O:26].[Na+].O>O1CCOCC1.[Os](=O)(=O)(=O)=O>[CH:17]([C:3]1[CH:2]([OH:1])[CH2:6][C:5](=[O:7])[C:4]=1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:26]
Reactant: O=C(O)CCCCCCC1=C(C=Cc2ccccc2)C(O)CC1=O
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=CC1=C(CCCCCCC(=O)O)C(=O)CC1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture consisting of 13 parts of dl- 3-hydroxy-5-oxo-2-styrylcyclopent-1-eneheptanoic acid, 17.8 parts of sodium periodate, 55 parts of water, 160 parts of dioxane and 2 parts of a 2% osmium tetroxide in dioxane solution is stirred under nitrogen at room temperature for about 4 hours. That reaction mixture is then extracted with ether and the ether layer is separated and extracted several times with 0.5% aqueous sodium chloride. The salt extracts are saturated with sodium chloride, then extracted with ether. The ether layer is separated, dried over anhydrous sodium sulfate, concentrated and dried under reduced pressure to afford dl- 2-formyl-3-hydroxy-5-oxocyclopent-1-eneheptanoic acid, characterized by an ultraviolet absorption maximum at about 228 millimicrons with a molecular extinction coefficient of about 10,100.