Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([F:32])=[C:9]2[C:13]=1[NH:12][CH:11]=[C:10]2[C:14](=[O:31])[C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][CH2:18]1)=[O:16])=[O:4].[BH4-].[Na+]>C(O)C>[CH3:1][NH:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([F:32])=[C:9]2[C:13]=1[NH:12][CH:11]=[C:10]2[CH:14]([OH:31])[C:15]([N:17]1[CH2:18][CH2:19][N:20]([C:23](=[O:30])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:21][CH2:22]1)=[O:16])=[O:4]
Reactant: CNC(=O)c1ccc(F)c2c(C(=O)C(=O)N3CCN(C(=O)c4ccccc4)CC3)c[nH]c12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CNC(=O)c1ccc(F)c2c(C(O)C(=O)N3CCN(C(=O)c4ccccc4)CC3)c[nH]c12
Reaction time: 8 h
Yield: 40 %

Procedure:
A suspension of 3-[2-(4-Benzoyl-piperazin-1-yl)-2-oxo-acetyl]-4-fluoro-1H-indole-7-carboxylic acid methylamide (A″′, 0.260 g., 0.60 mmol) in absolute ethanol (5 mL) under nitrogen atmosphere was treated with sodium borohydride (0.031 g, 0.8 mmol). The suspension became a solution within several minutes. The reaction was stirred overnight. Solvent was removed in-vaccuo and the residue was purified by silica gel column chromatography, eluting with ethyl acetate:methanol (100:0 changing to 90:10). Product fractions were pooled and dried in-vaccuo to give the title compound (Example 32, 0.106 g, 0.24 mmol, Y 40%). 1H—NMR (300 MHz, d-6 DMSO): 11.33 (s, 1H indole NH); 8.51 (d, 1H, CONH); 7.7-7.1 (m, 7H, aromatic); 6.85 (m, 1H, C5-H); 5.70 (b, 1H, OH); 5.27 (d, 1H, CHCO); 3.8-3.3 (2×br, 8H, piperazine)2.83 (d, 3H, CH3). LRMS (ES+) m/z [M+Na]+=460.9, (ES−) [M−H]−=437.0.
Reaction SMILES: [CH2:1]([N:3]([CH2:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:19][CH2:18]1)[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[CH2:14]O)[CH3:2].S(Cl)(Cl)=O.[F:33][C:34]([F:53])([F:52])[C:35]1[CH:36]=[C:37]([C@H:45]2[O:49][C:48](=[O:50])[NH:47][C@H:46]2[CH3:51])[CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1.N1C=CC=CC=1>[F:53][C:34]([F:33])([F:52])[C:35]1[CH:36]=[C:37]([C@H:45]2[O:49][C:48](=[O:50])[N:47]([CH2:14][C:5]3[CH:6]=[C:7]([C:10]([F:13])([F:12])[F:11])[CH:8]=[CH:9][C:4]=3[N:3]([CH2:16][C@H:17]3[CH2:18][CH2:19][C@H:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:21][CH2:22]3)[CH2:1][CH3:2])[C@H:46]2[CH3:51])[CH:38]=[C:39]([C:41]([F:42])([F:43])[F:44])[CH:40]=1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCOC(=O)C[C@H]1CC[C@H](CN(CC)c2ccc(C(F)(F)F)cc2CO)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)C[C@H]1CC[C@H](CN(CC)c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of ethyl [trans-4-({ethyl[2-(hydroxymethyl)-4-(trifluoromethyl)phenyl]amino}methyl)cyclohexyl]acetate (Step B; 60 mg; 0.149 mmol) in toluene (1 mL) was added dropwise to a stirred solution of thionyl chloride (12.3 μL; 0.169 mmol) in toluene (300 μL) at 0° C. The reaction stirred at room temperature for 1.5 h. Pyridine (27 mL) was added and the reaction was partitioned between toluene (10 mL) and H2O (10 mL). The aqueous layer was re-extracted with toluene (10 mL) and the combined organic layers were washed with brine (10 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was dissolved in DMF (1 mL) and (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (intermediate 17; 56 mg; 0.179 mmol) and potassium tert-butoxide (23.5 mg; 0.209 mmol) were added successively. The reaction stirred for 72 h and was quenched with sat. NH4Cl. The reaction was partitioned between sat. NH4Cl (10 mL) and EtOAc (10 mL). The aqueous layer was re-extracted with EtOAc (3×10 mL) and the combined organic layers were washed with brine (10 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-20% EtOAc/hexanes gradient) and chiral HPLC (1.5% IPA/heptane; ChiralPak IA column) to afford ethyl (trans-4-{[[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethyl)phenyl](ethyl)amino]methyl}cyclohexyl)acetate as a clear glass. LCMS=697.3 (M+1)+. 1H NMR (CDCl3, 500 MHz): δ 7.92 (s, 1 H), 7.81 (s, 2 H), 7.65 (s, 1 H), 7.58 (d, J=8.4 Hz, 1H), 7.30-7.27 (m, 1 H), 5.78 (d, J=8.1 Hz, 1 H), 4.88 (d, J=16.5 Hz, 1 H), 4.74-4.69 (m, 1 H), 4.11 (q, J=7.1 Hz, 2 H), 3.17-3.10 (m, 2 H), 3.05-2.97 (m, 2 H), 2.15 (d, J=6.8 Hz, 2 H), 1.80-1.68 (m, 4 H), 1.66-1.50 (m, 1 H), 1.46-1.39 (m, 1 H), 1.25 (t, J=7.1 Hz, 3 H), 1.07 (t, J=7.0 Hz, 3 H), 1.03-0.85 (m, 4H), 0.71 (d, J=6.6 Hz, 3 H).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:25])[C:13]([CH:23]=O)=[CH:14][N:15]3[CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:10][C:9]=2[F:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:33]([O:35][C:36](=[O:46])[CH2:37]P(OCC)(OCC)=O)[CH3:34].O>CN(C=O)C>[CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:25])[C:13](/[CH:23]=[CH:37]/[C:36]([O:35][CH2:33][CH3:34])=[O:46])=[CH:14][N:15]3[CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)=[CH:10][C:9]=2[F:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C/c1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
1.0 g of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbaldehyde was dissolved in 20 ml of DMF, and 2.0 g of potassium carbonate and 2.8 ml of ethyl(diethoxyphosphoryl)acetate were added, followed by overnight stirring at 60° C. The resulting reaction mixture was cooled to room temperature, water was added, and then the insoluble materials were collected by filtration to obtain 1.2 g of ethyl (2E)-3-[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]acrylate.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)=[C:2]=[S:3].[NH2:14][CH:15]([C:19]#[N:20])[C:16]([NH2:18])=[O:17]>CCOC(C)=O>[NH2:20][C:19]1[S:3][C:2]([NH:1][C:4]2[CH:5]=[C:6]3[C:11](=[CH:12][CH:13]=2)[N:10]=[CH:9][CH:8]=[CH:7]3)=[N:14][C:15]=1[C:16]([NH2:18])=[O:17]
Reactant: N#CC(N)C(N)=O
Reactant: S=C=Nc1ccc2ncccc2c1
Solvent: CCOC(C)=O
Product: NC(=O)c1nc(Nc2ccc3ncccc3c2)sc1N
Yield: 65.4 %

Procedure:
A mixture of 6-isothiocyanatoquinoline (0.50 g, 2.7 mmol) and 2-amino-cyanoacetamide (0.26g, 2.68 mmol) in EtOAc (20 mL) was refluxed for 90 min. The reaction mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography eluted with 2% MeOH in DCM to give 0.50 g (65% yield) of the titled compound.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[N:9]1([C:14]([CH2:16][N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1>O1CCOCC1>[O:6]=[C:5]([N:20]1[CH2:19][CH2:18][N:17]([CH2:16][C:14](=[O:15])[N:9]2[CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:22][CH2:21]1)[CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8]
Reactant: O=C(CN1CCNCC1)N1CCCC1
Reactant: O=C1CCCC(=O)O1
Solvent: C1COCCO1
Product: O=C(O)CCCC(=O)N1CCN(CC(=O)N2CCCC2)CC1
Reaction time: 4 h
Yield: 81.3 %

Procedure:
1.52 g of glutaric anhydride and then 2.62 g of pyrrolidinocarbonylmethylpiperazine are added to 10 cm3 of dry didoxane. After stirring for 4 hours, the precipitate formed is diluted with 10 cm3 of dioxane and then stirred for 1 hour. The insoluble matter is filtered on No. 4 sintered glass, rinsed several times with diethyl ether and then dried (90 Pa) at 20° C. to give 3.36 g of 5-oxo-5-[4-(2-oxo-2-pyrrolidin-1-yl ethyl)piperazin-1-yl]pentanoic acid in the form of a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:27]3[CH2:31]CC[CH2:28]3)[N:9]=[C:10]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[N:16](C(OC(C)(C)C)=O)[CH:15]=[CH:14]4)[C:3]=12.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:16]1[C:17]2[C:13](=[CH:12][C:11]([C:10]3[C:3]4[C:4](=[N:5][CH:6]=[N:7][C:2]=4[NH2:1])[N:8]([CH:27]([CH3:31])[CH3:28])[N:9]=3)=[CH:19][CH:18]=2)[CH:14]=[CH:15]1
Reactant: CC(C)(C)OC(=O)n1ccc2cc(-c3nn(C4CCCC4)c4ncnc(N)c34)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1nc(-c2ccc3[nH]ccc3c2)c2c(N)ncnc21

Procedure:
Tert-butyl 5-(4-amino-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1H-indole-1-carboxylate (BA88) was dissolved in 50:50 CH2Cl2:TFA and stirred for one hour at room temperature. The reaction mixture was concentrated in vacuo and purified using by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA89 (6.3 mg). ESI-MS (M+H)+ m/z calcd 319.1, found 319.2.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][C:9](/[CH:11]=[CH:12]/[CH:13]=[O:14])=[CH:10][C:5]=2[CH2:4][O:3]1.[BH4-].[Na+]>C1COCC1.CO.Cl>[OH:14][CH2:13]/[CH:12]=[CH:11]/[C:9]1[CH:8]=[CH:7][C:6]2[C:2](=[O:1])[O:3][CH2:4][C:5]=2[CH:10]=1
Reactant: O=C/C=C/c1ccc2c(c1)COC2=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C1OCc2cc(/C=C/CO)ccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-bath cooled flask containing a solution of (2E)-3-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)prop-2-enal (5 g, 26.6 mmol) in THF (20 mL) and methanol (20 mL) was added NaBH4 (1 g, 26.3 mmol), and the mixture was stirred for 1 hour at 0° C. The reaction mixture was then diluted with HCl (2 N, 20 mL) and extracted with EtOAc (300 mL). The organic layer was washed with water (30 mL) and brine (30 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified with silica gel chromatography (pet ether/EtOAc=2:1) to give the title product.
Reaction SMILES: [Cl:1][C:2]1[C:23]2[O:22][C:9]3[C:10](=[O:21])[N:11]([C@@H:13]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:14]([OH:16])=O)[CH2:12][C:8]=3[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.O>[N:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[NH:24][C:14](=[O:16])[C@@H:13]([N:11]1[CH2:12][C:8]2[CH2:7][C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:23]=3[O:22][C:9]=2[C:10]1=[O:21])[CH2:17][CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)C[C@@H](C(=O)O)N1CC2=C(Oc3c(Cl)cccc3C2)C1=O
Reactant: Nc1ccccn1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CC(C)C[C@@H](C(=O)Nc1ccccn1)N1CC2=C(Oc3c(Cl)cccc3C2)C1=O
Yield: 49.5 %

Procedure:
A solution of (S)-2-(5-chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-4-methyl-pentanoic acid (100 mg, 0.27 mmol) (Example 22, Step 1c), commercially available 2-aminopyridine (33 mg, 0.36 mmol), N-ethyl-N-dimethyaminopropyl carbodiimide hydrochloride (EDCI. HCl) (63 mg, 0.32 mmol), and N-hydroxybenzotriazole (HOBt) (44 mg, 0.32 mmol) in methylene chloride (1 mL) was stirred for 16 hours at 25° C. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue, upon silica gel flash chromatography using hexane-ethyl acetate gradient elution, afforded (S)-2-(5-chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-4-methyl-pentanoic acid pyridin-2-ylamide (55 mg, 45%), as a white solid. 1H NMR (DMSO-d6) δ: 10.88 (s, 1H), 8.34 (d, J=3.4 Hz, 1H), 8.01 (d, J=7.8 Hz, 1H), 7.77 (t, J=7.8 Hz, 1H), 7.40 (d, J=7.8 Hz, 1H), 7.23 (d, J=7.8 Hz, 1H), 7.13 (d, J=7.8 Hz, 2H), 5.08 (d, J=6.8 Hz, 1H), 4.43 (d, J=18.6 Hz, 1H), 4.06 (d, J=19.1 Hz, 1H), 3.82 (br. s., 2H), 1.78-1.94 (m, 1H), 1.61-1.74 (m, 1H), 1.47 (br. s., 1H), 0.94 (t, J=4.9 Hz, 6H).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25]([NH:28][CH3:29])[N:26]=[CH:27][C:22]=4[CH:21]=3)[CH:17]=[CH:16][C:15]=2[F:34])=[O:12])[N:7]([CH3:35])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][N:37]([CH3:41])[CH2:38]CN>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25]([NH:28][CH2:29][CH2:36][N:37]([CH3:41])[CH3:38])[N:26]=[CH:27][C:22]=4[CH:21]=3)[CH:17]=[CH:16][C:15]=2[F:34])=[O:12])[N:7]([CH3:35])[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)CCN
Reactant: CNc1ncc2cc(-c3ccc(F)c(NC(=O)Nc4cc(C(C)(C)C)nn4C)c3)c(=O)n(C)c2n1
Product: CN(C)CCNc1ncc2cc(-c3ccc(F)c(NC(=O)Nc4cc(C(C)(C)C)nn4C)c3)c(=O)n(C)c2n1

Procedure:
Using general method E, 1-(3-t-butyl-1-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-(8-methyl-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea from Example 12 (0.199 g, 0.389 mmol) and N1,N1-dimethylethane-1,2-diamine (0.214 ml, 1.94 mmol, 5.00 eq) were combined to afford 1-(3-t-butyl-1-methyl-1H-pyrazol-5-yl)-3-(5-(2-(2-(dimethylamino)ethylamino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluorophenyl)urea which was subsequently treated with HCl to afford hydrochloride salt (20.8 mg, 10% yield) as a white solid. 1H NMR (400 MHz, DMSO-d4): δ 9.07 (s, 1H), 8.91 (brs, 1H), 8.80-8.75 (brs, 1H), 8.47-8.44 (m, 1H), 8.01 (brs, 1H), 7.97 (s, 1H), 7.33-7.27 (m, 2H), 6.10 (s, 1H), 3.77-3.72 (m, 2H), 3.63 (s, 3H), 3.51 (brs, 3H), 3.37-3.33 (brm, 2H), 2.86 (m, 6H), 1.21 (s, 9H); MS (ESI) m/z: 536.2 (M+H+).
Reaction SMILES: [OH-].[Na+].O.C(=O)([O-])O.[Na+].Br[CH2:10][CH2:11]Br.[OH:13][C:14]1[C:19]([CH2:20][CH2:21][OH:22])=[C:18]([CH3:23])[N:17]=[C:16]([SH:24])[N:15]=1>CC(O)C>[OH:22][CH2:21][CH2:20][C:19]1[C:14](=[O:13])[N:15]2[CH2:10][CH2:11][S:24][C:16]2=[N:17][C:18]=1[CH3:23]
Reactant: Cc1nc(S)nc(O)c1CCO
Reactant: BrCCBr
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: Cc1nc2n(c(=O)c1CCO)CCS2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 40 parts of sodium hydroxide in 500 parts of water were added 400 parts of 2-propanol. In this mixture were dissolved 186.23 parts of 4-hydroxy-2-mercapto-6-methyl-5-pyrimidineethanol. The resulting solution was added dropwise, during a 2.66 hours period, to a stirred and refluxing mixture of 210 parts of sodium hydrogen carbonate, 1635 parts of 1,2-dibromoethane and 1600 parts of 2-propanol. Upon completion, stirring was continued for 2 hours at reflux temperature. The reaction mixture was cooled to room temperature and the solvent was evaporated. The residue was stirred three times in 750 parts of trichloromethane at room temperature. The trichloromethanephases were evaporated and the residue was crystallized from 300 parts of a mixture of trichloromethane and methanol (85:15 by volume) and 100 parts of hexane. The product was filtered off, washed with 2,2'-oxybispropane and dried in vacuo for 3 hours at 60° C., yielding 51 parts of 2,3-dihydro-6-(2-hydroxyethyl)-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one. The mother-liquor was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was boiled in 50 parts of a mixture of trichloromethane and methanol (85:15 by volume). After the addition of 50 parts of hexane, the whole was stirred to room temperature. The product was filtered off, washed with 2,2'-oxybispropane and dried, yielding 17 parts of 2,3-dihydro-6-(2-hydroxyethyl)-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>CN(C)C=O.C(OCC)(=O)C>[N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[N:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc[nH]n1
Reactant: CCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCCCn1ccc([N+](=O)[O-])n1
Reaction time: 16 h
Yield: 66.8 %

Procedure:
3-Nitro-1H-pyrazole (prepared in example 3, 100 mg, 0.89 mmol) was dissolved in anhydrous N,N-dimethylformamide (4 mL) and a 60% dispersion of sodium hydride in mineral oil (42 mg, 1.06 mmol) was added while stirring under nitrogen. After the effervescence ceased and the reaction stirred for an additional 10 min before 1-bromo-octane (183 μL, 1.06 mmol) was added. The reaction continued to stir under nitrogen for 4 h. The reaction was stored at −25° C. for 16 h. The solution was diluted with ethyl acetate (30 mL), washed with water (2×10 mL), saturated aqueous brine solution (10 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 25% ethyl acetate/hexanes to 75% ethyl acetate/hexanes) afforded 3-nitro-1-octyl-1H-pyrazole (134 mg, 56%) as a clear oil.
Reaction SMILES: Cl.[Br:2][C:3]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:6]2[N:7]([CH:13]([CH3:15])[CH3:14])[C:8]([CH2:10][CH2:11]Cl)=[N:9][C:5]=2[CH:4]=1.[F:22][C:23]([F:37])([F:36])[C:24]1[CH:25]=[C:26]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1>C(O)C>[Br:2][C:3]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:6]2[N:7]([CH:13]([CH3:15])[CH3:14])[C:8]([CH2:10][CH2:11][N:33]3[CH2:32][CH2:31][N:30]([C:26]4[CH:27]=[CH:28][CH:29]=[C:24]([C:23]([F:36])([F:37])[F:22])[CH:25]=4)[CH2:35][CH2:34]3)=[N:9][C:5]=2[CH:4]=1
Reactant: CC(C)n1c(CCCl)nc2cc(Br)c3ccccc3c21
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Agent: Cl
Solvent: CCO
Product: CC(C)n1c(CCN2CCN(c3cccc(C(F)(F)F)c3)CC2)nc2cc(Br)c3ccccc3c21

Procedure:
The compound of the title is prepared by condensing 5-bromo-2-(2-chloroethyl)-1-(1-methylethyl)-1H-naphth[1,2-d]imidazole hydrochloride with 1-(3-trifluoromethylphenyl)piperazine. M.p. 161°-162° C. (from ethanol).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)Cl.CO.[CH:17]([NH2:19])=O>>[F:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:5])[NH:19][CH:17]=[N:1]2)=[CH:7][CH:8]=1
Reactant: NC=O
Reactant: Nc1cc(F)ccc1C(=O)O
Solvent: CO
Solvent: ClCCl
Product: O=c1[nH]cnc2cc(F)ccc12
Temperature: 0 °C
Yield: 82 %

Procedure:
A solution of 2-amino-4-fluorobenzoic acid (3 g, 19.3 mmol) in formamide (30 ml) was heated at 150° C. for 6 hours. The reaction mixture was poured onto ice/water 1/1 (250 ml). The precipitated solid was collected by filtration, washed with water and dried to give 7-fluoro-3,4-dihydroquinazolin-4-one (2.6 g, 82%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[C:11]([CH3:20])=[CH:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[N:14][CH:15]=1.[I:21]I>S([O-])([O-])(=O)=O.[Ag+2].CO>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([I:21])=[CH:4][C:3]=1[C:10]1[C:11]([CH3:20])=[CH:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[N:14][CH:15]=1
Reactant: II
Reactant: COC(=O)c1cc(C)c(-c2ccc(OC)cc2F)cn1
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: COC(=O)c1cc(C)c(-c2cc(I)c(OC)cc2F)cn1

Procedure:
Methyl 5-(2-fluoro-4-methoxyphenyl)-4-methylpyridine-2-carboxylate (190 mg, 0.690 mmol), silver sulfate (430 mg, 1.380 mmol), iodine (0.071 ml, 1.380 mmol) and MeOH (10 mL) were stirred at room temperature overnight. The crude mixture was filtered. The filtrate was concentrated in vacuo. The resulting pot residue was purified by flash chromatography (SiO2, Biotage SNAP Cartridge, silica gel, KP-Sil, 50 g cartridge). The column was eluted by an EtOAc/hexane mixture (0% to 40%). Related fractions were pooled and evaporated to afford a colorless oil as the titled compound. LCMS calc.=400.99. found=402.08 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:19]2([OH:25])[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]2)[CH:16]=[CH:17][CH:18]=1>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:21]1[CH2:22][CH2:23][CH2:24][C:19]([OH:25])([C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([O:12][CH3:11])[CH:14]=2)[CH2:20]1)=[O:5]
Reactant: COc1cccc(C2(O)CCCNC2)c1
Reactant: O=C(Cl)c1ccccc1F
Product: COc1cccc(C2(O)CCCN(C(=O)c3ccccc3F)C2)c1

Procedure:
The compound of Example 1 was prepared according to the general preparation protocol A from 2-fluorobenzoyl chloride and 3-(3-methoxy-phenyl)-piperidine-3-ol.
Reaction SMILES: [SH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-:17].[Na+].II.[Na+].[Cl-]>O1CCOCC1.CO.O.O1CCCC1>[OH:17][CH2:4][C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[S:1][S:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: O=C(O)c1ccccc1S
Reactant: [OH-]
Agent: II
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: OCc1ccccc1SSc1ccccc1CO
Reaction time: 2 h

Procedure:
A solution of 30.8 g (0.20 mol) of o-mercaptobenzoic acid in 300 ml of dioxane was added to a mixture of 15.2 g (0.40 mol) lithium aluminum hydride in 300 ml of dioxane. 160 ml of tetrahydrofuran ("THF") was slowly added to this mixture with some loss of material due to bumping. The mixture was stirred for 2 hours followed by the slow addition of 15.2 ml of water, then 15.2 ml of 15% NaOH and finally 45.6 ml of water. The mixture was filtered with a methanol wash and the filtrate was concentrated to 20.0 g of oil. Methanol (250 ml) and 18.1 g (0.07 mol) of iodine were added and the mixture was stirred over the weekend. An equal volume of saturated NaCl solution was added and the solid was collected, washed with water, and recrystallized from aqueous ethanol. The yield of bis(2-hydroxymethylphenyl) disulfide was 10.0 g and had amp of 138.5°-139.5° C.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[C:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C.C(OCC)(=O)C>[C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[C:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2ccccc2c1C1=CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cc2ccccc2c(C2=CCCCC2)c1[C@H](OC(C)(C)C)C(=O)O
Yield: 59.4 %

Procedure:
A solution of above intermediate (S)-ethyl 2-tert-butoxy-2-(1-cyclohexenyl-3-methylnaphthalen-2-yl)acetate (8 mg, 0.021 mmol, 1 eq.) in ethanol (1.5 mL) and 1 N sodium hydroxide (0.42 mL, 20 eq.) was heated at 60° C. overnight. The reaction mixture was diluted with ethyl acetate and washed with brine. The aqueous layer was back-extracted with ethyl acetate and the combined organic layer was dried (MgSO4), filtered, concentrated and purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H2O+0.1% TFA). Product lyophilized to give 8 as a white powder (4.4 mg). Analytical HPLC (Gemini, 2-98% ACN/H2O+0.05% TFA, 10 minutes run): tR (min)=6.10. 1H-NMR: 400 MHz, (CD3OD) δ: 7.83 (m, 1H), 7.70 (m, 1H), 7.54 (m, 1H), 7.40 (m, 2H), 5.82, 5.62 (s, s, 1H), 2.58 (m, 3H), 2.62-2.16 (m, 4H), 1.92-1.80 (m, 4H), 1.03 (m, 9H). LCMS-ESI31 (m/z): [M−H]− calcd for C23H27O3: 351.46. Found: 351.1.
Reaction SMILES: [C:1]1(C)[C:2]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH2:12]([NH:20][CH:21]([NH2:23])[CH3:22])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>O.C(O)(C)C>[S:7]([C:2]1[CH:1]=[CH:6][C:5]([CH3:12])=[CH:4][CH:3]=1)([OH:10])(=[O:8])=[O:9].[CH2:12]([NH:20][CH:21]([NH2:23])[CH3:22])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: Cc1ccccc1S(=O)(=O)O
Agent: CCCCCCCCNC(C)N
Solvent: CC(C)O
Solvent: O
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: 25 °C
Yield: 99.5 %

Procedure:
A solution of toluenesulphonic acid (3 g, 0.0159 mol) in a mixture of water:isopropanol (20 ml, 1:1) was cooled to 0° C. and treated with N-(n-octyl)ethanediamine (3 g, 0.0175 mol) in isopropanol (10 ml). The solution was allowed to warm to room temperature and the solvent removed under reduced pressure to yield a solid which was recrystallized from isopropanol, to yield N-(n-octyl)ethanediamine tosylate (3 g) as white plates, m.p. 80°-85° C.