Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]3[N:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:27])[N:19]=[C:18]([C:28]([C:34]([F:37])([F:36])[F:35])([C:30]([F:33])([F:32])[F:31])[OH:29])[CH2:17]3)[CH:11]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[CH3:38][Mg]Cl>O1CCCC1>[Cl:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[N:20]1[CH:16]([C:12]2[CH:11]=[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([C:1]([OH:3])([CH3:38])[CH3:2])[CH:5]=3)[CH:15]=[CH:14][CH:13]=2)[CH2:17][C:18]([C:28]([C:34]([F:37])([F:36])[F:35])([C:30]([F:31])([F:32])[F:33])[OH:29])=[N:19]1
Reactant: C[Mg]Cl
Reactant: CC(=O)c1cccc(-c2cccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)c2)c1
Solvent: C1CCOC1
Product: CC(C)(O)c1cccc(-c2cccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)c2)c1
Temperature: -78 °C
Reaction time: 5 h
Yield: 51.3 %

Procedure:
To a mixture of 5-(3′-acetyl-biphenyl-3-yl)-1-(2-chloro-phenyl)-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (39.0 mg, 0.07 mmol) prepared in Example 224 in tetrahydrofuran (1.0 mL), was slowly added methylmagnesium chloride (in 3.0 M tetrahydrofuran, 120.0 uL, 0.36 mmol) under nitrogen atmosphere at −78° C. The reaction mixture was stirred at −78° C. for 5 hours, quenched with a saturated solution of ammonium chloride at 0° C., and then extracted with ethyl acetate. The extract was washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3) to give 20.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: Br[C:2]1[C:3](=[O:17])[N:4]([CH3:16])[C:5](=[O:15])[N:6]([CH2:8][CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])[N:7]=1.[F:18][C:19]([F:33])([F:32])[C:20]1[CH:21]=[C:22]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1>>[CH2:24]([OH:15])[CH2:25][CH2:20][CH3:19].[CH3:16][N:4]1[C:3](=[O:17])[C:2]([N:29]2[CH2:28][CH2:27][N:26]([C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([C:19]([F:32])([F:33])[F:18])[CH:21]=3)[CH2:31][CH2:30]2)=[N:7][N:6]([CH2:8][CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])[C:5]1=[O:15]
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: Cn1c(=O)c(Br)nn(CCCC(F)(F)F)c1=O
Product: CCCCO
Product: Cn1c(=O)c(N2CCN(c3cccc(C(F)(F)F)c3)CC2)nn(CCCC(F)(F)F)c1=O
Yield: 76 %

Procedure:
The compound 8 (oil) is prepared from the triazine 4a and from 1-(3-trifluoromethyl-phenyl)-piperazine according to the synthesis method 1 in n-butanol (yield: 76%).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[I-].C[S+](C)C.[CH3:12][CH:13]([CH3:22])[C:14]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)=[O:15]>O>[CH:13]([C:14]1([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH2:1][O:15]1)([CH3:22])[CH3:12]
Reactant: CC(C)C(=O)c1ccncc1
Reactant: CC(C)(C)[O-]
Agent: C[S+](C)C
Agent: [I-]
Agent: [K+]
Solvent: O
Product: CC(C)C1(c2ccncc2)CO1
Temperature: 0 °C
Yield: 91.3 %

Procedure:
A mixture of potassium tert-butoxide (0.098 g, 0.80 mmol) and trimethylsulfonium iodide (0.164 g, 0.8 mmol) was stirred at 0° C. To this was added 2-methyl-1-(pyridin-4-yl)propan-1-one (0.100 g, 0.671 mmol) slowly. The reaction mixture was stirred at 0° C. for 15 min. and then warmed to and stirred at 70° C. for 1 h. The reaction mixture was diluted with water and extracted with EtOAc (3×10 mL), organic layer dried on sodium sulfate and concentrated under vacuum to obtain 4-(2-isopropyloxiran-2-yl)pyridine (0.1 g). 1H NMR (CDCl3, freebase) δ (ppm): 8.19 (d, 2H), 7.26 (d, 2H), 3.05 (d, 1H), 2.71 (d, 1H), 2.28 (m, 1H), 1.80 (m, 1H), 0.97 (t, 3H).
Reaction SMILES: [CH3:1][CH:2]([CH3:34])[CH2:3][C@H:4]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:5][O:6][C:7]1[C:8]([C:23]([CH3:25])=[CH2:24])=[CH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[N:12]([CH3:21])[C:11]=2[CH:22]=1.[H][H]>[Pd].CO.C(OCC)(=O)C>[CH:23]([C:8]1[C:7]([O:6][CH2:5][C@@H:4]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:31])[CH3:32])[CH2:3][CH:2]([CH3:1])[CH3:34])=[CH:22][C:11]2[N:12]([CH3:21])[C:13](=[O:20])[C:14]3[C:19]([C:10]=2[CH:9]=1)=[CH:18][CH:17]=[N:16][CH:15]=3)([CH3:25])[CH3:24]
Reactant: [H][H]
Reactant: C=C(C)c1cc2c3ccncc3c(=O)n(C)c2cc1OC[C@H](CC(C)C)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)C[C@@H](COc1cc2c(cc1C(C)C)c1ccncc1c(=O)n2C)NC(=O)OC(C)(C)C
Yield: 1146 %

Procedure:
A mixture of (S)-tert-butyl (4-methyl-1-((6-methyl-5-oxo-9-(prop-1-en-2-yl)-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)pentan-2-yl)carbamate (0.1 g, 0.215 mmol) and palladium on carbon (0.07 g, 0.066 mmol) in MeOH (3 mL) and ethyl acetate (3 mL) was stirred at RT under a balloon of hydrogen gas for 24 h. The reaction mixture was filtered through diatomaceous earth (Celite®) and the filtrate was concentrated under reduced pressure to afford (S)-tert-butyl (1-((9-isopropyl-6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (0.04 g, 2.464 mmol, 1% yield) as a brown oil, which was carried on without further purification. LC/MS (ESI) m/e 468.4, [(M+H)+, calcd for C27H38N3O4, 468.3]; LC/MS retention time (method D): tR=1.00 min.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:24])[O:19]C(C)(C)C)=[C:13]([O:25][CH3:26])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:27]=[CH:28]/[CH2:29][N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[CH:4][N:3]=1.[CH3:35][C:36]([CH3:38])=[O:37]>Cl>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[C:7]3[C:2]([NH2:1])=[N:3][CH:4]=[C:5](/[CH:27]=[CH:28]/[CH2:29][N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])[C:6]=3[S:10][CH:9]=2)=[CH:12][C:13]=1[O:25][CH3:26].[CH3:35][C:36]([CH2:38][C:18]([OH:24])=[O:19])=[O:37]
Reactant: CC(C)=O
Reactant: CCN(CC)C/C=C/c1cnc(N)c2c(-c3ccc(NC(=O)OC(C)(C)C)c(OC)c3)csc12
Agent: Cl
Product: CC(=O)CC(=O)O
Product: CCN(CC)C/C=C/c1cnc(N)c2c(-c3ccc(N)c(OC)c3)csc12

Procedure:
A mixture of Example 365B (425 mg, 0.88 mmol) in acetone (10 mL) and 6N aqueous hydrochloric acid (2 mL) was stirred for 18 hours at ambient temperature then concentrated under reduced pressure. The residue was then purified by preparative reverse phase HPLC to provide the desired product as the diacetate salt. 1H NMR (DMSO-d6, 400 MHz) δ 7.89 (s, 1H), 7.39 (s, 1H), 6.82 (s, 1H), 6.73 (s, 2H), 6.20 (m, 1H), 5.65 (br s, 2H), 3.78 (s, 3H), 3.30 (d, 2H), 2.56 (q, 4H), 1.88 (s, 6H), 1.01 (t, 6H); MS m/e 383.4 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]#[N:9].[H-].[Na+].Cl[CH2:13][CH:14]=[CH:15][CH3:16]>CS(C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([CH2:13][CH:14]=[CH:15][CH3:16])[C:8]#[N:9]
Reactant: CC=CCCl
Reactant: N#CCc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC=CCC(C#N)c1ccccn1
Temperature: 25 °C

Procedure:
A solution of 5.9 g. of 2-pyridylacetonitrile in 15 ml. of dimethylsulfoxide is added to a suspension of 1.2 g. of sodium hydride in 25 ml. of dimethylsulfoxide with stirring. The mixture is heated on a stream bath for 2 hours, then cooled to room temperature. 1-Chloro-2-butene (4.5 g.) is added dropwise with stirring. The mixture is heated on a steam bath, with stirring, for 10 hours, then most of the solvent is removed in vacuo. Water is added to the residue, then 100 ml. of ether is added. The ethereal solution is separated from the aqueous layer and rinsed several times with water, then dried, concentrated and distilled to give 2-(2-pyridyl)-4-hexenenitrile.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:30])[CH3:9])=[CH:4][CH:3]=1.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33](B(O)O)[CH:32]=1>>[O:30]=[C:11]1[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:33]3[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12]1
Reactant: OB(O)c1cccnc1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCNS(C)(=O)=O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2cccnc2)cc1)N1CC[C@](CCCNS(C)(=O)=O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from N-(3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propyl)methanesulfonamide and pyridine-3-boronic acid following procedures analogous to those described in Example 1 Step 2. LC-MS Method 2 tR=1.466 min, m/z=497.3; 1H NMR (CDCl3) 1.33 (m, 1H), 1.53 (d, 3H), 1.63 (m, 1H), 1.84-2.03 (m, 2H), 2.18 (m, 1H), 2.30 (m, 2H), 2.84 (s, 3H), 2.93 (m, 1H), 3.02 (t, 2H), 4.30 (s, 1H), 5.64 (m, 1H), 7.02 (d, 2H), 7.22 (m, 2H), 7.31 (m, 5H), 7.77 (m, 1H), 7.80 (d, 1H), 8.71 (d, 1H), 8.93 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.O.[NH3:11].[OH-].[Na+]>C(#N)C>[NH2:11][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: N
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: NCc1ccc(Cl)nc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 58.1 %

Procedure:
A mixture of 14.99g of 2-chloro-5-(chloromethyl) pyridine, 63.01g of 25% ammonia water and 60ml of acetonitrile in a stainless steel autoclave was stirred for 2 hours in an oil bath of 80° C. After adding 12.3g of 30% sodium hydroxide aqueous solution, the reaction mixture was concentrated. The residue to which 200ml of ethanol were added was dried over anhydrous magnesium sulfate and, filtered to remove insoluble materials. The filtrate was concentrated and purified by a column chromatography [developing solvent: dichloromethane-methanol (4:1)] to afford 7.66g of 5-(aminomethyl)-2- chloropyridine as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3=[N:14][NH:15][C:16](=[O:21])[C:17]4[CH:18]=[CH:19][CH:20]=[C:11]([C:12]=43)[NH:10][CH:9]2[C:22]2[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.CC(O)=O.[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].Cl>C(Cl)Cl.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3=[N:14][NH:15][C:16](=[O:21])[C:17]4[CH:18]=[CH:19][CH:20]=[C:11]([C:12]=43)[NH:10][CH:9]2[C:22]2[CH:23]=[CH:24][C:25]([CH2:26][N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)=[CH:28][CH:29]=2)=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(F)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=c1[nH]nc2c3c(cccc13)NC(c1ccc(CN3CCCC3)cc1)C2c1ccc(F)cc1
Reaction time: 8 h
Yield: 26.2 %

Procedure:
To a stirred mixture of 4-(9-(4-fluorophenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (0.1 g, 0.26 mmol) in anhydrous DCM (4 mL) was added AcOH (94 mg, 1.56 mmol) at 25° C. for 0.5 h, then pyrrolidine (37 mg, 0.52 mmol) was added at 25° C., stirred overnight. NaBH(OAc)3 was added at ice bath, and stirred for 5 h. The mixture was concentrated to give the crude product. The crude product was dissolved in ethyl acetate and to this solution was added 2N HCl (10 mL). The aqueous phase was separated and 20% NaOH (20 ml) was added. The mixture was extracted with ethyl acetate and the organic phase was separated to give the title compound (30 mg, yield 26%). LC-MS (ESI) m/z: 441 (M+1)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8]([C:15]([OH:17])=[O:16])=[CH:7]2)([O-])=O.[H][H]>[Ni].CN(C)C=O>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8]([C:15]([OH:17])=[O:16])=[CH:7]2
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2[nH]c1=O
Reactant: [H][H]
Agent: [Ni]
Solvent: CN(C)C=O
Product: Nc1ccc2[nH]c(=O)c(C(=O)O)cc2c1

Procedure:
A solution of 3.63 g (14.9 mmol) of 1,2-dihydro-6-nitro-2-oxo-3-quinolinecarboxylic acid and 200 ml of dimethylformamide is hydrogenated using 1 g of Raney nickel catalyst at 52 psi and 23° until the required amount of hydrogen uptake is obtained. The catalyst is filtered off and the filtrate is evaporated to dryness. The residue is treated with ethanol and 3.0 g of the desired product and is filtered.
Reaction SMILES: [CH:1]([C:3]1[C:4]([F:15])=[CH:5][N:6]=[C:7]2[C:12]=1[N:11]=[C:10]([O:13][CH3:14])[CH:9]=[CH:8]2)=[CH2:2].[F:16][C@@H:17]1[CH2:21][NH:20][CH2:19][C@H:18]1[CH2:22][NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CCO>[C:27]1([CH2:26][O:25][C:24](=[O:33])[NH:23][CH2:22][C@H:18]2[C@H:17]([F:16])[CH2:21][N:20]([CH2:2][CH2:1][C:3]3[C:12]4[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[N:11]=4)[N:6]=[CH:5][C:4]=3[F:15])[CH2:19]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: C=Cc1c(F)cnc2ccc(OC)nc12
Reactant: O=C(NC[C@@H]1CNC[C@H]1F)OCc1ccccc1
Solvent: CCO
Product: COc1ccc2ncc(F)c(CCN3C[C@@H](CNC(=O)OCc4ccccc4)[C@H](F)C3)c2n1
Yield: 92.1 %

Procedure:
To a stirred solution of 8-ethenyl-7-fluoro-2-(methyloxy)-1,5-naphthyridine (0.44 g, 2.14 mmole) in EtOH (5 mL) was added (±)-phenylmethyl {[trans-4-fluoro-3-pyrrolidinyl]methyl}carbamate (0.54 g, 2.14 mmole). After 24 h at 80° C. the reaction contents were purified on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) affording the title compound (0.90 g, 92%) as a light yellow foam: LC-MS (ES) m/e 457 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15](=[N:24][NH2:25])[NH:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[Cl:23])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1.[CH:27]([O-])([O-])OC>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]4[N:16]([C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=5[Cl:23])[CH:27]=[N:25][N:24]=4)=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1
Reactant: COC([O-])[O-]
Reactant: NN=C(Nc1ccccc1Cl)c1cc2c(s1)-c1ccc(Br)cc1OCC2
Product: Clc1ccccc1-n1cnnc1-c1cc2c(s1)-c1ccc(Br)cc1OCC2
Temperature: 25 °C

Procedure:
A solution of crude 8-bromo-N-(2-chlorophenyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carbohydrazonamide (150 mg) was heated in a sealed vessel with methyl orthoformate at 90° C. for 3 h. The mixture was cooled to room temperature and concentrated to give a crude residue that was purified by flash column chromatography (10-100% ethyl acetate in hexanes) to give 273. 1H NMR (dmso-d6, 400 MHz) δ 8.89 (s, 1H), 7.84 (m, 2H), 7.75 (m, 1H), 7.66 (m, 1H), 7.46 (m, 2H), 7.28-7.23 (m, 2H), 6.66 (s, 1H), 4.23 (t, 2H), 3.02 (t, 2H). MS (ESI) 460.0
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:5]2=[N:4][CH:3]=1.[N:12]1([C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=2)[CH:16]=[CH:15][CH:14]=[N:13]1.O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:11][C:9]1[CH:8]=[CH:7][N:6]2[C:2]([C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([N:12]4[CH:16]=[CH:15][CH:14]=[N:13]4)[CH:22]=3)=[CH:3][N:4]=[C:5]2[CH:10]=1
Reactant: Clc1ccn2c(Br)cnc2c1
Reactant: OB(O)c1cccc(-n2cccn2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Clc1ccn2c(-c3cccc(-n4cccn4)c3)cnc2c1

Procedure:
3-Bromo-7-chloro-imidazo-[1,2-a]-pyridine (1 eq, 2.59 mmol, 600 mg) and 3-(1H-pyrazolyl)-phenylboronic acid (1.2 eq, 1.04 mmol, 195 mg) are dissolved in DME (5 ml) and water (1.5 ml) and Na2CO3 (0.65 eq, 1.68 mmol, 209 mg) is added. PdCl2(PPh3)2 (0.04 eq, 0.104 mmol, 72.8 mg) is added and the reaction mixture is heated using microwave radiation at 120° C. for 10 min. At the completion of this time the solvent is removed in vacuo and the reaction mixture is purified by flash column chromatography eluting with 9:1 DCM/MeOH to yield 7-chloro-3-(3-pyrazol-1-yl -phenyl)-imidazo[1,2-a]pyridine as a brown solid; [M+H]+=295
Reaction SMILES: C([Li])CCC.[C:6](#[N:8])[CH3:7].[CH2:9]([O:11][C:12]1[C:21]([O:22][CH3:23])=[CH:20][C:15]([C:16]([O:18]C)=O)=[C:14]([N:24]=[CH:25]N(C)C)[CH:13]=1)[CH3:10].C(O)(=O)C>C1COCC1.O>[CH2:9]([O:11][C:12]1[CH:13]=[C:14]2[C:15]([C:16](=[O:18])[C:7]([C:6]#[N:8])=[CH:25][NH:24]2)=[CH:20][C:21]=1[O:22][CH3:23])[CH3:10]
Reactant: CCOc1cc(N=CN(C)C)c(C(=O)OC)cc1OC
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CCOc1cc2[nH]cc(C#N)c(=O)c2cc1OC
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 83.1 %

Procedure:
Added 54.0 ml (135 mmol) n-butyl lithium to 150 ml THF and chilled to −78° C. under N2. Added dropwise over 20 minutes 7.05 ml (135 mmol) acetonitrile in 200 ml THF. Stirred 15 minutes and added a solution of 17.99 g (64.2 mmol) methyl 4-ethoxy-5-methoxy-2-(dimethylaminomethyleneamino)benzoate in 150 ml THF dropwise over 20 minutes. Let stir for 0.5 hour at −78° C. Added 11.0 ml (193 mmol) acetic acid and warmed gradually to 25° C. After 2.5 hours, stripped solvent, slurried residue with water, collected solids and dried in vacuo, giving 13.025 g of yellow solid: mass spectrum (electrospray m/e): M+H=245.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]=[O:14])=[C:11]([CH:15]([CH3:17])[CH3:16])[C:10]([C:18]([OH:20])=O)=[N:9]2)=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.O.[CH3:43][NH:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[CH3:52]>C(Cl)Cl>[CH3:43][N:44]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[CH3:52])[C:18]([C:10]1[C:11]([CH:15]([CH3:16])[CH3:17])=[C:12]([CH:13]=[O:14])[N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]=1)=[O:20]
Reactant: CC(C)c1c(C(=O)O)nn(-c2ccc(F)cc2)c1C=O
Reactant: CNCc1ccccc1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: Cc1ccccc1CN(C)C(=O)c1nn(-c2ccc(F)cc2)c(C=O)c1C(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 71.6 %

Procedure:
To a solution of 1-(4-fluoro-phenyl)-5-formyl-4-isopropyl-1H-pyrazole-3-carboxylic acid (1.50 g, 5.43 mmol) in CH2Cl2 (100 mL) at 25° C. was added EDCI (1.56 g, 8.14 mmol) followed by HOBt.H2O (1.25 g, 8.14 mmol) and the reaction was stirred for 10 min at 25° C. Subsequently, methyl-(2-methyl-benzyl)-amine (1.10 g, 8.14 mmol) was added and the reaction was stirred for an additional 6 hrs at 25° C. The organic layer was then washed with HCl, saturated NaHCO3 and brine. After drying over Na2SO4 and concentration, the product was purified by column chromatography (10-25 % EtOAc/Hex) to afford desired 1-(4-fluoro-phenyl)-5-formyl-4-isopropyl-1H-pyrazole-3-carboxylic acid methyl-(2-methyl-benzyl)-amide as an oil (1.53 g, 71.6%). MS(APCI+) 394.2 m/z (M+H).
Reaction SMILES: [OH:1][C:2]1([OH:16])[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH2:3]1.Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52].[C:53](=[O:56])([O-])[O-].[K+].[K+].Cl>C(Cl)(Cl)Cl.CN(C=O)C>[CH2:31]([O:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][O:16][C:2]1([O:1][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:56][CH2:53][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH3:31])[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:14][CH2:15]1)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52]
Reactant: CCCCCCCCCCCCCCCCCCCCCCOCCCCCCCCCCCCBr
Reactant: O=C([O-])[O-]
Reactant: O=C(C1=CCC(O)(O)C=C1)c1ccccc1
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCCCCCOCCCCCCCCCCCCOC1(OCCCCCCCCCCCCOCCCCCCCCCCCCCCCCCCCCCC)C=CC(C(=O)c2ccccc2)=CC1
Temperature: 90 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
To 4,4-dihydroxybenzophenone (196 mg, 915 μmol) were added DMF (20 ml), 1-(12-bromododecyloxy)docosane (1.1 g, 1.91 mmol) and potassium carbonate (379 mg, 2.74 mmol), and the mixture was stirred at 90° C. overnight. The reaction mixture was cooled to room temperature, and 0.5N hydrochloric acid (20 ml) and chloroform (20 ml) were added. After stirring for a while, the aqueous layer was removed, and the organic layer was washed with water (10 ml)×2. The organic layer was evaporated under reduced pressure, and the residue was washed with methanol. The precipitate was collected by filtration to give 4,4-di(12-docosoxydodecyloxy)benzophenone (1.04 g, 867 μmol, 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]3[CH2:13][N:14]([C:17]4[CH:18]=[N:19][C:20](F)=[CH:21][CH:22]=4)[C:15](=[O:16])[C:10]3=[N:9]2)=[CH:4][CH:3]=1.[CH2:24]([N:31]1[CH2:38][CH:37]2[CH:33]([CH2:34][NH:35][CH2:36]2)[CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CS(C)=O>[CH2:24]([N:31]1[CH2:38][CH:37]2[CH2:36][N:35]([C:20]3[N:19]=[CH:18][C:17]([N:14]4[CH2:13][C:11]5[C:10](=[N:9][N:8]([C:5]6[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=6)[CH:12]=5)[C:15]4=[O:16])=[CH:22][CH:21]=3)[CH2:34][CH:33]2[CH2:32]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C1c2nn(-c3ccc(Cl)cc3)cc2CN1c1ccc(F)nc1
Reactant: c1ccc(CN2CC3CNCC3C2)cc1
Solvent: CS(C)=O
Product: O=C1c2nn(-c3ccc(Cl)cc3)cc2CN1c1ccc(N2CC3CN(Cc4ccccc4)CC3C2)nc1
Temperature: 120 °C
Yield: 51.3 %

Procedure:
To a mixture of Example 34A (20 mg, 0.061 mmol) in DMSO (0.8 mL) was added 2-benzyloctahydropyrrolo[3,4-c]pyrrole (58 mg, 0.287 mmol). The resulting mixture was irradiated in microwave reactor at 120° C. for 30 min. The sealed tube was heated at 120° C. for 3 h and allowed to cool down to room temperature. The reaction mixture was subjected to filtration. The solid collected was further washed with MeOH (8 mL) and dried under vacuum to give product (16 mg). The obtained product was diluted with CH2Cl2 (0.8 mL) and TFA (0.2 ml). The resulting mixture was stirred at room temperature for 15 min. The solvent was evaporated to give a crude product which was further purified by preparative HPLC (PHENOMENEX® Luna Axia 5μ C18 30×100 mm; 10 min gradient from 70% A: 30% B to 0% A:100% B (A=90% H2O/10% MeOH+0.1% TFA); (13=90% MeOH/10% H2O+0.1% TFA); detection at 220 nm). The desired fraction was collected and concentrated under SPEEDVAC® to give Example 37 as white solid (9.2 mg, 38%). 1H NMR (CD3OD, 400 MHz) δ 3.02-3.90 (m, 10H), 4.47 (s, 2H), 4.94 (s, 2H), 7.09 (d, J=8.8 Hz, 1H), 7.40-7.53 (m, 7H), 7.60-7.80 (m, 2H), 8.25-8.30 (m, 1H), 8.39 (s, 1H), 8.60 (s, 1H). LCMS, [M+H]+=511.4.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:36])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)[CH2:23][CH2:22]3)[CH:16]=1)[C:11]([CH3:35])([CH3:34])[CH2:10]2)=[O:4].O.[OH-].[Li+].O.Cl>CO.O1CCCC1>[Cl:36][C:7]1[CH:8]=[C:9]2[C:14](=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=1)[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:22][CH2:23][N:24]([C:27]4[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=4)[CH2:25][CH2:26]3)[CH:16]=1)[C:11]([CH3:35])([CH3:34])[CH2:10]2
Reactant: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(N3CCN(c4ccc(Cl)cc4)CC3)c1)C(C)(C)C2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)Cc2cc(Cl)cc(C(=O)O)c2NC1c1cccc(N2CCN(c3ccc(Cl)cc3)CC2)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 78.4 %

Procedure:
A mixture of 6-chloro-2-{3-[4-(4-chloro-phenyl)-piperazin-1-yl]-phenyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (0.13 g, 0.25 mmol), lithium hydroxide hydrate (104 mg, 2.5 mmol), water (0.5 mL) in methanol (1 mL) and tetrahydrofuran (5 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 6-chloro-2-{3-[4-(4-chloro-phenyl)-piperazin-1-yl]-phenyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (100 mg, 80%) as a white solid: LC/MS m/e calcd for C28H29Cl2N3O2 M+: 510.5, observed: 510.0;