Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][C:6]([C:8]1[C@H:9]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:10]([C:16]([OH:18])=[O:17])=[C:11]([CH3:15])[NH:12][C:13]=1[CH3:14])=[O:7])#[N:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:39]1[CH:44]=[CH:43][CH2:42][CH2:41][CH2:40]1>O1CCCC1.C(OCC)(=O)C>[C:1]([CH2:3][CH2:4][O:5][C:6]([C:8]1[C@H:9]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:10]([C:16]([O:18][CH:40]2[CH2:41][CH2:42][CH2:43][CH2:44][O:39]2)=[O:17])=[C:11]([CH3:15])[NH:12][C:13]=1[CH3:14])=[O:7])#[N:2]
Reactant: CC1=C(C(=O)O)[C@@H](c2cccc([N+](=O)[O-])c2)C(C(=O)OCCC#N)=C(C)N1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1=C(C(=O)OCCC#N)[C@H](c2cccc([N+](=O)[O-])c2)C(C(=O)OC2CCCCO2)=C(C)N1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 19 mg of (4R)-5-(2-cyanoethoxycarbonyl)-1,4-dihydro-2,6-dimethyl-4 -(3-nitrophenyl )pyridine-3-carboxylic acid in 0.5 ml of tetrahydrofuran were added 5 mg of p-toluenesulfonic acid, and then 0.138 ml of 3,4-dihydro-2H-pyran. The mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with 5 ml of ethyl acetate, washed with water, and dried over anhydrous Glauber's salt (sodium sulfate), followed by distilling off the solvent under reduced pressure. The residue was purified using preparative TLC to obtain 16.4 mg of the objective compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:10]([C:11]([N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:12])=[C:4]2[C:3]=1[F:29].[CH3:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>O>[C:16]([O:15][C:14]([N:13]([CH3:21])[C:11]([C:10]1[C:9]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[N:8][N:5]2[CH:6]=[CH:7][C:2]([C:32]3[CH:33]=[C:34]([CH:38]=[CH:39][C:31]=3[CH3:30])[C:35]([OH:37])=[O:36])=[C:3]([F:29])[C:4]=12)=[O:12])=[O:20])([CH3:19])([CH3:18])[CH3:17]
Reactant: Cc1ccc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CN(C(=O)OC(C)(C)C)C(=O)c1c(-c2ccc(F)cc2)nn2ccc(Cl)c(F)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(C(=O)O)cc1-c1ccn2nc(-c3ccc(F)cc3)c(C(=O)N(C)C(=O)OC(C)(C)C)c2c1F
Temperature: 95 °C
Reaction time: 18 h

Procedure:
To a degassed solution containing tert-butyl 5-chloro-4-fluoro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-carbonyl(methyl)carbamate (0.10 g, 0.24 mmol), 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (0.078 g, 0.30 mmol), sodium carbonate (0.075 g, 0.71 mmol), dioxane (2.0 mL) and water (0.40 mL) was added tetrakis(tiphenylphosphine)palladium(0) (0.008 g, 0.007 mmol). The mixture was stirred at 95° C. for 18 h. The solution was cooled to room temperature, filtered to remove solids and adjusted to below pH 4 with 1N aqueous hydrochloric acid (2.0 mL). Water was added (10 mL) and the aqueous portion was extracted with ethyl acetate (2×15 mL). The combined organic portions were washed with brine (20 mL) and dried over magnesium sulfate. The mixture was filtered and concentrated to afford 3-(3-(tert-butoxycarbonyl(methyl)carbamoyl)-4-fluoro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-5-yl)-4-methylbenzoic acid as a residue which was used without further purification. LCMS retention time: 2.467 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Sunfire C18, 5 micron, C18, 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH3CN/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3CN/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 522 (MH+).
Reaction SMILES: ClC1C=CC(C2N=C(N3CCN(CC(C4C=CC(OC)=CC=4)O)CC3)SN=2)=CC=1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[N:41]=[C:40]([N:42]3[CH2:47][CH2:46][N:45]([CH2:48][C:49]([C:51]4[CH:56]=[CH:55][CH:54]=[C:53]([O:57][CH3:58])[CH:52]=4)=[O:50])[CH2:44][CH2:43]3)[S:39][N:38]=2)=[CH:33][CH:32]=1>>[Cl:30][C:31]1[CH:32]=[CH:33][C:34]([C:37]2[N:41]=[C:40]([N:42]3[CH2:43][CH2:44][N:45]([CH2:48][CH:49]([C:51]4[CH:56]=[CH:55][CH:54]=[C:53]([O:57][CH3:58])[CH:52]=4)[OH:50])[CH2:46][CH2:47]3)[S:39][N:38]=2)=[CH:35][CH:36]=1
Reactant: COc1cccc(C(=O)CN2CCN(c3nc(-c4ccc(Cl)cc4)ns3)CC2)c1
Agent: COc1ccc(C(O)CN2CCN(c3nc(-c4ccc(Cl)cc4)ns3)CC2)cc1
Product: COc1cccc(C(O)CN2CCN(c3nc(-c4ccc(Cl)cc4)ns3)CC2)c1

Procedure:
In analogy to the procedure described for the synthesis of 2-{4-[3-(4-Chloro-phenyl)-[1,2,4]thiadiazol-5-yl]-piperazin-1-yl}-1-(4-methoxy-phenyl)-ethanol (Example 54) the title compounds was prepared from 2-{4-[3-(4-Chloro-phenyl)-[1,2,4]thiadiazol-5-yl]-piperazin-1-yl}-1-(3-methoxy-phenyl)-ethanone through reduction as white solid. MS (m/e): 431.3 (MH+).
Reaction SMILES: C([N:4]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][C:20]3[C:28]([F:29])=[CH:27][C:26]([F:30])=[C:25]([NH2:31])[C:21]=3[C:22](=[O:24])[CH:23]=2)=[CH:14][C:13]=1[F:32])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]Br)(=O)C.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.O>CN(C)C=O>[NH2:31][C:25]1[C:21]2[C:22](=[O:24])[CH:23]=[C:18]([C:15]3[CH:16]=[CH:17][C:12]([NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[C:13]([F:32])[CH:14]=3)[O:19][C:20]=2[C:28]([F:29])=[CH:27][C:26]=1[F:30]
Reactant: CC(=O)N(CCCCCCBr)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Reactant: C1COCCN1
Solvent: CN(C)C=O
Solvent: O
Product: Nc1c(F)cc(F)c2oc(-c3ccc(NCCCCCCN4CCOCC4)c(F)c3)cc(=O)c12
Reaction time: 1.5 h

Procedure:
500 mg (1.07 mmol) of 5-amino-2-[4-(6-bromohexylamino)-3-fluorophenyl]-6,8-difluoro-4H-1-benzopyran-4-one obtained in Example 52 was dissolved in 15 ml of dimethylformamide, 0.93 ml of morpholine was added and the mixture was stirred at 50° to 60° C. for 1.5 hours. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol:triethylamine =200:10:1) and recrystallized from ethyl acetate/n-hexane to give Compound 55 which was converted into hydrochloride according to the same manner as that in Example 16 to give 349 mg (62%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:9]1)=O)(C)(C)C.Cl.ClC1[C:36]2[C:31](=[CH:32][C:33]([CH3:37])=[CH:34][CH:35]=2)[N:30]=[C:29]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[OH:44])[N:28]=1.C(N(CC)CC)C>O1CCOCC1.C(Cl)Cl>[OH:44][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=1[C:29]1[N:28]=[C:6]([N:8]2[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:9]2)[C:36]2[C:31](=[CH:32][C:33]([CH3:37])=[CH:34][CH:35]=2)[N:30]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CNC(=O)OCc2ccccc2)C1
Reactant: Cc1ccc2c(Cl)nc(-c3ccccc3O)nc2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1ccc2c(N3CC[C@H](CNC(=O)OCc4ccccc4)C3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.6 %

Procedure:
A solution of benzyl ((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methylcarbamate (0.20 g, 0.60 mmol) and 4 M HCl in dioxane (10 mL) was stirred for 3 h at room temperature. After evaporating the solvent under reduced pressure, the resulting solid was triturated with Et2O and dried under vacuum, then taken up in CH2Cl2 (10 mL). To this solution was added 2-(4-chloro-7-methylquinazolin-2-yl)phenol (0.16 g, 0.60 mmol) and triethylamine (0.25 mL, 1.8 mmol). The reaction mixture was stirred at room temperature overnight, then diluted with CH2Cl2 and washed with water. The CH2Cl2 solution was dried over Na2SO4, filtered, and concentrated. Purification via silica gel chromatography using 0-40% EtOAc in hexanes gave benzyl ((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate as a colorless oil (0.19 g, 68%). LC/MS: m/z 469.1 (M+H)+ at 2.58 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: C([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:24])(C)=C.O.Cl.C(Cl)Cl>CO>[C:14]1([CH2:13][N:6]2[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:4][C:5]2=[O:24])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: C=C(C)n1c(=O)n(Cc2cccc3ccccc23)c2ccccc21
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: O=c1[nH]c2ccccc2n1Cc1cccc2ccccc12
Temperature: 60 °C
Yield: 92.9 %

Procedure:
1-Isopropenyl-3-naphthalen-1-ylmethyl-1,3-dihydro-benzimidazol-2-one (1.6 g, 5.1 mmol) is dissolved in MeOH (5.0 mL) and water (5.0 mL) is added into the solution. To this heterogeneous reaction mixture is added 37% hydrochloric acid (4.0 mL). The reaction mixture is heated to 60° C. for 30 min and then water (50 mL) and CH2Cl2 (50 mL) are added. The organic layer is separated and the aqueous layer is extracted with CH2Cl2 (3×50 mL). The organic layers are combined, washed with Sat. NaHCO3 (100 mL), Sat. NH4Cl (100 mL) and water (3×100 mL), dried over MgSO4 and concentrated to give 1.3 g (93%) of crude product which is pure enough for the next step.
Reaction SMILES: [CH:1]1([C:5]2[C:14](I)=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH3:16])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19]>C1COCC1.C(N(CC)CC)C.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.[Cu](I)I>[CH:1]1([C:5]2[C:14]([C:22]#[C:21][Si:18]([CH3:20])([CH3:19])[CH3:17])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH3:16])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cc(I)c(C2CCC2)cc1C
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C#C[Si](C)(C)C)c(C2CCC2)cc1C
Temperature: 80 °C
Yield: 97.3 %

Procedure:
A mixture of methyl 4-cyclobutyl-5-iodo-2-methylbenzoate (compound 152.3, 1.32 g, 4 mmol), trimethylsilylacetylene (663 μl, 4.8 mmol), Pd(PPh3)2Cl2 (85 mg, 0.12 mmol) and copper iodide (CuI, 46 mg, 0.24 mmol) in THF (8 ml) and triethylamine (2 ml) was degassed and then heated to 80° C. for 1.5 hours under nitrogen. After cooling to ambient temperature, the reaction was filtered through celite and concentrated. The residue was dissolved in ethyl acetate (EtOAc), washed with brine, dried over MgSO4 and concentrated. The residue was purified by flash chromatography (SiO2; 3% EtOAc in Hexane) to give 1.17 g (97%) of the title compound as a liquid. 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 7.15 (s, 1H), 4.01-3.75 (m, 4H), 2.63 (s, 3H), 2.54-2.31 (m, 2H), 2.27-2.12 (m, 2H), 2.12-1.98 (m, 1H), 1.94-1.80 (m, 1H), 0.28 (s, 9H).
Reaction SMILES: P(Cl)(Cl)Cl.[ClH:5].Cl[C:7]([C:17]#[N:18])([CH2:13][CH2:14][CH:15]=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9]>CN(C=O)C>[Cl:5][C:17]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=[CH:15][N:18]=1
Reactant: Cl
Reactant: CCOC(=O)C(Cl)(C#N)CCC=O
Solvent: CN(C)C=O
Solvent: ClP(Cl)Cl
Product: CCOC(=O)c1cccnc1Cl
Temperature: 90 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
To 35 mL of DMF were added dropwise 6.85 g of PCl3 (50 mmol). Anhydrous HCl was introduced for 5 minutes while keeping the temperature around 70° C. Ethyl 2-chloro-2-cyano-5-oxopentanoate (7.83 g, 38.5 mmol) in 10 mL of DMF was added at 55° C. The resulting mixture was stirred for 2 h at 90° C., cooled to room temperature, quenched with water, extracted with CH2Cl2, dried over MgSO4, concentrated and distilled to give 4.4 g of the title compound (62%).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][N:22]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:23](=[O:26])[CH2:24][CH3:25])[CH2:16]1)(OC(C)(C)C)=O.[NH:33]1[CH:37]=[CH:36][N:35]=[C:34]1C=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[NH:33]1[CH:37]=[CH:36][N:35]=[C:34]1[CH2:8][N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][N:22]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:23](=[O:26])[CH2:24][CH3:25])[CH2:16]1
Reactant: CCC(=O)N(CC1CCCN(C(=O)OC(C)(C)C)C1)c1ccccc1
Reactant: O=Cc1ncc[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)N(CC1CCCN(Cc2ncc[nH]2)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.7 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added dropwise to a solution of N-(1-Boc-piperidin-3-ylmethyl)-N-phenyl-propionamide 5 (21 mg, 0.061 mmol) in 0.5 mL of dry CH2Cl2 at 0° C. (ice-water). The reaction mixture was stirred at room temperature for 30 minutes. TLC showed the reaction was complete. After removal of the solvents, the residue was dried under vacuum for 3 hrs. The crude compound was dissolved in DMF (0.5 mL) and 2-imidazole carboxaldehyde (8.7 mg, 1.5 eq.) was added. The mixture was stirred at room temperature for 30 min. NaB(OAc)3H (95%, 20.3 mg, 1.5 eq.) was introduced in one portion, and the mixture was shaken at room temperature overnight. The mixture was quenched with 5 mL of aqueous potassium carbonate (sat.), then extracted with ethyl acetate (3×10 mL). The extracts were combined and washed with aqueous NaHCO3 (sat., 2×5 mL), brine (10 mL), and dried over anhydrous sodium sulfate. After the solvent was removed, the remaining oily residue was purified by preparative thin layer chromatography (EtOAc/MeOH, 9:1) to afford N-[1-(1H-Imidazol-2-ylmethyl)-piperidin-3-ylmethyl]-N-phenyl-propionamide 11 as a colorless oil (10.7 mg, 54%). LRMS 327.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:19]3=[C:20]4[N:15]([CH:16]([CH3:21])[CH2:17][CH2:18]3)[CH:14]=[C:13]([C:22]([OH:24])=[O:23])[C:12](=[O:25])[C:11]4=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Cl:26][CH2:27][C:28](Cl)=[O:29]>C(O)(=O)C>[OH2:23].[Cl:26][CH2:27][C:28]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:19]3=[C:20]4[N:15]([CH:16]([CH3:21])[CH2:17][CH2:18]3)[CH:14]=[C:13]([C:22]([OH:24])=[O:23])[C:12](=[O:25])[C:11]4=[CH:10][CH:9]=2)=[CH:4][CH:3]=1)=[O:29]
Reactant: CC1CCc2c(-c3ccc(N)cc3)ccc3c(=O)c(C(=O)O)cn1c23
Reactant: O=C(Cl)CCl
Solvent: CC(=O)O
Product: CC1CCc2c(-c3ccc(NC(=O)CCl)cc3)ccc3c(=O)c(C(=O)O)cn1c23
Product: O
Reaction time: 0.33 h

Procedure:
To a 0.8 g sample of 8-(4-aminophenyl)-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid in 5 ml of hot acetic acid was added dropwise 0.3 ml of chloroacetyl chloride. The resulting solution was cooled and stirred for 20 minutes and then filtered. The solid was dried to provide golden crystals of 8-(4-chloroacetamidophenyl)-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid hydrate, m.p. 297° C. Analysis: Calculated for C22H19N2O4Cl.0.5 H2O: %C, 63.4; %H, 4.6; %N, 6.7; Found: %C, 62.9; %H, 4.8; %N, 6.7. The structural assignment was confirmed by infrared and nuclear magnetic resonance spectral analyses.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[NH:14][N:13]=[CH:12][CH:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O[CH2:16][C@H:17]([NH:20]C(=O)OC(C)(C)C)[CH2:18][CH3:19]>>[ClH:1].[NH2:20][C@H:17]([CH2:18][CH3:19])[CH2:16][N:13]1[CH:12]=[CH:11][C:10]([C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[CH:9]=2)=[N:14]1
Reactant: N#Cc1ccc(-c2ccn[nH]2)cc1Cl
Reactant: CC[C@H](CO)NC(=O)OC(C)(C)C
Product: CC[C@@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: Cl
Yield: 54.2 %

Procedure:
The Mitsunobu reaction was conducted as described in Example 3(c) using 2-chloro-4-(1H-pyrazol-5-yl)benzonitrile (0.60 g, 2.95 mmol) and (R)-tert-butyl 1-hydroxybutan-2-ylcarbamate (0.61 g, 3.24 mmol) as starting materials. 0.249 g (31%) of the title compound was obtained after workup. 1H-NMR (400 MHz; d6-DMSO): δ 0.91 (t, 3H), 1.22 (d, 3H), 3.33 (broad s, NH2HCl overlapping with water) 3.99 (dd, 1H), 4.12 (dd, 1H), 4.44-4.86 (m, 1H), 6.97 (d, 1H), 7.86 (d, 1H), 7.92-7.99 (m, 2H), 8.11 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([N:7]2[N:11]=[N:10][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8]2)[S:4][C:3]=1[C:18]([OH:20])=O.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.[CH2:51]([NH2:58])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>CN(C)C=O.ClCCl>[CH2:51]([NH:58][C:18]([C:3]1[S:4][C:5]([N:7]2[N:11]=[N:10][C:9]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[N:8]2)=[CH:6][C:2]=1[CH3:1])=[O:20])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: NCc1ccccc1
Reactant: Cc1cc(-n2nnc(-c3ccccc3)n2)sc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(-n2nnc(-c3ccccc3)n2)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 10 %

Procedure:
To a solution of 3-methyl-5-(5-phenyl-2H-tetrazol-2-yl)thiophene-2-carboxylic acid (0.12 g, 0.40 mmol) in anhydrous N,N-dimethylformamide (5 mL) was added 1-hydroxybenzotriazole (0.65 g, 0.48 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (0.09 g, 0.48 mmol), N,N-diisopropylethylamine (0.21 mL, 1.20 mmol) and benzylamine (0.05 mL, 0.48 mmol). The reaction mixture was stirred at ambient temperature for 18 hours, diluted with dichloromethane (30 mL) and washed with saturated aqueous sodium bicarbonate (5 mL) and brine (5 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography to afford the title compound as a white solid in 10% yield (0.02 g): mp 155-158° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.23-8.19 (m, 2H), 7.53-7.51 (m, 4H), 7.39-7.35 (m, 5H), 6.09 (br s, 1H), 4.65 (d, J=6.0, 2H), 2.58 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 165.4, 161.9, 140.1, 137.6, 130.9, 129.1, 129.0, 128.9, 128.8, 127.9, 127.8, 127.1, 126.4, 122.7, 44.3, 16.2; MS (ES+) m/z 376.3 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])[CH3:2].Cl[C:11]([CH3:19])([CH2:13][CH2:14][C:15](Cl)([CH3:17])[CH3:16])[CH3:12].C1(O)C=CC=CC=1>>[CH2:1]([C:3]1[C:4]([OH:9])=[CH:5][C:6]2[C:11]([CH3:19])([CH3:12])[CH2:13][CH2:14][C:15]([CH3:17])([CH3:16])[C:7]=2[CH:8]=1)[CH3:2]
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Reactant: CCc1ccccc1O
Solvent: Oc1ccccc1
Product: CCc1cc2c(cc1O)C(C)(C)CCC2(C)C

Procedure:
In a manner similar to Example 7(a) above, by the reaction of 15 g (0.123 mol) of 2-ethylphenol with 22.5 g (0.123 mol) of 2,5-dichloro-2,5-dimethylhexane, 25.4 g (89%) of the expected phenol of melting point 88-9° C. were obtained after chromatography on a silica column eluted with dichloromethane.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].Br[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[CH2:14]([O:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[Br:1])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(O)c(Br)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccc(OCc2ccccc2)c(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 66.6E (53.2 g, 230 mmol) in DMSO (45.0 mL) was added 1-(bromomethyl)benzene (35.6 mL, 299 mmol). After cooling in an ice water bath, cesium carbonate (128 g, 391 mmol) was carefully added to the mixture, and the mixture was allowed to warm to room temperature. After overnight stirring, the mixture was diluted with water and extracted three times with EtOAc. The organic layers were combined and then washed with brine. After drying over anhydrous magnesium sulfate and filtration, the organic solvent was removed under reduced pressure to yield 66.11C as a white solid.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]([CH3:8])[CH2:6][CH2:5][CH2:4][CH:3]1[NH2:9].Cl[C:11](OC1C=CC([N+]([O-])=O)=CC=1)=[O:12].C(N(C(C)C)CC)(C)C.[Cl:32][C:33]1[CH:42]=[C:41]2[C:36]([C:37]([N:43]3[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]3)=[CH:38][CH:39]=[N:40]2)=[CH:35][CH:34]=1>C(Cl)Cl.CO>[Cl:32][C:33]1[CH:42]=[C:41]2[C:36]([C:37]([N:43]3[CH2:48][CH2:47][N:46]([C:11]([NH:9][CH:3]4[CH2:4][CH2:5][CH2:6][CH:7]([CH3:8])[CH:2]4[CH3:1])=[O:12])[CH2:45][CH2:44]3)=[CH:38][CH:39]=[N:40]2)=[CH:35][CH:34]=1
Reactant: CC1CCCC(N)C1C
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Product: CC1CCCC(NC(=O)N2CCN(c3ccnc4cc(Cl)ccc34)CC2)C1C

Procedure:
As described for example 78, 2,3-dimethyl-cyclohexanamine (154 mg, 1.21 mmol), 4-nitrophenyl chloroformate (244 mg, 1.21 mmol), diisopropyl(ethyl)amine (209 mg, 1.62 mmol), and 7-chloro-4-(piperazin-1-yl)quinoline (200 mg, 0.81 mmol) are reacted affording the title product after flash chromatography with CH2Cl2-MeOH. 1H NMR (DSMO-d6) δ 0.7–0.9 (m, 7H), 1.13–1.92 (m, 8H), 3.2 (m, 1H), 3.6 (br. s, 4H), 3.9 (br. s, 4H), 7.2 (m, 1H), 7.7 (m, 1H), 8.0 (s, 1H), 8.2 (m, 1H), 8.6 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:9][C:10]2[CH:15]=[C:14]([NH:16][CH2:17][CH:18]3[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]3)[C:13]([N+:31]([O-])=O)=[CH:12][N:11]=2)=[N:7][CH:8]=1)#[N:2].O.[Sn](Cl)Cl>C(O)C>[NH2:31][C:13]1[C:14]([NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]2)=[CH:15][C:10]([NH:9][C:6]2[CH:5]=[N:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=2)=[N:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(CNc2cc(Nc3cnc(C#N)cn3)ncc2[N+](=O)[O-])C1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCC(CNc2cc(Nc3cnc(C#N)cn3)ncc2N)C1
Temperature: 70 °C
Yield: 56.2 %

Procedure:
tert-Butyl 3-((2-(5-cyanopyrazin-2-ylamino)-5-nitropyridin-4-ylamino)methyl)piperidine-1-carboxylate (265 mg, 0.583 mmol) was dissolved in ethanol (20 mL) and tin (II) chloride hydrate (658 mg, 2.92 mmol) was added. The suspension was heated for 30 min at 70° C. Solvents were removed by evaporation and the residue was dissolved in ethyl acetate and aqueous saturated sodium hydrogen carbonate. The mixture was filtered and the residue was washed thoroughly with ethyl acetate. The two phases of the filtrate were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried (Na2SO4) and solvent was removed by evaporation affording tert-butyl 3-((5-amino-2-(5-cyanopyrazin-2-ylamino)pyridin-4-ylamino)methyl)piperidine-1-carboxylate (139 mg, 56%). The crude product was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[OH-].[K+].F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([CH3:21])[CH:13]=1.[OH-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([CH3:21])[CH:13]=1
Reactant: Oc1cccc(Cl)c1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2cccc(Cl)c2)ccc1[N+](=O)[O-]
Temperature: 110 °C
Yield: 47.1 %

Procedure:
To a suspension of 3-chloro-phenol (1.65 g, 12.89 mmol) in DMF (10 mL), was added KOH (1.45 g, 25.78 mmol) and the mixture heated at 110° C. for 30 min. The mixture was cooled to 25° C. and 4-fluoro-2-methyl-1-nitro-benzene (0.5 g, 3.22 mmol) was added. This mixture was then heated to 130° C. for 12 h. The reaction mixture was treated with 10% NaOH solution and extracted with EtOAc (3×25 mL). The organic phase was washed with brine (3×5 mL), dried over sodium sulfate and concentrated. The residue was purified by column chromatography (silica, 0.5% EtOAc in hexanes) to afford 4-(3-chloro-phenoxy)-2-methyl-1-nitro-benzene (400 mg, 47%). MS (M+H)+=263; 1H NMR (CDCl3) δ: 8.05 (d, J=7.1 Hz, 1H), 7.33 (t, J=6.0 Hz, 1H), 7.20 (d, J=5.3 Hz, 1H), 7.06 (s, 1H), 7.03-6.85 (m, 3H), 2.59 (s, 3H).