Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)CCN(C)C.[Li]CCCC.[C:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[SH:24])([CH3:17])([CH3:16])[CH3:15].[Li]C(CC)C.[Br:30]C(F)(F)C(F)(F)Br>C1CCCCC1.C1COCC1>[Br:30][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:14]([CH3:17])([CH3:15])[CH3:16])[C:19]=1[SH:24]
Reactant: FC(F)(Br)C(F)(F)Br
Reactant: CC(C)(C)c1ccccc1S
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CC(C)(C)c1cccc(Br)c1S
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a solution of tetramethylethylenediamine (198.4 mmol, 30 mL) in cyclohexane (140 mL) is slowly added n-BuLi (198.4 mmol, 99.2 mL; 2M solution in cyclohexane) at 23° C. The resulting solution is cooled to 0° C. A solution of 2-tert-butylthiophenol (15.0 g, 90.2 mmol) in cyclohexane (40 mL) is then added at a rate such that the temperature stays below 10° C. The reaction is then stirred at 0° C. for 5 h and is then allowed to warm to 23° C. overnight. To the resulting yellow solution at 23° C. is added sec-BuLi (90.2 mmol, 69.4 mL of 1.3M solution in cyclohexane) over 0.5 h. The resulting solution gradually turns orange. After 1.5 h, the orange, cloudy reaction mixture is cannulated into a stirring solution of 1,2-dibromotetrafluoroethane (180.4 mmol, 21.5 mL) in THF (50 mL) over 1 h. After addition is complete, the resulting reaction mixture is quenched with 1N HCl (80 mL), and extracted with hexanes (3×100 mL). The hexanes are dried (MgSO4) and evaporated to a dark oil (29.48 g). This oil is taken up in 1N NaOH (100 mL), and extracted with CH2 Cl2 (3×50 mL). The organic phase is discarded, and the aqueous phase is acidified with 12N HCl, and extracted with CH2Cl2 (3×100 mL). The organic phase is dried (MgSO4) and evaporated to provide the title compound as a yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:12]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:22]=2)([CH3:20])[CH2:13][CH2:14][C:15](OCC)=[O:16])[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[NH2:32][CH:33]1[CH2:38][C:37]([CH3:40])([CH3:39])[NH:36][C:35]([CH3:42])([CH3:41])[CH2:34]1>>[C:1]([C:5]1[CH:6]=[C:7]([C:12]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([C:28]([CH3:29])([CH3:30])[CH3:31])[CH:22]=2)([CH3:20])[CH2:13][CH2:14][C:15]([NH:32][CH:33]2[CH2:34][C:35]([CH3:42])([CH3:41])[NH:36][C:37]([CH3:40])([CH3:39])[CH2:38]2)=[O:16])[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOC(=O)CCC(C)(c1ccc(O)c(C(C)(C)C)c1)c1ccc(O)c(C(C)(C)C)c1
Reactant: CC1(C)CC(N)CC(C)(C)N1
Product: CC1(C)CC(NC(=O)CCC(C)(c2ccc(O)c(C(C)(C)C)c2)c2ccc(O)c(C(C)(C)C)c2)CC(C)(C)N1

Procedure:
Reacting ethyl 4,4-bis-(3-tert.-butyl-4-hydroxyphenyl)-valerate analogously with 4-amino-2,2,6,6-tetramethylpiperidine produces 4-[4,4-bis-(3-tert.-butyl-4-hydroxyphenyl)-valeramido]-2,2,6,6-tetramethylpiperidine having a melting point 133°.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:7]=[C:8]([CH3:29])[CH:9]=[C:10]2[C:15]=1[N:14](C(OCC(C)C)=O)[CH:13]=[C:12]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:11]2=[O:28])(=O)C.BrN1C(=O)CCC1=O.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.C(O)C>ClCCl>[CH:5]([C:6]1[CH:7]=[C:8]([CH2:29][N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)[CH:9]=[C:10]2[C:15]=1[N:14]=[CH:13][C:12]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:11]2[OH:28])=[O:4]
Reactant: C1COCCN1
Reactant: CCOC(=O)c1cn(C(=O)OCC(C)C)c2c(COC(C)=O)cc(C)cc2c1=O
Agent: O=C1CCC(=O)N1Br
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1cnc2c(C=O)cc(CN3CCOCC3)cc2c1O
Reaction time: 0.17 h

Procedure:
A stirred solution of 3-ethyl 1-isobutyl 8-((acetyloxy)methyl)-6-methyl-4-oxo-1,3-(4H)-quinolinedicarboxylate (Preparation 26, 3.0 g) and N-bromosuccinimide (3.0 g) in dichloromethane (300 mL) is irradiated with a 650 watt sun lamp for 20 min. Morpholine (15 mL) is added to the solution. After 10 min, ethanol (20 mL) is added, and the solvents are removed at 50° C./20 mm. The reaction is repeated on the same scale. The reaction mixtures are combined and partitioned between chloroform (250 mL) and water (150 mL). The chloroform layer is washed twice with water, and the chloroform is evaporated. The residual oil is chromatographed on silica gel (1% methanol/chloroform) to give 2.15 g of the title compound. Physical characteristics: M.p. 202-204° C.; 1H NMR (CDCl3) δ1.43, 2.50, 3.69, 3.74, 4.42, 8.19, 8.59, 8.67, 10.18, 11.8. Anal. Found: C, 62.42; H, 5.92; N, 8.03.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].Cl[CH2:10][CH2:11][CH2:12][C:13](O)=[O:14]>Cl>[NH:7]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[N:8]=[C:10]1[CH2:11][CH2:12][CH2:13][OH:14]
Reactant: Nc1ccccc1N
Reactant: O=C(O)CCCCl
Agent: Cl
Product: OCCCc1nc2ccccc2[nH]1
Yield: 42.6 %

Procedure:
A mixture of 1,2-Phenylenediamine (1.0 g, 12.0 mmol) and 4-chlorobutyric acid (1.5 mL, 15.17 mmol) were refluxed in 4N HCl (13 mL) for 16 hours under N2 to give the title compound as white solid (900 mg, 50%). 1H NMR (CD3OD) □2.04-2.08 (m, 2H), 2.97 (t, 2H, J=7.8 Hz), 5.64 (t, 2H, J=6.6 Hz), 7.15-7.21 (m, 2H), 7.47-7.49 (m, 2H); ES-MS m/z 177.1 (M+H).
Reaction SMILES: [BH4-].[Na+].C([O:6][C:7]1[C@:8]2([CH2:24][CH2:23][C@H:22]3[C@@H:13]([C@H:14]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][O:38][C:39](=[O:41])[CH3:40])[CH2:15][C:16]4[CH:17]=[C:18]([O:25][CH2:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH:19]=[CH:20][C:21]=43)[C:10]2=[CH:11][CH:12]=1)[CH3:9])(=O)C.C(O)(=O)C>C(O)C.O>[C:39]([O:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][C@@H:14]1[CH2:15][C:16]2[CH:17]=[C:18]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:19]=[CH:20][C:21]=2[C@@H:22]2[C@@H:13]1[C:10]1[C@@:8]([CH2:24][CH2:23]2)([CH3:9])[C@@H:7]([OH:6])[CH2:12][CH:11]=1)(=[O:41])[CH3:40]
Reactant: CC(=O)OCCCCC[C@@H]1Cc2cc(OCc3ccccc3)ccc2[C@H]2CC[C@]3(C)C(OC(C)=O)=CC=C3[C@H]12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)OCCCCC[C@@H]1Cc2cc(OCc3ccccc3)ccc2[C@H]2CC[C@@]3(C)C(=CC[C@@H]3O)[C@H]12
Reaction time: 1 h
Yield: 51 %

Procedure:
A solution of 1.25 g of sodium borohydride in 90 ml of ethanol and 18 ml of water is added in drops to a solution of 4.58 g of 17-acetoxy-7α-(5-acetoxypentyl)-3-benzyloxy-estra-1,3,5(10),14,16-pentaene in 26.8 ml of tetrahydrofnfiran and 161 ml of ethanol at room temperature, and the mixture is stirred for 1 hour. The reaction mixture is mixed with 4 ml of glacial acetic acid, concentrated by evaporation, and the residue is taken up in ethyl acetate. The organic phase is washed with sodium bicarbonate, dried on sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with hexane/ethyl acetate. 2.16 g of 7α-(5-acetoxypentyl)-3-benzyloxy-estra-1,3,5(10),14-tetraen-17β-ol is obtained as foam.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:23][CH2:24][CH:25]=[O:26])[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:27]1([Mg]Br)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.[Mg].C1(Br)CCCCC1>O1CCCC1.CCOCC>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:23][CH2:24][CH:25]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[OH:26])[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CCCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reactant: Br[Mg]C1CCCCC1
Agent: [Mg]
Solvent: BrC1CCCCC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC(CCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)C1CCCCC1
Reaction time: 0.25 h

Procedure:
A solution of 0.4 g of 3-(3,4-dibenzyloxyphenyl)propionaldehyde in 5 ml of anhydrous tetrahydrofuran was cooled to 0° to 5° C. and then 5 ml of an ether solution of cyclohexyl magnesium bromide prepared from 0.12 g of metallic magnesium and 0.82 g of cyclohexyl bromide was added dropwise to the solvent. Thereafter, the reaction mixture was stirred for 15 minutes and after adding thereto 50 ml of an aqueous 5% hydrochloric acid solution, the product was extracted with 30 ml of toluene. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to provide an oily product. The product was applied to silica gel column chromatography and eluted with toluene to provide 0.2 g of 3-(3,4-dibenzyloxyphenyl)-1-cyclohexyl-1-propanol.
Reaction SMILES: [Cl-].CS(C)=[O:4].ClCCl.[F:9][C:10]1[C:15]2[CH:16]=C(O)[O:18][C:14]=2[C:13]([F:20])=[CH:12][CH:11]=1.C(N([CH2:26][CH3:27])CC)C>O>[F:9][C:10]1[C:15]2[CH:16]=[C:27]([CH:26]=[O:4])[O:18][C:14]=2[C:13]([F:20])=[CH:12][CH:11]=1
Reactant: Oc1cc2c(F)ccc(F)c2o1
Reactant: CCN(CC)CC
Reactant: CS(C)=O
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: O=Cc1cc2c(F)ccc(F)c2o1
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
Oxazalyl chloride (0.26 ml) was added to 0.42 ml dimethyl sulfoxide and 7 ml dichloromethane at −78° C. and stirred for 3 minutes at the same temperature. 272 mg of the 4,7-difluoro-2-hydroxybenzofuran was added thereto at the same temperature and stirred for 40 minutes. After 1.2 ml triethylamine was added to the reaction mixture, the temperature was raised to room temperature, and the mixture was stirred at room temperature for 30 minutes. After water was added to the reaction mixture, it was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and then evaporated. The resulting residue was subjected to silica gel chromatography (developing solvent: 5% ethyl acetate/n-hexane) to give 169 mg of 4,7-difluorobenzofuran-2-carbaldehyde as a colorless solid.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[NH:26][C:27](=[O:31])[CH:28]([CH3:30])[NH2:29].C(N(CC)CC)C>O1CCOCC1>[Cl:15][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:29][CH:28]([C:27](=[O:31])[NH:26][C:17]1[CH:18]=[CH:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:16]=1)[CH3:30])[C:11]([C:12]([OH:14])=[O:13])=[CH:10]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: CC(N)C(=O)Nc1ccc2ccccc2c1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(Nc1nc2ccc(Cl)cc2cc1C(=O)O)C(=O)Nc1ccc2ccccc2c1
Temperature: 135 °C
Reaction time: 24 h
Yield: 59.5 %

Procedure:
A mixture of 2,6-dichloroquinoline-3-carboxylic acid (194 mg, 0.8 mmol), DL-alanine-β-naphthylamide (251 mg, 1 mmol) and triethylamine (900 mg, 8.9 mmol) in dioxane (1 mL) is stirred for 24 h at 135° C. in closed reaction vial. After evaporation of solvents in vacuo, the residue is acidified by addition of 2N HCl, and the precipitated solid is collected on filter, washed with water and recrystallized from MeOH-water to give the title compound (200 mg, 60%) as yellow needles.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH2:5][CH2:4][N:3]1[C:13](Cl)=[O:14].[CH3:16][N:17]1[CH:21]=[C:20]([C:22]2[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]3[CH:30]=[CH:31][C:32]([NH2:35])=[N:33][CH:34]=3)[CH:23]=2)[CH:19]=[N:18]1>C(Cl)Cl>[CH3:16][N:17]1[CH:21]=[C:20]([C:22]2[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]3[CH:30]=[CH:31][C:32]([NH:35][C:13]([N:3]4[CH2:4][CH2:5][N:6]([CH:7]5[CH2:12][CH2:11][O:10][CH2:9][CH2:8]5)[C:2]4=[O:1])=[O:14])=[N:33][CH:34]=3)[CH:23]=2)[CH:19]=[N:18]1
Reactant: O=C(Cl)N1CCN(C2CCOCC2)C1=O
Reactant: Cn1cc(-c2cc(Oc3ccc(N)nc3)ncn2)cn1
Solvent: ClCCl
Product: Cn1cc(-c2cc(Oc3ccc(NC(=O)N4CCN(C5CCOCC5)C4=O)nc3)ncn2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
A 0° C. solution of Example B2 (0.14 g, 0.60 mmol) in DCM (3 mL) was treated drop-wise with a solution of 5-((6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)pyridin-2-amine (0.08 g, 0.30 mmol) and TEA (0.1 mL, 0.9 mmol) in DCM (2 mL), warmed to RT and stirred for 2 h. The mixture was concentrated to dryness, purified via silica gel chromatography (MeOH/DCM), treated with Et2O and the resulting solid collected via filtration to afford N-(5-((6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (93 mg, 67%). 1H NMR (400 MHz, DMSO-d6): δ 10.94 (s, 1 H), 8.62 (d, J=1.1 Hz, 1 H), 8.46 (s, 1 H), 8.22 (m, 1 H), 8.16 (d, J=0.7 Hz, 1 H), 8.04 (d, J=9.0 Hz, 1 H), 7.74 (dd, J=9.0, 2.9 Hz, 1 H), 7.42 (d, J=1.1 Hz, 1 H), 3.89 (s, 3 H), 4.00-3.70 (m, 5 H), 3.42-3.39 (m, 4 H), 1.76-1.65 (m, 2 H), 1.59 (m, 2 H); MS (ESI) m/z: 465.2 (M+H+).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:11](=[O:12])[N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])=[O:21])[CH:14]=2)[C:9]2[N:31]=[CH:32][CH:33]=[CH:34][C:8]=2[N:7]=1)([OH:3])=O.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.[CH3:56][N:57]1[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1>O1CCOCC1.C(OCC)(=O)C>[CH3:30][O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[NH:22][C:20](=[O:21])[NH:19][C:15]1[CH:14]=[C:13]([N:10]2[C:11](=[O:12])[C:6]([CH2:5][CH2:4][C:1]([N:60]3[CH2:61][CH2:62][N:57]([CH3:56])[CH2:58][CH2:59]3)=[O:3])=[N:7][C:8]3[CH:34]=[CH:33][CH:32]=[N:31][C:9]2=3)[CH:18]=[CH:17][CH:16]=1
Reactant: CN1CCNCC1
Reactant: COc1ccccc1NC(=O)Nc1cccc(-n2c(=O)c(CCC(=O)O)nc3cccnc32)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccccc1NC(=O)Nc1cccc(-n2c(=O)c(CCC(=O)N3CCN(C)CC3)nc3cccnc32)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred suspension of 2-(2-carboxyethyl)-3-oxo-4-(3-[3-(2-methoxyphenyl)ureido]phenyl]-3,4-dihydropyrido[2,3-b]pyrazine (115 mg) and 1-hydroxybenzotriazole (40 mg) in dry dioxane (10 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (47 mg) and N-methylpiperazine (30 mg). The mixture was stirred at room temperature for 4 hours, diluted with ethyl acetate, washed with water. After evaporation of the solvents, crude residue was crystallized from ethanol to give 4-[3-[3-(2-methoxyphenyl)ureido]phenyl]-2-[2-(4-methylpiperazin-1-yl)carbonylethyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine.
Reaction SMILES: CO[C:3](=[O:37])[N:4]=[C:5](SC)[C:6]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28](=[O:31])[NH:29][CH3:30])=[C:22]([O:32][CH2:33][CH3:34])[CH:21]=1)=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=C(C)O[N:15]=2)=[CH:10][CH:9]=1.[CH3:38][C:39]1[C:40]([NH:45][NH2:46])=[N:41][CH:42]=[CH:43][CH:44]=1.C[O:48]C(=O)N=C(SC)C(C1C=C(OC)C2OCOCC=2C=1)=NC1C=CC(C2N=C(C)ON=2)=CC=1.N(C1N=CC=CN=1)N>>[C:33]([OH:48])(=[O:32])[CH3:34].[C:14]([C:11]1[CH:12]=[CH:13][C:8]([NH:7][CH:6]([C:5]2[NH:4][C:3](=[O:37])[N:45]([C:40]3[C:39]([CH3:38])=[CH:44][CH:43]=[CH:42][N:41]=3)[N:46]=2)[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]([NH:29][CH3:30])=[O:31])=[C:22]([O:32][CH2:33][CH3:34])[CH:21]=2)=[CH:9][CH:10]=1)(=[NH:18])[NH2:15]
Reactant: CCOc1cc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)ccc1OCC(=O)NC
Reactant: Cc1cccnc1NN
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc2c(c(OC)c1)OCOC2
Agent: NNc1ncccn1
Product: CC(=O)O
Product: CCOc1cc(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccc3C)c(=O)[nH]2)ccc1OCC(=O)NC

Procedure:
The same procedure was carried out as in Examples (21i)-(21j), except that {2-(3-ethoxy-4-methylcarbamoylmethoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester (Example (126a)) and (3-methylpyridin-2-yl)hydrazine were used instead of respectively the {2-(8-methoxy-4H-benzo[1,3]dioxin-6-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester in Example (21i) and 2-hydrazinopyrimidine in Example (21i), to give the title compound.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].Br[C:16]1[CH:20]=[CH:19][S:18][CH:17]=1>CCOCC.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:3]([C:16]1[CH:20]=[CH:19][S:18][CH:17]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: Brc1ccsc1
Reactant: CCCCCCCCCCCCBr
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: [Mg]
Solvent: CCOCC
Product: CCCCCCCCCCCCc1ccsc1
Yield: 84.9 %

Procedure:
Dried ethyl ether (40 ml) was added to activated magnesium (1.22 g; 50 mmol), and 1-bromododecane (12.46 g; 50 mmol) was added thereto to prepare a Grignard reagent. Then, Ni(dppp)Cl2 (33 mg) was added thereto, and 3-bromothiophene (8 g; 49 mmol) dissolved in 10 ml of ether was slowly added dropwise. The reaction solution was refluxed for one day, and then a mixture of 2N HCl/ice (50 ml) was added to terminate the reaction. The resultant was extracted from ethyl ether, and the solvent was distilled off under reduced pressure. The residue was dissolved in DMF (50 ml) and filtered to remove remaining paraffin. The filtrate was concentrated, and then the residue was distilled off under vacuum to obtain a colorless liquid 3-dodecylthiophene (10.5 g; 85%).
Reaction SMILES: C(O[C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]([OH:12])=O)=[O:7])(C)(C)C.C(OC(NC(C(C)(C)C)C(O)=O)=O)(C)(C)C.[NH2:36][C@H:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39][C@H:38]1[OH:46].C(OC(=O)NC(C(=O)NC1C2C(=CC=CC=2)CC1O)C(C)(C)C)(C)(C)C.ClNC(=O)[O-].C([O:80][C:81]([C:83]1([NH:88][C:89]([CH:91]2[CH2:95][CH:94]([O:96][C:97]3[C:106]4[C:101](=[CH:102][C:103]([O:107][CH3:108])=[CH:104][CH:105]=4)[N:100]=[C:99]([C:109]4[CH:114]=[CH:113][CH:112]=[CH:111][CH:110]=4)[CH:98]=3)[CH2:93][N:92]2C(=O)NC(C(=O)NC2C3C(=CC=CC=3)CC2O)C(C)(C)C)=[O:90])[CH2:85][CH:84]1[CH:86]=[CH2:87])=[O:82])C>>[OH:46][C@@H:38]1[CH2:39][C:40]2[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=2)[C@@H:37]1[NH:36][C:10]([C@@H:9]([NH:8][C:6]([N:92]1[CH2:93][C@H:94]([O:96][C:97]2[C:106]3[C:101](=[CH:102][C:103]([O:107][CH3:108])=[CH:104][CH:105]=3)[N:100]=[C:99]([C:109]3[CH:114]=[CH:113][CH:112]=[CH:111][CH:110]=3)[CH:98]=2)[CH2:95][C@H:91]1[C:89]([NH:88][C@:83]1([C:81]([OH:82])=[O:80])[CH2:85][C@H:84]1[CH:86]=[CH2:87])=[O:90])=[O:7])[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:12]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)NC(C(=O)NC1c2ccccc2CC1O)C(C)(C)C)C(=O)OCC
Reactant: N[C@H]1c2ccccc2C[C@H]1O
Agent: CC(C)(C)OC(=O)NC(C(=O)NC1c2ccccc2CC1O)C(C)(C)C
Agent: CC(C)(C)OC(=O)NC(C(=O)O)C(C)(C)C
Agent: O=C([O-])NCl
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@H]1c2ccccc2C[C@H]1O)C(=O)O
Yield: 5 %

Procedure:
(2S)-tert-butoxycarbonylamino-3-phenylpropanoic acid was attached to the resin as described for the preparation of compound 16 followed by reaction with (1S,2R)-1-amino-2-indanol as described for the preparation of 17 and removal of the Boc group as described for 18. The afforded compound was then reacted with the chlorocarbamate achieved from 12 as described for the preparation of 13 which, after purification by HPLC, gave the title compound (2.4 mg, 5% yield), Purity by HPLC >95% M+H+796.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:16]([O:18]C)=O)[C:5]2[C:6]3[C:14](=O)[CH2:13][NH:12][CH2:11][C:7]=3[NH:8][C:9]=2[CH:10]=1.CN1CC2NC3C=CC=C4C(=O)[NH:35][N:36]=C(C=2C=34)C1.[CH3:38][C:39]([CH3:41])=O>>[F:1][C:2]1[CH:3]=[C:4]2[C:16](=[O:18])[NH:35][N:36]=[C:14]3[C:6]4[C:5]2=[C:9]([NH:8][C:7]=4[CH2:11][N:12]([CH:39]([CH3:41])[CH3:38])[CH2:13]3)[CH:10]=1
Reactant: CN1CC2=NNC(=O)c3cccc4[nH]c(c2c34)C1
Reactant: CC(C)=O
Reactant: COC(=O)c1cc(F)cc2[nH]c3c(c12)C(=O)CNC3
Product: CC(C)N1CC2=NNC(=O)c3cc(F)cc4[nH]c(c2c34)C1

Procedure:
Compound 46 was prepared from methyl 7-fluoro-4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate and acetone according to the procedures similar to those for Compound 44. 1H NMR (DMSO-d6) δ 11.8 (s, 1H), 10.1 (s, 1H), 7.35 (dd, 1H, J=2.4, 9.6 Hz), 7.18 (dd, 1H, J=2.4, 10.2 Hz), 3.82 (s, 2H), 3.32 (s, 2H), 2.98-3.00 (m, 1H), 1.09 (d, 6H, J=7.2 Hz). MS (ESI) m/e [M+1]+ 287.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19](O)=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][C:27]([F:36])([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23].[CH2:37]([S:39]([NH2:42])(=[O:41])=[O:40])[CH3:38]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:42][S:39]([CH2:37][CH3:38])(=[O:41])=[O:40])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][C:27]([F:36])([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:26][CH2:25]1)=[O:23]
Reactant: CCS(N)(=O)=O
Reactant: Cc1ccc(Cl)c(Nc2c(C(=O)N3CCC(F)(c4ccccc4)CC3)cnc3c(C(=O)O)cnn23)c1
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cc(C)ccc3Cl)c(C(=O)N3CCC(F)(c4ccccc4)CC3)cnc12
Yield: 21.5 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-chloro-5-methylphenylamino)-6-(4-fluoro-4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (71 mg, 0.14 mmol) obtained in step 2 and ethanesulfonamide (74 mg, 0.7 mmol), the title compound (18 mg, 22%) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8]C(C#N)=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:3]=1.[OH-:17].[Na+].Cl.[CH3:20][CH2:21][OH:22]>>[Br:1][C:2]1[CH:9]=[CH:8][C:20]([C:21]([OH:17])=[O:22])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:3]=1
Reactant: [OH-]
Reactant: CCO
Reactant: N#Cc1ccc(Br)cc1Oc1ccccc1
Agent: Cl
Agent: [Na+]
Product: O=C(O)c1ccc(Br)cc1Oc1ccccc1
Temperature: 25 °C

Procedure:
4-Bromo-2-phenoxy-benzonitrile (35.3 g, 129 mmol) was added to 130 mL EtOH, followed by the addition of 340 mL of 20% NaOH (aq). The reaction was heated to reflux for 20 h. The mixture was cooled to room temperature and poured into 6 N HCl to form a precipitate. The solid was collected by vacuum filtration and dissolved in 3:1 THF-ethyl ether and washed with brine. The organic phase was dried over magnesium sulfate, and concentrated. The solids were dried in a vacuum oven at 60° C. overnight to give 35.1 g (128 mmol) of the desired product. MS m/z (MH+) 292.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[CH2:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH:13]1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(OCC)C>[CH2:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH:13]1[O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6]
Reactant: COc1ccc(C=O)cc1O
Reactant: OC1Cc2ccccc2C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(C=O)cc1OC1Cc2ccccc2C1
Yield: 20.7 %

Procedure:
A solution of 3-hydroxy-4-methoxy-benzaldehyde (15.2 g, 100 mmol, 1 eq), 2-indanol (12.1 g, 90 mmol, 0.9 eq), and triphenylphosphine (26.2 g, 100 mmol, 1 eq) in dry THF (300 mL) was treated dropwise with diisopropylazodicarboxylate (19.6 mL, 100 mmol, 1 eq). The reaction mixture was stirred at reflux for 16 hours, then cooled and diluted with diethyl ether (500 mL). The solution was washed with water (2×150 mL), 1 M NAOH (4×125 mL), and saturated NaCl (sodium chloride) (2×100 mL), dried with CH2Cl2, then concentrated to provide a syrup, which solidified upon standing. The solid was suspended in diethyl ether (350 mL) and stirred overnight to break up all chunks. The solid was collected by vacuum filtration and recrystallized from ethanol/water (21.4 g). The ethereal filtrate was concentrated and purified by flash chromatography (silica gel, 7.5×36 cm Biotage KP-Sil column, eluted with 25% ethyl acetate in heptane) to yield an additional 5 g of product. 1H NMR (300 MHz, CDCl3) δ9.86 (s, 1H), 7.49-7.44 (m, 2H), 7.25-7.16 (m, 4H), 6.97 (d, J=8.7 Hz, 1H), 5.29-5.22 (m, 1H), 3.89 (s, 1H), 3.45 (dd, J=16.7, 6.6 Hz, 2H), 3.24 (dd, J=16.7, 3.6 Hz, 2H). 13C NMR (75 MHz, CDCl3) 190.9, 155.5, 147.9, 140.4, 130.0, 126.9, 126.8, 124.7, 112.1, 111.0, 78.9, 56.1, 39.7.