Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3([CH3:17])[O:16][CH2:15][CH2:14][O:13]3)=[CH:8][C:7]=2[C:18]2[C:19]3[N:26]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:25]([CH3:35])=[C:24]([C:36]([OH:38])=O)[C:20]=3[N:21]=[CH:22][N:23]=2)[CH2:3][CH2:2]1.[NH2:39][C@H:40]1[CH2:45][CH2:44][C@H:43]([NH:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])[CH2:42][CH2:41]1>>[C:49]([O:48][C:47](=[O:53])[NH:46][C@H:43]1[CH2:42][CH2:41][C@H:40]([NH:39][C:36]([C:24]2[C:20]3[N:21]=[CH:22][N:23]=[C:18]([C:7]4[CH:8]=[C:9]([C:12]5([CH3:17])[O:13][CH2:14][CH2:15][O:16]5)[CH:10]=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)[C:19]=3[N:26]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:32])[CH3:34])[C:25]=2[CH3:35])=[O:38])[CH2:45][CH2:44]1)([CH3:52])([CH3:50])[CH3:51]
Reactant: Cc1c(C(=O)O)c2ncnc(-c3cc(C4(C)OCCO4)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Product: Cc1c(C(=O)N[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)c2ncnc(-c3cc(C4(C)OCCO4)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(2-methyl-1,3-dioxolan-2-yl)phenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c13) and commercially available tert-butyl trans-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[C:25]([CH3:26])=[C:24]([CH3:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[N:16]=1>>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:15]2[N:16]=[C:11]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:12]3[C:25]([CH3:26])=[C:24]([CH3:27])[S:23][C:13]=3[N:14]=2)[CH:18]=1
Reactant: Cc1sc2nc(-c3cccnc3)nc(Cl)c2c1C
Reactant: NCc1ccc(F)cc1
Product: Cc1sc2nc(-c3cccnc3)nc(NCc3ccc(F)cc3)c2c1C

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(pyridin-3-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(4-fluorobenzylamino)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH:12]([CH3:15])[CH2:13][CH3:14])[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[BH4-].[Na+]>CO>[NH2:2][C@@H:3]([CH:12]([CH3:15])[CH2:13][CH3:14])[C@@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5]
Reactant: CCC(C)[C@H](N)C(=O)c1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCC(C)[C@H](N)[C@H](O)c1ccccc1
Temperature: 10 °C

Procedure:
The 2-(S)-amino-3-methyl-1-phenyl-1-pentanone hydrochloride (24.2 g, 0.106 mmol.) prepared above was dissolved in methanol (250 mL). The solution was stirred under chilling with ice to maintain the solution temperature at a temperature of lower than 10° C., and to this was portionwise added sodium borohydride (3.8 g, 0.10 mmol.). The reaction mixture was stirred for one hour at the same temperature, and concentrated under reduced pressure. To the residue were added chloroform (100 mL), water (50 mL), and 2N aqueous sodium hydroxide solution. The chloroform layer was separated, and the aqueous layer was subjected to extraction using chloroform. The chloroform portions were combined, successively washed with water and aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, to give the titled compound as a white crystalline product (17.8 g, yield: 87%).
Reaction SMILES: [C:1]1([C@H:7]2[NH:13][C:12](=[O:14])[C@@H:11]([NH:15][C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:10][S:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>O1CCCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.S([O-])([O-])(=O)=O.[Mg+2]>[O:14]=[C:12]1[C@@H:11]([NH:15][C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17])[CH2:10][S:9][CH2:8][C@@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:13]1[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CCOC(=O)CBr
Reactant: O=C(N[C@H]1CSC[C@@H](c2ccccc2)NC1=O)OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])[O-]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CN1C(=O)[C@@H](NC(=O)OCc2ccccc2)CSC[C@H]1c1ccccc1

Procedure:
A solution of (3R-cis)-tetrahydro-3-phenyl-6-[[(phenylmethoxy)carbonyl]amino]-1,4-thiazepine-5(4H)-one (1.16 g., 3.25 mmol) [prepared as described by Yanagisawa et al., J. Med. Chem., Vol. 30, p. 1984-1991 (1987)] in distilled tetrahydrofuran (30 ml.), under an atmosphere of argon, was cooled to 0° C. and treated with powdered potassium hydroxide (540 mg., 10 mmol) and tetrabutylammonium bromide (97 mg, 0.3 mmol). Ethyl bromoacetate (501 mg., 3 mmol) was added dropwise with stirring. The mixture was stirred cold for two hours and then additional ethyl bromoacetate (501 mg., 3 mmol) was added. The mixture was stirred cold for an additional two hours and then diluted with ethyl acetate (50 ml) and anhydrous magnesium sulfate was added. The reaction mixture was filtered through a magnesium sulfate pad and the pad was washed several times with ethyl acetate. The filtrate was poured into cold 1N hydrochloric acid solution (40 ml) and the layers were separated. The organic layer was dried (magnesium sulfate), filtered and freed of solvent in vacuo leaving an oil which was purified by chromatography on silica gel, eluting with 10-30% ethyl acetate in hexane to give 730 mg. of product; Rf =0.32 (ethyl acetate:hexanes, 1:2).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C@H:30]12[CH2:37][C@H:33]([C@@H:34]([OH:36])[CH2:35]1)[CH2:32][NH:31]2>>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20]([N:31]5[CH2:32][C@@H:33]6[CH2:37][C@H:30]5[CH2:35][C@@H:34]6[OH:36])=[O:21])=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25]([N:26]([CH3:28])[CH3:27])=[O:29])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O[C@H]1C[C@@H]2C[C@H]1CN2
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4C[C@@H]5C[C@H]4C[C@@H]5O)cn3)nc2n1C1CCCC1
Yield: 63 %

Procedure:
The 6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinic acid was combined with (1S,4S,5S)-2-azabicyclo[2.2.1]heptan-5-ol following amide formation method 3 which gave 7-cyclopentyl-2-(5-((1S,4S,5S)-5-hydroxy-2-azabicyclo[2.2.1]heptane-2-carbonyl)pyridin-2-ylamino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (40 mg, 63% yield). 1H NMR (400 MHz, CDCl3) δ ppm 9.84 (br. s., 0.4H, Rotamer) 9.54 (br. s., 0.6H, Rotamer) 8.98-8.82 (m, 1H) 8.80 (s, 0.4H, Rotamer) 8.59 (s, 0.6H, Rotamer) 8.57-8.48 (m, 1H) 7.97 (d, J=7.07 Hz, 0.4H, Rotamer) 7.86 (d, J=6.57 Hz, 0.6H, Rotamer) 6.46 (s, 1H) 4.78 (m, 1H) 4.74 (br. s., 0.4H, Rotamer) 4.46 (br. s., 1H) 4.17 (br. s., 0.6H, Rotamer) 4.07 (d, J=9.09 Hz, 0.4H, Rotamer) 3.91 (d, 1=11.62 Hz, 0.6H, Rotamer) 3.64-3.49 (m, 0.6H, Rotamer) 3.49-3.269 (m, 1H+0.4H, Rotamer) 3.15 (s, 6H) 2.73 (m, 0.6H, Rotamer) 2.67 (m, 0.4H, Rotamer) 2.57 (m, 2H) 2.25-1.92 (m, 5H) 1.81-1.42 (m, 5H) HR-MS (m/z MH+) 490.26 RT 4.25 min
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][C:14]=2[C:23]([O:25]C)=O.Cl.[OH-].[NH4+:29]>C1COCC1.C(OCC)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][C:14]=2[C:23](=[O:25])[NH2:29]
Reactant: [NH4+]
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccc1C
Agent: Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccccc1Cn1c2cccc(O)c2c2c(C(N)=O)cccc21
Yield: 36 %

Procedure:
A solution of the 9-[(2-methylphenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (260 mg, 0.75 mM) in 10 mL THF and 30 mL concentrated aqueous ammonium hydroxide was sonicated for 5 hours at 40-50° C. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted three times with ethyl acetate. The combined organic extracts were washed with H2O and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient hexanes/ethyl acetate) to afford 90 mg (36%) of the 9-[(2-methylphenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as a tan solid. 1H NMR (DMSO-d6) δ10.5 (s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H), 7.7 (m, 1H), 7.5 (m, 2H), 7.3 (m, 2H), 7.1 (t, 1H, J=8 Hz), 6.95 (d, 1H, J=8 Hz), 6.85 (t, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), 5.95 (d, 1H, J=8 Hz), 5.7 (s, 2H), and 2.5 (s, 3H). IR (KBr, cm−1) 3451, 3191, 1627, 1600, 1584, 1562, 1435, 1329, 1322, 1263, and 774. MS (ES) m/e 329, 331.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[N:13]=[CH:12][C:11]([C:14]([O:16]CC)=[O:15])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>CCO>[O:1]1[CH2:2][CH2:3][CH:4]([O:7][C:8]2[N:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: CCOC(=O)c1ccc(OC2CCOCC2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(OC2CCOCC2)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.4 %

Procedure:
Ethyl 6-(oxan-4-yloxy)pyridine-3-carboxylate (Intermediate 236, 0.239 g, 0.95 mmol) was dissolved in EtOH (5 mL), 2M aq. sodium hydroxide (1.43 mL, 2.85 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was concentrated under vacuum and the residue acidified to pH 6 by adding 2M aq. hydrochloric acid. The mixture was then extracted with DCM, followed by chloroform/isopropanol. The organic layer was separated using a hydrophobic frit and concentrated under vacuum to afford the title compound as a white solid (0.162 g, 47%), which was used directly in the next step without further purification. Method C HPLC-MS: MH+ requires m/z=224 Found: m/z=224, Rt=1.06 min (91%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([NH:9][CH2:10][CH2:11][C:12]2[CH:25]=[CH:24][C:15]([O:16][CH:17]([CH3:23])[C:18]([O:20]CC)=[O:19])=[CH:14][CH:13]=2)=[N:7][CH:8]=1)[CH3:2].[F:26][C:27]([F:38])([F:37])[O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1>>[CH2:1]([C:3]1[CH:8]=[N:7][C:6]([N:9]([CH2:33][C:32]2[CH:35]=[CH:36][C:29]([O:28][C:27]([F:26])([F:37])[F:38])=[CH:30][CH:31]=2)[CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:16][CH:17]([CH3:23])[C:18]([OH:20])=[O:19])=[CH:24][CH:25]=2)=[N:5][CH:4]=1)[CH3:2]
Reactant: CCOC(=O)C(C)Oc1ccc(CCNc2ncc(CC)cn2)cc1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Product: CCc1cnc(N(CCc2ccc(OC(C)C(=O)O)cc2)Cc2ccc(OC(F)(F)F)cc2)nc1

Procedure:
In a two-step sequence similar to the previous example, alkylation of the above intermediate ethyl 2-(4-{2-[(5-ethylpyrimidin-2-yl)amino]ethyl}phenoxy)propanoate with 4-trifluoromethoxy-benzylbromide (1 eq) (1.5 eq NaH; 80C) followed by hydrolysis of the intermediate ester afforded the title compound.
Reaction SMILES: [CH:1]1([CH:7]([NH:26][C:27]2[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][S:23][CH3:24])=[CH:15][CH:14]=3)[O:10][C:9]=2[CH3:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:36][NH:37][CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41].Cl.C(N=C=NCCCN(C)C)C.O.OC1C2N=NNC=2C=CC=1>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([N:37]([CH3:36])[CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[O:32])=[CH:29][CH:28]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][CH2:22][S:23][CH3:24])=[CH:17][CH:18]=3)[O:10][C:9]=2[CH3:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CSCCCOc1ccc(-c2cc(C(Nc3ccc(C(=O)O)cc3)C3CCCCC3)c(C)o2)cc1
Reactant: CCOC(=O)CCNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2cc(-c3ccc(OCCCSC)cc3)oc2C)C2CCCCC2)cc1
Yield: 100 %

Procedure:
A solution of 4-{[cyclohexyl(2-methyl-5-{4-[3-(methylsulfanyl)propoxy]phenyl}furan-3-yl)methyl]amino}benzoic acid (494 mg), ethyl 3-(methylamino)propanoate (157 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (230 mg), hydroxybenzotriazole monohydrate (184 mg) and triethylamine (167 μL) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 4 hr. Ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and water, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (607 mg, 100%) as an oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[N:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:26][NH:27][O:28][CH3:29]>CN(C=O)C>[CH3:29][O:28][N:27]([CH3:26])[C:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][N:2]=1)=[O:12]
Reactant: O=C(O)c1n[nH]c2ccccc12
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1n[nH]c2ccccc12
Temperature: 62.5 °C
Yield: 78.9 %

Procedure:
1H-indazole-3-carboxylic acid (CX) (100 g, 617 mmol) in DMF was treated with carbonyldiimidazole (110 g, 678 mmol) at room temperature until the evolution of gas ceased (ca. 15 minutes). The reaction was heated to 60-65° C. for 2 h and then allowed to cool to room temperature. N,O-Dimethylhydroxylamine-HCl (66.2 g, 678 mmol) was added as a solid and the mixture was heated to 65° C. for 3 h. The reaction was concentrated to a paste, taken up in DCM and washed subsequently with water and 2 N HCl. The product could be seen coming out of solution. The solid was filtered and rinsed separately with EtOAc. The EtOAc and DCM layers were separately washed with sodium bicarbonate followed by brine, dried over MgSO4 and concentrated under reduced pressure. The resulting solids were combined, triturated with 1:1 mixture of DCM-ether, filtered, and dried to produce N-methoxy-N-methyl-1H-indazole-3-carboxamide (CXI) as a white solid (100 g, 487 mmol, 79% yield). 1H NMR (DMSO-d6) δ ppm 3.46 (s, 3H), 3.69-3.85 (m, 3H), 7.13-7.31 (m, 1H), 7.41 (t, J=7.25 Hz, 1H), 7.56-7.65 (m, 1H), 7.93-8.08 (m, 1H); ESIMS found for C10H11N3O2 m/z 206 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[Br:22][C:23]1[CH:24]=[C:25]([C:29]2[C:33]3[CH:34]=[N:35][CH:36]=[CH:37][C:32]=3[N:31]([CH2:38][CH2:39][NH:40][CH3:41])[N:30]=2)[CH:26]=[CH:27][CH:28]=1>CN(C)C=O.C(O)C>[Br:22][C:23]1[CH:24]=[C:25]([C:29]2[C:33]3[CH:34]=[N:35][CH:36]=[CH:37][C:32]=3[N:31]([CH2:38][CH2:39][N:40]([CH3:41])[CH2:19][C@@H:17]([OH:18])[CH2:16][O:15][C:12]3[CH:11]=[CH:10][C:9]([C:6]4[C:5]5[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]=5[O:8][N:7]=4)=[CH:14][CH:13]=3)[N:30]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: CNCCn1nc(-c2cccc(Br)c2)c2cnccc21
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Solvent: CN(C)C=O
Solvent: CCO
Product: CN(CCn1nc(-c2cccc(Br)c2)c2cnccc21)C[C@@H](O)COc1ccc(-c2noc3cc(F)ccc23)cc1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and {2-[3-(3-bromo-phenyl)-pyrazolo[4,3-c]pyridin-1-yl]-ethyl}-methyl-amine (Table No. 1, SM 6) in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=616.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:8])([CH3:7])[CH:5]([CH2:9][CH:10]=O)[CH2:4][CH:3]=1.[C:12]([CH:17]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:14][CH2:15][CH3:16])=[O:13]>C(OC)(C)(C)C>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:1])=[CH:3][CH2:4][CH:5]1[CH2:9][CH:10]=[CH:17][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CC1=CCC(CC=O)C1(C)C
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: COC(C)(C)C
Product: CCOC(=O)C=CCC1CC=C(C)C1(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 89.7 %

Procedure:
To a flame-dried 250 ml round bottom flask campholenic aldehyde (10.0 g, 65.7 mmol) and methyl tertiary-butyl ether (MTBE) (100 ml) were added to give a solution and the flask was slowly cooled to 0° C. in an ice water bath. (Carbethoxymethylene)triphenyl-phosphorane (22.8 g, 66.0 mmol) was slowly added to the solution. The reaction mixture was stirred at 0° C. for 20 min then stirred at room temperature for about 24 h. After the reaction was completed, the reaction mixture was reduced to half its volume in vacuo and 100 ml of hexanes was added. The flask containing the reaction mixture and hexanes was then placed in an ice bath for 30 min. The reaction mixture was then filtered through a plug of filter paper, celite, silica, and sand and washed three times, first with hexanes, then 9:1 and then 1:1 Hexanes/MTBE. The combined eluates were concentrated in vacuo and purifed via flash column chromatography (1:8 Hexanes/Ethyl Acetate (AcOEt)) to give ethyl 4-(2,2,3-trimethylcyclopent-3-enyl)but-2-enoate (13.1 g, 89%) as an oil. The NMR data is indicated below.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([OH:31])=[C:26]([O:29][CH3:30])[CH:27]=4)[N:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(C1C=CC(NC2C=CC(OC3C4C(=CC(OCCCCl)=C(OC)C=4)N=CC=3)=CC=2)=CC=1)(C)(C)C.C(OC([N:74]1[CH2:79][CH2:78][CH:77]([CH2:80]O)[CH2:76][CH2:75]1)=O)(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(Cl)(Cl)Cl.CC(C)=O.C(OCC)(=O)C.O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:31][CH2:80][CH:77]5[CH2:78][CH2:79][NH:74][CH2:75][CH2:76]5)=[C:26]([O:29][CH3:30])[CH:27]=4)[N:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: COc1cc2c(Oc3ccc(Nc4ccc(C(C)(C)C)cc4)cc3)ccnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: COc1cc2c(Oc3ccc(Nc4ccc(C(C)(C)C)cc4)cc3)ccnc2cc1OCCCCl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COc1cc2c(Oc3ccc(Nc4ccc(C(C)(C)C)cc4)cc3)ccnc2cc1OCC1CCNCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 85.1 %

Procedure:
(4-Tert-butylphenyl)-[4-(6-methoxy-7-hydroxy-4-quinolyloxy)-phenyl]amine (compound 21) (0.8 g) (starting compound A), tert-butyl-4-(hydroxymethyl)-1-piperidine carboxylate (0.59 g) (starting compound B), and triphenylphosphine (0.85 g) were dissolved in tetrahydrofuran (25 ml), and the solution was stirred at room temperature for 20 min. Under ice cooling, 40% diethyl azodicarboxylate (1.5 ml) was added to the reaction solution, and the mixture was stirred at room temperature overnight. Water and ethyl acetate were added to the reaction solution. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and was dried over sodium sulfate. The solvent was removed by evaporation under the reduced pressure. The crude was dissolved in a 30% trifluoroacetic acid/chloroform solution (15 ml), and the solution was stirred at room temperature for 30 min. The solvent was removed by evaporation under the reduced pressure, and the residue was then purified by chromatography on silica get using chloroform/acetone for development to give (4-tert-butylphenyl)-{4-[6-methoxy-7-(4-piperidinylmethoxy)-4-quinolyloxy]phenyl}amine (0.84 g, yield 86%).
Reaction SMILES: C1(PC2C=CC=CC=2)C=CC=CC=1.[N:14]([CH:17]([C:19]1[O:20][C:21]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[C:22]([CH3:24])[N:23]=1)[CH3:18])=[N+]=[N-]>CO>[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([C:21]2[O:20][C:19]([CH:17]([NH2:14])[CH3:18])=[N:23][C:22]=2[CH3:24])=[CH:30][CH:29]=1
Reactant: Cc1nc(C(C)N=[N+]=[N-])oc1-c1ccc(Cl)cc1
Agent: c1ccc(Pc2ccccc2)cc1
Solvent: CO
Product: Cc1nc(C(C)N)oc1-c1ccc(Cl)cc1
Reaction time: 3 h

Procedure:
SiliaBond® Diphenylphosphine (1500 mg, 1.19 mmol/g) was added to a solution of 2-(1-azidoethyl)-5-(4-chlorophenyl)-4-methyloxazole (366 mg, 1.393 mmol) in anhydrous methanol (15 ml) and shaken for 3 hours. The reaction was filtered and concentrated in vacuo. Flash column chromatography (silica, 40 g) eluting with 2-10% MeOH/DCM afforded 160 mg (white solid). HRMS(B) tR=1.73 min; MS m/z 236.0716
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].[CH3:31][N:32]([CH3:47])[C:33]([CH3:46])([CH3:45])[CH2:34][O:35][C:36]1[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][C:37]=1[F:44]>>[CH3:47][N:32]([CH3:31])[C:33]([CH3:45])([CH3:46])[CH2:34][O:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][CH2:2][CH2:1][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=2[C@@H:14]2[CH2:23][CH2:22][C:21]3[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=3[CH2:15]2)=[CH:38][C:37]=1[F:44]
Reactant: CCNc1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CN(C)C(C)(C)COc1ccc(C=O)cc1F
Product: COc1cc(NCCCc2ccc(OCC(C)(C)N(C)C)c(F)c2)c([C@@H]2CCc3cc(O)ccc3C2)cc1OC
Yield: 37.4 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4,5-dimethoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 4-(2-dimethylamino-2-methylpropoxy)-3-fluorobenzaldehyde (55 mg) according to an analogous synthetic method to Example 264 and purified by LC-MS, the title compound (10 mg) was obtained.
Reaction SMILES: [C:1]([N:8]1C=CN=C1)([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[S:2].N[N:14]1[CH2:18][C:17]2[C:19]3[C:24]([CH:25]=[CH:26][C:16]=2[S:15]1)=[CH:23][CH:22]=[CH:21][CH:20]=3>C(#N)C>[CH2:18]1[C:17]2[C:19]3[C:24]([CH:25]=[CH:26][C:16]=2[S:15][N:14]1[NH:8][C:1]([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[S:2])=[CH:23][CH:22]=[CH:21][CH:20]=3
Reactant: NN1Cc2c(ccc3ccccc23)S1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: S=C(NN1Cc2c(ccc3ccccc23)S1)n1ccnc1
Yield: 27 %

Procedure:
A solution of 1,1'-thiocarbonyldiimidazole (1.8 g, 20 mmol) and 2-aminonaptho[1,2]thiazole (2.0 g, 20 mmol) in acetonitrile (150 mL) was stirred at 65° C. for 24 h. The resulting precipitate was collected by filtration to provide 1.69 g (46%) of the titled product.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:20]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=O)([O-:22])=[O:21].[N+](C1C=C(C=CC=1)[CH:37]([Cl:39])[Cl:38])([O-])=O>C(Cl)(Cl)(Cl)Cl>[Cl:38][C:37]([Cl:39])=[CH:26][C:25]1[CH:28]=[CH:29][CH:30]=[C:23]([N+:20]([O-:22])=[O:21])[CH:24]=1
Reactant: O=[N+]([O-])c1cccc(C(Cl)Cl)c1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cccc(C=C(Cl)Cl)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A solution of 32.8 g. of triphenylphosphine in 70 ml. of carbon tetrachloride is stirred for 3 hours at 60° C. to prepare in situ the reagent triphenylphosphine dichloromethylene. A solution of 18.9 g. of 3-nitro benzaldehyde in 60 ml. of carbon tetrachloride is added and the mixture is continued to be stirred at 60° C. for an additional 2 hours, when vapour phase chromatography indicates that all the starting 3-nitrobenzenealdehyde has disappeared and two new peaks in a ratio of 1:1 show the formation of a mixture of ββ-dichloro3-nitrostyrene and 3-nitrobenzalchloride. The reaction mixture is decanted from the solid residues and concentrated in vacuo to an oil. This is treated with ether, and again separated from some solid precipitate and the solution is again concentrated in vacuo. The oily residue is then carefully distilled in high vacuo to give essentially pure β,β-dichloro-3-nitrostyrene.