Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6]([C:12]1[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[C:16]([N:18]=[C:19]=[S:20])[CH:17]=1)=[CH:5]2.[NH2:23][C@@H:24]([CH2:33][OH:34])[C@H:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[OH:26]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6]([C:12]1[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[C:16]([NH:18][C:19]([NH:23][C@@H:24]([CH2:33][OH:34])[C@@H:25]([OH:26])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[S:20])[CH:17]=1)=[CH:5]2
Reactant: N[C@@H](CO)[C@@H](O)c1ccccc1
Reactant: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1N=C=S
Product: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1NC(=S)N[C@@H](CO)[C@@H](O)c1ccccc1

Procedure:
The product from Example 35, Step A, 5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenyl isothiocyanate (0.316 g, 1.0 mmol) was reacted with (1S,2S)-(+)-2-amino-1-phenyl-1,3-propanediol (0.167 g, 1.0 mmol) according to the procedure for Example 23, Step B to give the product after trituration with hexanes/ethyl acetate, 1/1, v/v and filtration through silica gel using hexanes/ethyl acetate, 1/1, v/v as eluant The resulting orange oil/foam was triturated with hexanes/ether to give the product as an orange solid (0.155 g), mp (slow decomposition).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[C:23]([Cl:26])[C:24]=1[OH:25])[NH2:21]>>[F:16][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)=[N:7][C:2]([NH:21][C:20]2[CH:19]=[C:18]([Cl:17])[C:24]([OH:25])=[C:23]([Cl:26])[CH:22]=2)=[N:3][CH:4]=1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Product: Oc1cccc(Nc2nc(Nc3cc(Cl)c(O)c(Cl)c3)ncc2F)c1

Procedure:
In a like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and 3,5-dichloro-4-hydroxyaniline were reacted to produce 5-Fluoro-N2-(3,5-dichloro-4-hydroxyphenyl)-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.47 (bs, 1H), 9.35 (bs, 1H), 9.22 (bs, 2H), 8.09 (d, 1H, J=3.6 Hz), 7.70 (s, 2H), 7.31 (dd, 1H, J=1.2 and 9.3 Hz), 7.10 (t, 1H, J=7.5 Hz), 7.00 (bs, 1H), 6.48 (dd, 1H, J=1.2 and 6.9 Hz); LCMS: purity: 93%; MS (m/e): 382(MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[CH3:37][C:38](=C)[CH2:39]O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][CH2:26][C:38]([CH3:39])=[CH2:37])=[C:18]([CH3:24])[CH:17]=1
Reactant: C=C(C)CO
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C=C(C)COC(=O)Nc1cc(C)c(Oc2ccnc3cc(OC)c(OC)cc23)cc1C
Yield: 47.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 2-methyl-2-propen-1-ol (17 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (31 mg, yield 45%).
Reaction SMILES: [CH3:1][C:2]1[N:10]([C:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([O:20][CH3:21])=[CH:5][C:4]=2[C:3]=1[CH2:22][C:23](O)=[O:24].C([N:28](CC)CC)C.C(OC(Cl)=O)C(C)C>C1COCC1>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C:11]([N:10]2[C:9]3[C:4](=[CH:5][C:6]([O:20][CH3:21])=[CH:7][CH:8]=3)[C:3]([CH2:22][C:23]([NH2:28])=[O:24])=[C:2]2[CH3:1])=[O:12])=[CH:18][CH:17]=1
Reactant: CCN(CC)CC
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c(CC(N)=O)c(C)n2C(=O)c1ccc(Cl)cc1
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
Indomethacin (10 g; 0.028 mol) in 150 mL THF was treated with triethylamine (4.8 mL; 0.035 mol) and cooled to -10° C. Isobutylchloroformate (4.4 mL; 0.033 mol) was added and the reaction was stirred at -10° C. for 10 min. The ice bath was removed and NH3 was bubbled through the solution for 15 min. The resulting pale yellow solid was collected, slurried in CH2Cl2 and filtered again. The product was used with no further purification.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:4]=[C:5]([CH:9]([NH:11][C:12](=[O:19])[CH2:13][CH:14]2[CH2:18][CH2:17]CC2)[CH3:10])[C:6](=[O:8])[N:7]=1.[CH2:27](O)C>CCOCC>[NH2:1][C:2]1[N:3]([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:4]=[C:5]([CH:9]([NH:11][C:12](=[O:19])[CH2:13][CH2:14][CH:18]([CH3:17])[CH3:27])[CH3:10])[C:6](=[O:8])[N:7]=1
Reactant: CCO
Reactant: CC(NC(=O)CC1CCCC1)c1nn(Cc2ccccc2)c(N)nc1=O
Solvent: CCOCC
Product: CC(C)CCC(=O)NC(C)c1nn(Cc2ccccc2)c(N)nc1=O

Procedure:
N-[1-(3-amino-2-benzyl-2,5-dihydro-5-oxo-as-triazin-6-yl)ethyl]-cyclopentylacetamide, m.p. 195°-196.5° (from a mixture of ethanol and ether).
Reaction SMILES: O.[Sn](Cl)Cl.[Cl:5][C:6]1[CH:14]=[C:13]([Cl:15])[C:12]([N+:16]([O-])=O)=[CH:11][C:7]=1[C:8]([OH:10])=[O:9].C([O-])(O)=O.[Na+].CC(O)=O>CCO>[Cl:5][C:6]1[CH:14]=[C:13]([Cl:15])[C:12]([NH2:16])=[CH:11][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Cl)cc1Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: Nc1cc(C(=O)O)c(Cl)cc1Cl
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
Tin(II) Chloride hydrate (50 g, 0.29 mol) was added to a solution of 2,4-dichloro-5-nitrobenzoic acid 1-2 (10.0 g, 0.045 mol) in EtOH (200 mL). The mixture was stirred for 70° C. for 30 min, cooled and poured onto ice. The pH of the mixture was adjusted to 8 using saturated aqueous NaHCO3. The suspension was left to stir at room temperature for 5 h and re-acidified to pH 5 with glacial AcOH. The resulting white suspension was continuously washed with EtOAc, the extracts combined, washed with brine, dried over Na2SO4, filtered and concentrated to afford the desired amine 1-3 as an off-white solid (8.8 g, 96%). 1H NMR (400 MHz, CD3OD) δ7.27 (s, 1H), 7.30 (s, 1H).
Reaction SMILES: [NH2:1][C@H:2]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].Cl.[CH3:14]O>>[CH3:14][O:4][C:3](=[O:5])[C@H:2]([NH2:1])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1
Reactant: CO
Reactant: N[C@@H](C(=O)O)c1ccc(F)cc1
Agent: Cl
Product: COC(=O)[C@H](N)c1ccc(F)cc1

Procedure:
(R)-Amino-(4-fluoro-phenyl)-acetic acid was treated with HCl gas (8 g) dissolved in methanol at room temperature for 24 hours. The reaction mixture was concentrated and aqueous sodium bicarbonate was added until the pH of the mixture remained basic. The aqueous layer was extracted three times with dichloromethane. The combined extracts were dried (Na2SO4) and concentrated afford the title compound as an oil. 1HNMR (400 MHz, CDCl3) δ 1.90 (br s, 2H), 3.67 (s, 3H), 4.58 (s, 1H), 7.00 (m, 2H), 7.30 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@@H:4]([NH:15][CH2:16][CH:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1)[CH3:18])[CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[I-].ClC1C=CC=C[N+]=1C.[CH3:38][O:39][CH:40]([O:45][CH3:46])[CH2:41][C:42](O)=[O:43].C(N(CCCC)CCCC)CCC>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:28])[C@@H:4]([N:15]([CH2:16][CH:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1)[CH3:18])[C:42](=[O:43])[CH2:41][CH:40]([O:45][CH3:46])[O:39][CH3:38])[CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COC(CC(=O)O)OC
Reactant: COC(=O)[C@H](CCOCc1ccccc1)NCC(C)Nc1ccc(Cl)c(Cl)c1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCCCN(CCCC)CCCC
Product: COC(=O)[C@H](CCOCc1ccccc1)N(CC(C)Nc1ccc(Cl)c(Cl)c1)C(=O)CC(OC)OC
Yield: 95.5 %

Procedure:
A solution of 1.26 g (2.96 mmol) of (S)-4-benzyloxy-2-[2-(3,4-dichloro-phenylamino)-propylamino]-butyric acid methyl ester in 30 ml CH2Cl2 was treated with a solution of 0.91 g (3.55 mmol) of 2-chloro-1-methylpyridinium iodide and 0.48 g (3.55 mmol) of 3,3-dimethoxy-propionic acid (synthesized from methyl 3,3-dimethoxy-propionate by hydrolysis with LiOH) in 20 ml of CH2Cl2. The suspension was cooled and treated at 0° C. with 1.77 ml (7.41 mmol) of tributylamine. The cooling bath was removed after 10 min and stirring was continued over night. The reaction was extracted with 10% aq. KHSO4 solution/diethyl ether (3×). The organic phases were washed with 10% aq. KHSO4 solution (2×), sat. aq. NaHCO3 solution, 10% aq. NaCl solution and dried over Na2SO4 to yield 1.53 g (96%) of the title compound as a 71:29 mixture of the (R) and (S) diastereomers. Yellow oil, MS: 541.2 (MH+, 2Cl).
Reaction SMILES: [CH3:1][Si:2]([CH3:41])([CH3:40])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:23][CH:22]3[N:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:19]([CH2:20][CH2:21]3)[CH2:18]2)[CH:9]=1.[I:42]N1C(=O)CCC1=O>CC#N.C(Cl)Cl>[CH3:39][Si:36]([CH3:38])([CH3:37])[CH2:35][CH2:34][O:33][CH2:32][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:40])[CH3:41])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([I:42])=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:23][CH:22]3[N:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:19]([CH2:20][CH2:21]3)[CH2:18]2)[CH:9]=1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n1)C2
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C2CCC1CC(c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n1)C2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87.7 %

Procedure:
To the “anti” tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (6.04 g, 10 mmol) in CH3CN (40 mL) and DCM (40 mL) was added N-iodosuccinimide (2.5 g, 11 mmol) portionwise and the resulting mixture was stirred at room temperature for 1.5 h, at which time LC/MS confirmed full conversion of starting material to product. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel. Elution with EtOAc/Hexanes (0-50%) gave tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (6.4 g, 88%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:16][C:11]2[N:12]=[N:13][CH:14]=[CH:15][C:10]=2[CH:9]=1.[F:17][C:18]([F:38])([F:37])[C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=1[C:29]1[N:30]=[N:31][C:32]([CH2:35]Cl)=[CH:33][CH:34]=1>>[F:38][C:18]([F:17])([F:37])[C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:26])[F:27])[CH:22]=[CH:21][C:20]=1[C:29]1[N:30]=[N:31][C:32]([CH2:35][N:13]2[CH:14]=[CH:15][C:10]3=[CH:9][C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])=[N:16][C:11]3=[N:12]2)=[CH:33][CH:34]=1
Reactant: Fc1ccccc1-c1cc2ccnnc2[nH]1
Reactant: FC(F)(F)c1ccc(-c2ccc(CCl)nn2)c(C(F)(F)F)c1
Product: Fc1ccccc1-c1cc2ccn(Cc3ccc(-c4ccc(C(F)(F)F)cc4C(F)(F)F)nn3)nc-2n1
Yield: 17.8 %

Procedure:
Prepared analogously to the method described for 2-[5[(4-methoxy-2-trifluoro-methylphenyl)-[1,3,4]thiadiazol-2-ylmethyl]-6-(2-fluorophenyl)-2H-pyrrolo[2,3-c]pyridazine beginning with 6-(2-fluorophenyl)-7H-pyrrolo[2,3-c]pyridazine (50 mg, 0.234 mmol) and 3-(2,4-Bis-trifluoromethylphenyl)-6-chloromethylpyridazine (95 mg, 0.27 mmol) to produce the titled compound (21.6 mg, 18%). 1H-NMR: (d6-DMSO, 400 MHz) δ 8.78 (d, 1H), 8.38 (dt, 1H), 8.21 (d, 2H), 8.02 (d, 1H), 7.95 (d, 1H), 7.89 (d, 1H), 7.86 (d, 1H), 7.47 (m, 1H), 7.31 (m, 2H), 7.12 (d, 1H), 6.22 (s, 2H). LCMS calculated for C25H14F7N5: 517.11, found 518.15 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:15]=[C:16]([C:19]5[C:20]([N:35]([CH3:40])[S:36]([CH3:39])(=[O:38])=[O:37])=[CH:21][C:22]6[O:26][C:25]([C:27]([OH:29])=O)=[C:24]([C:30](=[O:33])[NH:31][CH3:32])[C:23]=6[CH:34]=5)[CH:17]=[CH:18][C:13]=4[O:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1.C1C=CC2N(O)N=[N:47][C:45]=2C=1.CCN=C=NCCCN(C)C.Cl.CN.CCN(CC)CC>CN(C=O)C>[F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:15]=[C:16]([C:19]5[C:20]([N:35]([CH3:40])[S:36]([CH3:39])(=[O:37])=[O:38])=[CH:21][C:22]6[O:26][C:25]([C:27]([NH:47][CH3:45])=[O:29])=[C:24]([C:30]([NH:31][CH3:32])=[O:33])[C:23]=6[CH:34]=5)[CH:17]=[CH:18][C:13]=4[O:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: On1nnc2ccccc21
Reactant: CNC(=O)c1c(C(=O)O)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc2c1C(=O)NC
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.5 %

Procedure:
A mixture of compound 5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-2-carboxylic acid (50 mg, 0.09 mmol), HOBT (24 mg, 0.17 mmol), EDCI (102 mg, 0.53 mmol), methanamine hydrochloride (42 mg, 0.62 mmol) and Et3N (72 mg, 0.71 mmol) in DMF (2 mL) was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, the residue was purified by prep-TLC (DCM:MeOH=200:1) to give the product 5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-N2,N3-dimethyl-6-(N-methylmethylsulfonamido)benzofuran-2,3-dicarboxamide (20 mg, yield: 39%). 1H NMR (CDCl3, 400 MHz) δ 10.49 (br s, 1H), 8.81 (s, 1H), 7.68 (s, 1H), 7.49 (s, 2H), 7.24˜7.17 (m, 3H), 7.12 (d, J=8.2 Hz, 1H), 6.88˜6.81 (m, 1H), 6.01 (s, 2H), 3.39 (s, 3H), 3.12 (d, J=5.2 Hz, 3H), 3.02 (d, J=4.8 Hz, 3H), 2.65 (s, 3H). MS (M+H)+: 578.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:12]([F:15])([F:14])[F:13])[C:5]2[N:6]([C:8]([NH2:11])=[N:9][N:10]=2)[N:7]=1.[O-:16][CH2:17][CH3:18].[Na+].O.[CH2:21]([OH:23])[CH3:22]>>[CH2:17]([O:16][C:2]1[CH:3]=[C:4]([C:12]([F:15])([F:14])[F:13])[C:5]2[N:6]([C:8]([NH2:11])=[N:9][N:10]=2)[N:7]=1)[CH3:18].[CH2:17]([O:16][C:2]1[CH:3]=[C:4]([C:12]([O:23][CH2:21][CH3:22])([F:15])[F:13])[C:5]2[N:6]([C:8]([NH2:11])=[N:9][N:10]=2)[N:7]=1)[CH3:18]
Reactant: CCO
Reactant: CC[O-]
Reactant: Nc1nnc2c(C(F)(F)F)cc(Cl)nn12
Agent: [Na+]
Solvent: O
Product: CCOc1cc(C(F)(F)F)c2nnc(N)n2n1
Product: CCOc1cc(C(F)(F)OCC)c2nnc(N)n2n1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
6-Chloro-8-trifluoromethyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine (W2.004; 65 mg) was initially charged in ethanol (6 ml) and admixed with sodium ethoxide (21 mg). The reaction mixture was stirred at 50° C. for 4 h. After cooling, the mixture was admixed with water and concentrated. The residue was taken up in ethyl acetate and washed with water three times. The ethyl acetate phase was dried over sodium sulfate, filtered and concentrated. The crude product was purified by means of preparative HPLC (met. E). The product-containing fractions, each of them clean, were combined, freed of the acetonitrile, adjusted to pH 9 with sodium hydrogencarbonate and extracted three times with ethyl acetate. The combined organic extracts were dried over sodium carbonate, filtered and concentrated. 15 mg of 6-ethoxy-8-trifluoromethyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine and 23 mg of 6-ethoxy-8-(ethoxydifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine were obtained.
Reaction SMILES: [OH:1][CH2:2][C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.[C:13](N1C=CN=C1)(N1C=CN=C1)=[O:14].Cl.[NH2:26][C@@H:27]([CH2:35][NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>C1COCC1>[C:3]12([CH2:2][O:1][C:13]([NH:26][C@@H:27]([CH2:35][NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])=[O:14])[CH2:12][CH:7]3[CH2:6][CH:5]([CH2:11][CH:9]([CH2:8]3)[CH2:10]1)[CH2:4]2
Reactant: CC(C)(C)OC(=O)NC[C@H](N)C(=O)OC(C)(C)C
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: OCC12CC3CC(CC(C3)C1)C2
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC[C@H](NC(=O)OCC12CC3CC(CC(C3)C1)C2)C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 4 h
Yield: 58.8 %

Procedure:
A solution of 10.9 g (65.4 mmol) of (1-hydroxymethyl)adamantane and 10.6 g (65.4 mmol) of carbonyldiimidazole in 60 ml of THF were stirred at 50° C. for 1.5 h. 9.7 g (32.7 mmol) of tert-butyl (S)-2-amino-3-tert-butoxycarbonylaminopropionate hydrochloride in 25 ml of THF and 5.6 ml (32.7 mmol) of diisopropylethylainine were added, and the mixture was stirred at 60° C. for 4 h and allowed to stand at room temperature overnight. The solvent was removed in vacuo and the residue was chromatographed on silica gel using heptane/ethyl acetate (7/3). 8.7 g (59%) of the title compound were obtained as a colorless oil.
Reaction SMILES: CC1(C)[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:16]([O:18][CH2:19]C)=[O:17])[CH:5]=[CH:4][C:3]1=2.CC1(C)C2C(=CC=C(C#C)C=2)[S:26]CC1.COC(Cl)=O.C([Li])CCC>>[CH3:12][C:9]1([CH3:13])[C:8]2[C:3](=[CH:4][CH:5]=[C:6]([C:14]#[C:15][C:16]([O:18][CH3:19])=[O:17])[CH:7]=2)[S:26][CH2:11][CH2:10]1
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCS2
Reactant: CCOC(=O)C#Cc1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: COC(=O)Cl
Agent: [Li]CCCC
Product: COC(=O)C#Cc1ccc2c(c1)C(C)(C)CCS2

Procedure:
Employing the same general procedure as used for the preparation of ethyl 3-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)propiolate (Compound A), but instead using 2.0 g (10 mmols) of (4,4-dimethyl-thiochroman-6-yl)ethyne, 2 g (21.3 mmols) of methylchloroformate and 11 mmols of n-butyl lithium the title compound was obtained as a yellow solid.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[Cl:18])[N:14]([CH2:19][C:20]1[N:25]=[C:24]([C:26]([O:28][CH3:29])=[O:27])[CH:23]=[CH:22][CH:21]=1)[C:13]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[CH:12]2)C1C=CC=CC=1>FC(F)(F)C(O)=O.O.CSC>[Cl:18][C:17]1[CH:16]=[C:15]2[C:11]([CH:12]=[C:13]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:14]2[CH2:19][C:20]2[N:25]=[C:24]([C:26]([O:28][CH3:29])=[O:27])[CH:23]=[CH:22][CH:21]=2)=[CH:10][C:9]=1[OH:8]
Reactant: COC(=O)c1cccc(Cn2c(-c3ccccc3)cc3cc(OCc4ccccc4)c(Cl)cc32)n1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CSC
Product: COC(=O)c1cccc(Cn2c(-c3ccccc3)cc3cc(O)c(Cl)cc32)n1
Yield: 70.4 %

Procedure:
A solution of methyl 6-(5-benzyloxy-6-chloro-2-phenylindol-1-ylmethyl)pyridine-2-carboxylate (372 mg) in trifluoroacetic acid/water/dimethyl sulfide (95/5/10, 7.7 mL) was stirred at room temperature for 80 hours. The reaction mixture was concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution (20 mL) was added to the residue and this resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was triturated in dichloromethane/hexane (2/1). The precipitate was collected by filtration, washed with dichloromethane/hexane (2/1), and air-dried to obtain the title compound (213 mg).
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3]([NH2:5])=[NH:4].C(=O)([O-])[O-].[K+].[K+].[C:14]([CH2:19][C:20](OCC)=[O:21])(=O)[CH2:15][CH2:16][CH3:17].Cl>O>[OH:21][C:20]1[CH:19]=[C:14]([CH2:15][CH2:16][CH3:17])[N:5]=[C:3]([C:2]([Cl:7])([Cl:6])[Cl:1])[N:4]=1
Reactant: CCCC(=O)CC(=O)OCC
Reactant: N=C(N)C(Cl)(Cl)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCCc1cc(O)nc(C(Cl)(Cl)Cl)n1
Reaction time: 8 h
Yield: 11 %

Procedure:
A mixture of 15.0 g (0.09 mole) trichloroacetamidine, 12.6 g (0.09 mole) potassium carbonate, 14.6 g (0.09 mole) ethyl butyrylacetate and 300 ml water was stirred overnight. The aqueous solution was decanted from the oil that formed and acidified with hydrochloric acid. The precipitate that formed was filtered, washed, and dried to give 2.6 g (11% yield). An analytical sample that was recrystallized from ligroin had mp 107°-110° C. The structure was confirmed via infrared and elemental analysis.
Reaction SMILES: C1([Si](C2C=CC=CC=2)(Cl)[Cl:8])C=CC=CC=1.[C:16]([O:20]C(=O)C)([CH3:19])([CH3:18])[CH3:17]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:16]([Cl:8])([CH3:19])([CH3:18])[CH3:17].[CH3:17][C:16]([Cl:8])=[O:20]
Reactant: CC(=O)OC(C)(C)C
Reactant: Cl[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Product: CC(=O)Cl
Product: CC(C)(C)Cl

Procedure:
Example 1 was repeated using 2.27 g. (9 m mols) of diphenyldichlorosilane, 1.0 g. (8.6 m mols) of t-butylacetate and 0.07 g. of tetrabutylammonium bromide, except that the reaction mass was heated at 200° C. for 3 hours. A 48% conversion to t-butyl chloride and a 15% conversion to CH3COCl was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH:6]=[CH:7][C:8]([NH:10][C:11]2[CH:21]=[CH:20][C:14]([C:15]([O:17]CC)=[O:16])=[CH:13][CH:12]=2)=[O:9])=[CH:4][CH:3]=1.[OH-].[K+].C(O)C.Cl>O>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH:6]=[CH:7][C:8]([NH:10][C:11]2[CH:21]=[CH:20][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(NC(=O)C=Cc2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(C=Cc1ccc(Cl)cc1)Nc1ccc(C(=O)O)cc1
Reaction time: 1.5 h

Procedure:
A solution of 7.1 g. of p-(p-chlorocinnamamido)benzoic acid, ethyl ester and 1.6 g. of potassium hydroxide in 50 ml. of 95% ethanol is stirred at 75° C. overnight. A 25 ml. portion of water and 200 mg. of potassium hydroxide are added, and stirring is continued at 75° C. for 1.5 hours. The mixture is then diluted with 150 ml. of water, adjusted to pH 3 with 37% hydrochloric acid, and the precipitate is collected and dried. The solid is boiled in 100 ml. of methyl cellosolve, cooled, and the solid is collected, washed with ethanol, and dried, giving 5.51 g. of the desired product as a white powder, m.p. 333°-336° C. (dec.).
Reaction SMILES: FC1C=C[C:5]([NH:8]C(=O)OC)=[C:4]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[N:22]([CH2:34][C:35]4[C:40]([F:41])=[CH:39][C:38]([F:42])=[CH:37][C:36]=4[F:43])[N:23]=[C:24]4[C:29]=3[CH:28]=[CH:27][CH:26]=[C:25]4[C:30]([F:33])([F:32])[F:31])[CH:16]=2)C=1.[F-:44].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:62]1[CH2:66]O[CH2:64][CH2:63]1>>[F:44][C:63]1[CH:64]=[C:4]2[C:5](=[CH:66][CH:62]=1)[NH:8][C:14]([C:15]1[CH:16]=[C:17]([C:21]3[N:22]([CH2:34][C:35]4[C:40]([F:41])=[CH:39][C:38]([F:42])=[CH:37][C:36]=4[F:43])[N:23]=[C:24]4[C:29]=3[CH:28]=[CH:27][CH:26]=[C:25]4[C:30]([F:32])([F:33])[F:31])[CH:18]=[CH:19][CH:20]=1)=[CH:13]2
Reactant: [F-]
Reactant: COC(=O)Nc1ccc(F)cc1C#Cc1cccc(-c2c3cccc(C(F)(F)F)c3nn2Cc2c(F)cc(F)cc2F)c1
Reactant: C1CCOC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Product: Fc1cc(F)c(Cn2nc3c(C(F)(F)F)cccc3c2-c2cccc(-c3cc4cc(F)ccc4[nH]3)c2)c(F)c1

Procedure:
A solution of methyl [4-fluoro-2-({3-[2-(2,4,6-trifluorobenzyl)-7-(trifluoromethyl)-2H-indazol-3-yl]phenyl}ethynyl)phenyl]carbamate (0.07 g, 0.12 mmol) and tetrabutylammonium fluoride (0.24 mL, 0.24 mmol, 1M solution in THF) in 2 mL THF was heated at 60° C. for 21 hours. The reaction mixture was concentrated in vacuo and the residue purified by normal phase HPLC (silica, hexane-EtOAC, 19:1) to give 0.045 g of product as a white solid.