Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C@H:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][C@H:9]1[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].B>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:15][C@H:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:13][C@H:9]1[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](OCc2ccccc2)C[C@H]1C(=O)O
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](OCc2ccccc2)C[C@H]1CO
Reaction time: 2 h
Yield: 100.8 %

Procedure:
A solution of trans-N-t-butoxycarbonyl-4-benzyloxy-L-proline (3.32 g, 10.3 mmol) in 20 mL of THF was cooled in an ice/acetone bath and a solution of borane in THF (1M, 20.6 mL, 20.6 mrnmol) was added dropwise. The solution was stirred for 2 hours then the cooling bath was removed and the mixture stirred overnight. The reaction was quenched by the careful addition of water followed by the addition of 20 mL of 1N aqueous HCl and then poured into ethyl acetate. The layers were separated and the aqueous layer extracted with 2 portions of ethyl acetate. The combined organic extracts were 2M aqueous sodium carbonate, water and brine, dried, filtered and concentrated to provide 3.19 g (100%) of the title compound. MS (DCI, NH3): 308 (MH+).
Reaction SMILES: [OH:1][CH:2]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:26]=[C:25]([C:27]3[C:31]([C:32]([F:35])([F:34])[F:33])=[C:30]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[O:29][N:28]=3)[O:24][N:23]=2)=[CH:18][CH:17]=1)[CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([CH2:10][C:11]([O:13]CC)=[O:12])[CH2:5]1.Cl>C(#N)C>[OH:1][CH:2]([C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:26]=[C:25]([C:27]3[C:31]([C:32]([F:35])([F:34])[F:33])=[C:30]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[O:29][N:28]=3)[O:24][N:23]=2)=[CH:20][CH:21]=1)[CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([CH2:10][C:11]([OH:13])=[O:12])[CH2:5]1
Reactant: CCOC(=O)C[C@H]1CCCN(CC(O)c2ccc(-c3noc(-c4noc(-c5ccccc5)c4C(F)(F)F)n3)cc2)C1
Agent: Cl
Solvent: CC#N
Product: O=C(O)C[C@H]1CCCN(CC(O)c2ccc(-c3noc(-c4noc(-c5ccccc5)c4C(F)(F)F)n3)cc2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 96.6 %

Procedure:
To a mixture of ethyl 2-((3R)-1-(2-hydroxy-2-(4-(5-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidin-3-yl)acetate (72 mg, 0.126 mmol) in acetonitrile (5 mL) was added 6N HCl (5 mL). The reaction mixture was stirred at room temperature for 3 days. The reaction mixture was filtered and purified by HPLC. HPLC conditions: PHENOMENEX® Luna C18 5 micron column (250×30 mm); 25-100% CH3CN/water (0.1% TFA); 25 minute gradient; 30 mL/min. Isolated fractions with correct mass were freeze-dried overnight to yield 66 mg of 2-((3R)-1-(2-hydroxy-2-(4-(5-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidin-3-yl)acetic acid as a TFA salt. 1H NMR (400 MHz, MeOH-d3) δ ppm 8.12 (2H, d, J=8.35 Hz), 7.71 (2H, d, J=7.47 Hz), 7.49-7.66 (5H, m), 5.16 (1H, dd, J=9.67, 4.39 Hz), 3.81 (1H, d, J=11.86 Hz), 3.56 (1H, d, J=11.42 Hz), 3.14-3.33 (2H, m), 2.83-2.94 (1H, m), 2.72 (1H, t, J=11.86 Hz), 2.16-2.38(3H, m), 1.78-1.92 (3H, m), 1.10-1.33 (1H, m). MS (m+1)=543. HPLC Peak RT=3.24 minutes (Analytical Method A). Purity=98%.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][O:10][CH2:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[N+:19]([O-])([OH:21])=[O:20].N>CC(C)=O.O>[N+:19]([C:4]1[CH:3]=[CH:2][C:1]([N:7]2[CH2:12][CH2:11][O:10][CH2:9][C:8]2=[O:13])=[CH:6][CH:5]=1)([O-:21])=[O:20]
Reactant: O=C1COCCN1c1ccccc1
Reactant: O=[N+]([O-])O
Agent: N
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: O=C1COCCN1c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 2-liter flask, 177 g (1.0 mol) of 4-phenyl-3-morpholinone (VIII) are introduced at internal temperature 10° C. in 4 portions into 728 g (7.4 equivalents) of concentrated sulphuric acid. The mixture is then heated to 25° C. and stirred at this temperature for 30 minutes. The solution is cooled to −5° C. and admixed within one hour with 101.8 g (1.05 equivalents) of 65% nitric acid. The mixture is stirred at −5° C. for one hour. 1300 ml of demineralized water are metered into this solution at 10° C. Subsequently, a pH of 7.4 is established, likewise at 10° C., with 25% aqueous ammonia solution. The suspension is admixed with 2000 g of acetone and heated to 40° C. In the course of this, the product goes into solution, so that the phases can be separated. 1500 g of acetone/water mixture are distilled off at standard pressure from the organic phase, in the course of which the product precipitates out. The suspension is cooled to 10° C. and stirred for a further 30 minutes, and the product is isolated. The moist product is washed with 320 g of cold acetone and dried at 50° C. under reduced pressure.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[NH2:14].[I:16]I>CCO.S([O-])([O-])(=O)=O.[Ag+2]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([I:16])[C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[NH2:14]
Reactant: II
Reactant: COC(=O)c1ccc(C(F)(F)F)cc1N
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: COC(=O)c1cc(I)c(C(F)(F)F)cc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
A mixture of 2-amino-4-trifluoromethyl-benzoic acid methyl ester (51.5 g, 235 mmol), iodine (55.1 g, 217 mmol) and silver sulfate (73.3 g, 234 mmol) in EtOH (1560 mL) was stirred for 1 h at r.t. under nitrogen. The suspension was then filtered and the filtrate diluted with EtOAc and washed once with a 10% aqueous sodium thiosulfate solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 2-amino-5-iodo-4-trifluoromethyl-benzoic acid methyl ester (67.5 g, 196 mmol, 83%) as a brown solid, m.p. 101-103° C., ESI-MS: m/z 346 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:39]=[CH:38][C:8]([O:9][CH2:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:29][C@H:28]([CH2:30][NH:31][C:32](=S)[CH2:33]C)[O:27][C:26]4=[O:36])=[CH:21][C:20]=3[F:37])[CH2:15][CH2:14]2)=[O:12])=[CH:7][CH:6]=1)[CH3:3].C(Cl)(=[O:42])C>C(N(CC)CC)C>[CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]([N:13]2[CH2:14][CH2:15][N:16]([C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:29][C@H:28]([CH2:30][NH:31][C:32](=[O:42])[CH3:33])[O:27][C:26]4=[O:36])=[CH:21][C:20]=3[F:37])[CH2:17][CH2:18]2)=[O:12])=[CH:38][CH:39]=1)[CH3:3]
Reactant: CCC(=S)NC[C@H]1CN(c2ccc(N3CCN(C(=O)COc4ccc(CN(C)C)cc4)CC3)c(F)c2)C(=O)O1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCN(C(=O)COc4ccc(CN(C)C)cc4)CC3)c(F)c2)C(=O)O1

Procedure:
As described for the preparation of 27, the reaction of 26 (prepared from 264 mg of 25) with acetyl chloride and triethylamine gave the acetamide which was purified by silica gel chromatography with 5% MeOH-0.5%NH4OH—CH2Cl2 followed by crystallization from Et2OAc to give 73 mg of 29, a white solid; 1HNMR [300 MHz, (CD3)2SO] δ 1.81 (s, 3H), 2.45 (s, 6H), 2.93. 3.00 (s, s, 4H), 3.38 (t, 2H), 3.60 (s, 4H), 3.68 (dd, 1H), 3.85 (s, 2H), 4.06 (t, 1H), 4.69 (m, 1H), 4.88 (s, 2H), 6.94 (d, 2H), 7.06 (t, 1H), 7.16 (dd, 1H), 7.33 (d, 2H), 7.49 (dd, 1H), 8.24 (t, 1H).
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([C:8]1([CH3:22])[CH2:12][O:11][C:10]([CH3:14])([CH3:13])[N:9]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=O)(=O)[CH3:2].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:32]2)=CC=1>C1(C)C=CC=CC=1>[CH3:13][C:10]1([CH3:14])[N:9]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:8]([CH3:22])([C:6]2[S:32][C:1]([CH3:2])=[N:4][N:5]=2)[CH2:12][O:11]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(=O)NNC(=O)C1(C)COC(C)(C)N1C(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Product: Cc1nnc(C2(C)COC(C)(C)N2C(=O)OC(C)(C)C)s1
Temperature: 110 °C
Reaction time: 5 h
Yield: 95.2 %

Procedure:
To a solution of 420 mg of tert-butyl 4-[(2-acetylhydrazino)carbonyl]-2,2,4-trimethyl-1,3-oxazolidine-3-carboxylate in 13 ml of toluene was added 309 mg of 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide, followed by stirring at 110° C. for 5 hours. The reaction mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 228 mg of tert-butyl 2,2,4-trimethyl-4-(5-methyl-1,3,4-thiadiazol-2-yl)-1,3-oxazolidine-3-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[N:12](C(OC(C)(C)C)=O)[CH:11]=[C:10]3[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[N:24]=2)=[N:4][N:3]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[O:32]1[CH2:31][CH2:30][N:29]([C:25]2[N:24]=[C:23]([C:10]3[C:9]4[C:13](=[CH:14][CH:15]=[C:7]([C:5]5[S:6][C:2]([NH2:1])=[N:3][N:4]=5)[CH:8]=4)[NH:12][CH:11]=3)[CH:28]=[CH:27][CH:26]=2)[CH2:34][CH2:33]1
Reactant: CC(C)(C)OC(=O)n1cc(-c2cccc(N3CCOCC3)n2)c2cc(-c3nnc(N)s3)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nnc(-c2ccc3[nH]cc(-c4cccc(N5CCOCC5)n4)c3c2)s1
Yield: 22.6 %

Procedure:
A solution of tert-butyl 5-(5-amino-1,3,4-thiadiazol-2-yl)-3-(6-morpholinopyridin-2-yl)-1H-indole-1-carboxylate (212 mg, 0.443 mmol) in DCM/TFA (1:1, 4 mL) was stirred at RT for 1 h, then the solvent was removed. The residue was diluted with DCM and washed with sat. NaHCO3. The organic layer was dried, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 0.5-4.5% MeOH in DCM) to give 5-(3-(6-morpholinopyridin-2-yl)-1H-indol-5-yl)-1,3,4-thiadiazol-2-amine (38.0 mg, 0.100 mmol, 22.7%) as a light brown solid. MS (ESI, pos. ion) m/z: 379 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 11.67 (1H, d, J=2.2 Hz), 8.82 (1H, d, J=1.6 Hz), 8.11 (1H, d, J=2.5 Hz), 7.74 (1H, dd, J=8.6, 1.8 Hz), 7.53-7.62 (1H, m), 7.48 (1H, d, J=8.6 Hz), 7.30 (1H, s), 7.22 (1H, d, J=7.4 Hz), 6.64 (1H, d, J=8.4 Hz), 3.79-3.93 (4H, m), 3.55-3.67 (4H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([OH:13])[NH:10][N:9]=2)=[C:4]([F:14])[CH:3]=1.S(OC)(O[CH3:19])(=O)=O.N.Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([OH:13])[N:10]([CH3:19])[N:9]=2)=[C:4]([F:14])[CH:3]=1
Reactant: COS(=O)(=O)OC
Reactant: Oc1cc(-c2ccc(Cl)cc2F)n[nH]1
Agent: Cl
Agent: N
Solvent: Cc1ccccc1
Product: Cn1nc(-c2ccc(Cl)cc2F)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.7 %

Procedure:
50 g of 3-(4-chloro-2-fluorophenyl)-5-hydroxy-1H-pyrazole from Example 1.1 were initially charged in 1500 ml of toluene. 35.5 g of dimethyl sulfate were then added, and the mixture was heated at reflux for 3 h. After cooling to room temperature, the mixture was made alkaline using ammonia, stirred overnight and acidified by addition of hydrochloric acid. The mixture was then cooled to 0° C., and the precipitated solid was filtered off. After drying, 49.4 g of 3-(4-chloro-2-fluorophenyl)-5-hydroxy-1-methyl-1H-pyrazole were obtained as crude product (purity according to NMR about 80%, impurity essentially starting material), which was purified by recrystallization from toluene to >95% purity. Yield 49.4 g, 74.1%. M.p.: 204° C.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[Te:11][CH:10]([CH3:12])[NH2+:9][C:8]=2[CH:13]=1.C(=O)(O)[O-].[Na+]>O>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[Te:11][C:10]([CH3:12])=[N:9][C:8]=2[CH:13]=1
Reactant: COc1ccc2c(c1)[NH2+]C(C)[Te]2
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COc1ccc2[te]c(C)nc2c1
Yield: 97 %

Procedure:
5-Methoxy-2-methylbenzotellurazolium chloride (Example 13) (3.7 g=0.012 mole) was suspended in water, sodium bicarbonate in excess of that stoichiometrically required was added, and the free base product was extracted with diethyl ether. After washing with saturated sodium sulfate solution, the organic phase was dried and evaporated under reduced pressure to give a residual oil (3.2 g) which was identified by its nuclear magnetic resonance spectra. C, H, N, O and Te elemental analyses were in agreement with that expected for the structural formula.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[NH:7][C:8]2[C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1.Cl[CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25]>>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[N:10]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:9]2[CH:11]=[CH:12][CH:13]=[C:14]([C:15]([O:17][CH3:18])=[O:16])[C:8]=2[N:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: COCCCc1nc2cccc(C(=O)OC)c2[nH]1
Product: COCCCc1nc2c(C(=O)OC)cccc2n1COCC[Si](C)(C)C

Procedure:
Analogously to Example 228e, 4.3 g of methyl 2-(3-methoxypropyl)-3-H-benzoimidazole-4-carboxylate and 3.54 ml of (2-chloromethoxyethyl)trimethylsilane are reacted. The title compound is obtained as a brown solid. Rf=0.33 (95:5 dichloromethane-methanol); Rt=4.26.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=2)=[CH:5][CH:4]=1.Br[C:19]1[CH:20]=[CH:21][C:22]2[C:23]3[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30][CH2:29][C:24]=3[N:25]([CH3:28])[C:26]=2[CH:27]=1>>[CH3:28][N:25]1[C:26]2[CH:27]=[C:19]([N:12]3[CH:13]=[CH:14][C:9]([C:6]4[CH:7]=[N:8][C:3]([C:2]([F:1])([F:16])[F:17])=[CH:4][CH:5]=4)=[CH:10][C:11]3=[O:15])[CH:20]=[CH:21][C:22]=2[C:23]2[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30][CH2:29][C:24]1=2
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Reactant: O=c1cc(-c2ccc(C(F)(F)F)nc2)cc[nH]1
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)nc5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Yield: 59 %

Procedure:
4-(6-(Trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one (131 mg, 0.54 mmol) and tert-butyl 7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (200 mg, 0.54 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (167 mg, 59%) as a green solid: 1H NMR (300 MHz, CDCl3) δ 8.99 (d, J=2.0 Hz, 1H), 8.10 (dd, J=8.1, 1.8 Hz, 1H), 7.84 (d, J=8.2 Hz, 1H), 7.60-7.54 (m, 2H), 7.32 (d, J=1.9 Hz, 1H), 7.07 (d, J=8.0 Hz, 1H), 6.93 (d, J=1.8 Hz, 1H), 6.49 (dd, J=7.1, 2.0 Hz, 1H), 4.66 (s, 2H), 3.85 (br m, 2H), 3.65 (s, 3H), 2.84 (s, 2H), 1.50 (s, 9H).
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:17][CH2:16][CH2:15][C@H:11]2[C:12]([OH:14])=O)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C1(C)C(S(O)(=O)=O)=CC=CC=1.[CH2:30]([O:37][C:38](=[O:48])[C@H:39]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[NH2:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([O:37][C:38](=[O:48])[C@H:39]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[NH:40][C:12](=[O:14])[C@@H:11]1[CH2:15][CH2:16][CH2:17][N:10]1[S:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:18])=[CH:6][CH:5]=1)(=[O:8])=[O:9])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Agent: Cc1ccccc1S(=O)(=O)O
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](Cc2ccccc2)C(=O)OCc2ccccc2)cc1

Procedure:
N-(Toluene-4-sulfonyl)-L-proline was coupled to L-phenylalanine benzyl ester toluenesulfonic acid salt using the procedure described in Method 3 to give the title compound as an oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[N:5]([CH3:11])[N:4]=1)[CH3:2].O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH:43]=[CH:44][C:45]=1[CH3:46])[O:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([CH:34]=[C:35]([NH:37][C:38]([CH:40]3[CH2:42][CH2:41]3)=[O:39])[N:36]=2)[N:33]=1>CN(C)C=O.CN(C)C(=O)C>[CH:40]1([C:38]([NH:37][C:35]2[N:36]=[C:31]3[CH:30]=[CH:29][C:28]([O:27][C:26]4[CH:43]=[CH:44][C:45]([CH3:46])=[C:24]([NH:23][C:8]([C:6]5[N:5]([CH3:11])[N:4]=[C:3]([CH2:1][CH3:2])[CH:7]=5)=[O:10])[CH:25]=4)=[N:33][N:32]3[CH:34]=2)=[O:39])[CH2:41][CH2:42]1
Reactant: CCc1cc(C(=O)O)n(C)n1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: CCc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2C)n(C)n1
Yield: 66.7 %

Procedure:
In the same manner as in Example 259 and using 3-ethyl-1-methyl-1H-pyrazole-5-carboxylic acid (120 mg, 0.80 mmol), tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (170 μL, 2.0 mmol), N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.62 mmol) and N,N-dimethylacetamide (7 mL) as starting materials, the title compound (190 mg, 68%) was obtained as a white solid.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][CH2:21][C:22]1[O:23][C:24]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:25]([C:27](O)=[O:28])[N:26]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:27]([C:25]3[N:26]=[C:22]([CH2:21][O:20][CH3:19])[O:23][C:24]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:28])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: COCc1nc(C(=O)O)c(-c2ccccc2)o1
Product: COCc1nc(C(=O)Nc2ccn(Cc3ccc(C(C)=O)o3)n2)c(-c2ccccc2)o1

Procedure:
Following general procedure B followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 2-methoxymethyl-5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=0.99 min; [M+H]+=421.61.
Reaction SMILES: CS(OO[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])(=O)=O.[NH2:25][C:26]1[CH:36]=[CH:35][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][CH:27]=1>CN(C)P(N(C)C)(N(C)C)=O>[CH3:22][Si:21]([CH3:24])([CH3:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][NH:25][C:26]1[CH:27]=[CH:28][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:35][CH:36]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: C[Si](C)(C)CCCCCCCCCCCCCCOOS(C)(=O)=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(NCCCCCCCCCCCCCC[Si](C)(C)C)cc1

Procedure:
A solution of 20.8 g. 14-(trimethylsilyl)tetradecyloxy methanesulfonate and 20 g. ethyl 4-aminobenzoate in 50 ml. hexamethylphosphoramide was stirred at 110° for 18 hr. The reaction was diluted with 100 ml. water and extracted three times with 150 ml. portions of methylene chloride. The combined organic layers were washed with brine, dried with anhydrous magnesium sulfate, passed through a pad of hydrous magnesium silicate, and evaporated. The residue was crystallized from 250 ml. ethanol to yield the title compound as a crystalline solid, m.p. 91°-92° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:7][C:8]([NH2:12])=[N:9]2)=[CH:4][CH:3]=1.[CH2:19]([N:21]=[C:22]=[O:23])[CH3:20].C(N(C(C)C)CC)(C)C>>[NH2:12][C:8]1[CH:7]=[C:6]([N:13]2[CH2:18][CH2:17][N:16]([C:22]([NH:21][CH2:19][CH3:20])=[O:23])[CH2:15][CH2:14]2)[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Reactant: CCN=C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)N1CCN(c2cc(N)nc3cc(Cl)ccc23)CC1

Procedure:
As described for example 159, 7-chloro-4-(1-piperazinyl)-2-quinolinamine, ethylisocyanate, and diisopropylethyl amine, are reacted to give the product. LC-MS: 333 (M++1). 1H NMR (DMSO-d6): 61.0 (t, 3H), 2.8–3.0 (m, 4H), 3.0–3.14 (q, 2H), 3.45–3.6 (m, 4H), 6.25 (s, 1H), 6.4–6.55 (s, 2H), 6.55–6.65 (m, 1H), 7.1–7.2 (m, 1H), 7.35–7.4 (m, 1H), 7.7–7.8 (d, 1H).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[CH:18][C:17]=1[O:24][CH2:25][CH:26]1[CH2:28][CH2:27]1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[CH:18][C:17]=1[O:24][CH2:25][CH:26]1[CH2:28][CH2:27]1
Reactant: OCc1ccc(Cl)c(OCC2CC2)c1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(Cl)c(OCC3CC3)c2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and [4-chloro-3-(cyclopropylmethoxy)phenyl]methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 0.36-0.40 (2H, m), 0.62-0.67 (2H, m), 1.25-1.32 (1H, m), 3.88 (2H, d, J=6.8 Hz), 5.18 (2H, s), 5.72 (1H, d, J=1.6 Hz), 6.92 (1H, dd, J=4.0 Hz, 8.0 Hz), 7.01 (1H, d, J=1.6 Hz), 7.37 (1H, d, J=8.0 Hz), 7.40 (1H, dd, J=1.2 Hz, 5.2 Hz), 7.56 (1H, d, J=2.0 Hz), 8.04 (1H, s), 8.68 (1H, d, J=5.2 Hz). [M+H] Calc'd for C20H17ClN4O2, 381; Found, 381.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:11]1[CH:12]=[CH:13][C:14]2[CH2:15][N:16]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17][CH2:18][O:19][C:20]=2[N:21]=1.O>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]1([O:7][C:11]2[CH:12]=[CH:13][C:14]3[CH2:15][N:16]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17][CH2:18][O:19][C:20]=3[N:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCOc2nc(Cl)ccc2C1
Reactant: OC1CCCCC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOc2nc(OC3CCCCC3)ccc2C1
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 65 %

Procedure:
To a solution of cyclohexanol (0.19 mL) in toluene (4 mL) was added sodium hydride (0.14 g), and the resulting mixture was stirred at 70° C. for 15 min under a nitrogen atmosphere. A mixture of tert-butyl 8-chloro-2,3-dihydropyrido[3,2-f][1,4]oxazepine-4(5H)-carboxylate (0.50 g), BINAP (0.033 g), Pd2(dba)3 (0.024 g) and toluene (4 mL) was added, and the resulting mixture was stirred at 100° C. for 2 hr under an argon atmosphere. The reaction solution was poured into water, and the resulting product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→40% ethyl acetate/hexane) to give tert-butyl 8-(cyclohexyloxy)-2,3-dihydropyrido[3,2-f][1,4]oxazepine-4(5H)-carboxylate (0.40 g, 65%) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[CH:5][CH:4]=1.Cl.[NH2:20][OH:21]>>[F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][C:11](=[N:20][OH:21])[CH2:10][CH2:9]2)=[CH:5][CH:4]=1
Reactant: O=C1CCN(Cc2ccc(C(F)(F)F)cc2)CC1
Reactant: NO
Agent: Cl
Product: ON=C1CCN(Cc2ccc(C(F)(F)F)cc2)CC1

Procedure:
1-(4-Trifluoromethylbenzyl)-4-piperidone oxime is prepared from 1-(4-trifluoromethylbenzyl)4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH3:12][C:13]1([CH3:30])[CH2:22][CH2:21][C:20]([CH3:24])([CH3:23])[C:19]2[CH:18]=[C:17]([CH:25]=[CH:26][C:27](Cl)=[O:28])[CH:16]=[CH:15][C:14]1=2>>[CH3:12][C:13]1([CH3:30])[CH2:22][CH2:21][C:20]([CH3:23])([CH3:24])[C:19]2[CH:18]=[C:17]([CH:25]=[CH:26][C:27]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=3)=[O:28])[CH:16]=[CH:15][C:14]1=2
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CC1(C)CCC(C)(C)c2cc(C=CC(=O)Cl)ccc21
Product: COC(=O)c1ccc(NC(=O)C=Cc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1

Procedure:
In a similar manner to that of Example 1(d), by reaction of 1.5 g (10 mmol) of methyl 4-amino-benzoate with 2.8 g (10 mmol) of 3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acryloyl chloride, 3.2 g (82%) of the expected methyl ester are obtained.