Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[CH:37]=[CH:36][C:12]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([CH2:21][O:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1.C(N(CC)CC)C>C(#N)C>[C:1]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][CH:18]([CH2:21][O:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:19][CH2:20]2)=[CH:36][CH:37]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(CCN2CCC(COC(c3ccccc3)c3ccccc3)CC2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)Nc1ccc(CCN2CCC(COC(c3ccccc3)c3ccccc3)CC2)cc1
Yield: 17.6 %

Procedure:
Acetic anhydride (68 mg, 0.67 mmol) was added dropwise to a stirred solution of 1-(4-aminophenethyl)-4-(diphenylmethoxymethyl)piperidine (180 mg, 0.45 mmol) (see Example 21) and triethylamine (55 mg, 0.54 mmol) in acetonitrile (5 ml) and the mixture heated under reflux for 2 hours and evaporated. The residue was partitioned between ethyl acetate and 10% aqueous potassium carbonate and the layers separated. The aqueous layer was extracted into ethyl acetate and the combined organic layers were dried over magnesium sulphate and evaporated. The residue was triturated with ethyl acetate and the resulting solid collected, washed with ethyl acetate and dried to give the title compound (35 mg) as an off-white solid which was characterised containing 0.25 equivalents of water.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH:5]1[NH:9]C(=O)N[C:6]1=[O:11].N1C=CN=C1.[OH2:17]>>[NH2:9][C@H:5]([C:6]([OH:11])=[O:17])[CH2:4][CH2:3][S:2][CH3:1]
Reactant: O
Reactant: CSCCC1NC(=O)NC1=O
Agent: c1c[nH]cn1
Product: CSCC[C@H](N)C(=O)O
Temperature: 25 °C
Yield: 50 %

Procedure:
A mixture of 1.74 g. of 5-(β-methylthioethyl)hydantoin, 68 mg. of imidazole and 20 ml. of water was heated to 160° C. in a 50 ml. autoclave and then allowed to react for 3 hours at 160° C., while being stirred. After the reaction was over, the autoclave was rapidly cooled to room temperature and the residual pressure was released. The autoclave was given a good wash with water to take off the reaction mixture, and then the reaction mixture was subjected to evaporation to dryness by means of a rotary evaporator. The resulting solid was shaken sufficiently with 100 ml. of methyl acetate. The methyl acetate insoluble matter was separated from the methylacetate solution. A portion of of the insoluble matter was recrystallized from water and then subjected to an infrared absorption spectrum and melting point measurements (m.p. 267° C., decomposed). Thus, it was found to be methionine. On the other hand, the methyl acetate soluble matter was found to be unreacted 5-(β-methylthioethyl)hydantoin and a negligible amount of by-products. According to a copper chelatemetric colorimetry of the insoluble matter (the colorimetry was conducted according to the method described in the specification of Japanese Laid-Open Patent Application No. 116008/1974), it was found that 0.75 g. of methionine (yield 50%) was attained.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][OH:12])=[CH:6][CH:5]=1.[C:13]([C:15]1[CH:16]=[C:17]([NH:26][C:27](=O)[O:28]C2C=CC=CC=2)[CH:18]=[CH:19][C:20]=1[S:21]([CH2:24][CH3:25])(=[O:23])=[O:22])#[N:14]>C1COCC1>[C:13]([C:15]1[CH:16]=[C:17]([NH:26][C:27](=[O:28])[O:12][CH2:11][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([Br:3])=[CH:5][CH:6]=2)[CH:18]=[CH:19][C:20]=1[S:21]([CH2:24][CH3:25])(=[O:23])=[O:22])#[N:14]
Reactant: CCS(=O)(=O)c1ccc(NC(=O)Oc2ccccc2)cc1C#N
Reactant: OCCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1ccc(NC(=O)OCCc2ccc(Br)cc2)cc1C#N
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 99.4 %

Procedure:
NaH (138 mg, 3.45 mmol, 60% dispersion in oil) was added to a solution of 2-(4-bromophenyl)ethanol (833 mg, 4.1 mmol) in THF (7 mL) at 0° C. and stirred for 10 min. The mixture was cooled to −40° C. and 25A (500 mg, 1.38 mmol) in THF (7 mL) was added. After stirring warming to 0° C. over 1 h and stirring at 0° C. for 3 h the mixture was partitioned between EtOAc and brine (100 mL each). The layers were separated and the organic layer washed with 5% NaOH, brine and concentrated in vacuo. The crude solid was purified by flash chromatrography (0% to 50% EtOAc in Hexanes) to yield 26A (600 mg, 99%) as a white solid. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.12 (t, J=7.47 Hz, 2 H) 2.95 (t, J=6.59 Hz, 2 H) 3.38 (q, J=7.18 Hz, 2 H) 4.36 (t, J=6.59 Hz, 2 H) 7.27 (d, J=8.35 Hz, 2 H) 7.92 (dd, 1 H) 8.00 (d, 1 H) 8.08 (d, J=2.20 Hz, 1 H) 10.51 (s, 1 H).
Reaction SMILES: C([O:4][CH2:5]/[C:6](/[CH3:14])=[CH:7]/[C:8]1[CH:13]=CC=C[CH:9]=1)C=C.[CH:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:14][CH:6]([CH2:7]/[C:8](/[CH3:13])=[CH:9]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:5]=[O:4]
Reactant: C=CCOC/C(C)=C/c1ccccc1
Reactant: c1ccccc1
Product: C/C(=C\c1ccccc1)CC(C)C=O
Temperature: 25 °C
Yield: 10 %

Procedure:
The (1E)-[3-(allyloxy)-2-methyl-1-propenyl]benzene (107.79 g, 0.571 mol), [RuCl2(PPh3)3] (3.13 g), BHT (1 g) and benzene (500 ml) were heated together in an autoclave in an oil bath at 190° C. for 4 hours. After cooling to room temperature, solvents were evaporated and the product purified by column chromatography on silica gel (eluent: heptanes/ethyl acetate 10:1) followed by bulb-to-bulb distillation (88° C./0.009 mbar) to give 11.21 g of the desired compound (0.060 mol, 10%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:16]2[C@@H:15]3[CH2:17][C@@H:14]3[CH2:13][C:12]=2[C:11]([C:18]([OH:20])=O)=[N:10]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Si]([O:61][CH2:62][C@H:63]([C:65]1[CH:70]=[CH:69][N:68]=[CH:67][CH:66]=1)[NH2:64])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>CN(C=O)C>[OH:61][CH2:62][C@@H:63]([NH:64][C:18]([C:11]1[C:12]2[CH2:13][C@H:14]3[CH2:17][C@H:15]3[C:16]=2[N:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[N:10]=1)=[O:20])[C:65]1[CH:70]=[CH:69][N:68]=[CH:67][CH:66]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H](N)c1ccncc1
Reactant: O=C(O)c1nn(-c2ccc(F)cc2F)c2c1C[C@H]1C[C@@H]21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@H](CO)c1ccncc1)c1nn(-c2ccc(F)cc2F)c2c1C[C@H]1C[C@@H]21
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.1 %

Procedure:
To a stirred solution of Intermediate 1 (see Example 1.1, 20 mg, 0.072 mmol), HATU (33 mg, 0.087 mmol) and DIEA (0.025 mL, 0.145 mmol) in DMF (1 mL) was added (S)-2-(tert-butyldimethylsilyloxy)-1-(pyridin-4-yl)ethanamine (18 mg, 0.072 mmol). The reaction mixture was stirred at room temperature for 1 h, and then treated with 1 M TBAF solution in THF (0.144 mL, 0.144 mmol). The reaction was stirred at room temperature for 1 h, and then purified by preparative LCMS to give the title compound as white solid (6.3 mg). LCMS m/z=397.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.48 (td, J=4.8 and 3.5 Hz, 1H), 1.14-1.19 (m, 1H), 2.10-2.15 (m, 1H), 2.25-2.31 (m, 1H), 2.93 (d, J=16.6 Hz, 1H), 3.03 (dd, J=6.2 and 16.5 Hz, 1H), 3.96-4.02 (m, 2H), 5.15-5.19 (m, 1H), 7.00-7.05 (m, 2H), 7.31 (d, J=5.4 Hz, 2H), 7.56 (d, J=7.5 Hz, 1H), 7.62-7.68 (m, 1H), 8.54 (d, J=5.4 Hz, 2H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][C:10]=1[F:16])(C)(C)C.[F:18][C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1>>[F:16][C:10]1[CH:11]=[C:12]([O:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([F:18])[CH:20]=2)[CH:13]=[CH:14][C:9]=1[CH2:8][NH2:7]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Br)cc1F
Reactant: Oc1cccc(F)c1
Product: NCc1ccc(Oc2cccc(F)c2)cc1F
Yield: 28.4 %

Procedure:
Use a method similar to Preparation 30, using (4-bromo-2-fluorobenzyl)-carbamic acid tert-butyl ester (2.12 g, 7.0 mmol) and m-fluorophenol (1.57 g, 14 mmol) to give the title compound (468 mg, 47% overall).
Reaction SMILES: C(OP(NC1SC=C(/C(=N/OC)/C(O)=O)N=1)(OCC)=O)C.Cl[CH2:23][C:24]1[CH2:31][S:30][CH:29]2[N:26]([C:27](=[O:53])[CH:28]2[NH:32][C:33](=[O:52])[C:34]([C:38]2[N:39]=[C:40]([NH:43][P:44]([O:49][CH2:50][CH3:51])([O:46][CH2:47][CH3:48])=[O:45])[S:41][CH:42]=2)=[N:35][O:36][CH3:37])[C:25]=1[C:54]([O:56][CH2:57][C:58]1[CH:63]=[CH:62][C:61]([O:64][CH3:65])=[CH:60][CH:59]=1)=[O:55].[SH:66][C:67]1[S:71][N:70]=[N:69][CH:68]=1.[Na].O>CC(C)=O>[CH3:65][O:64][C:61]1[CH:60]=[CH:59][C:58]([CH2:57][O:56][C:54]([C:25]2[N:26]3[CH:29]([S:30][CH2:31][C:24]=2[CH2:23][S:66][C:67]2[S:71][N:70]=[N:69][CH:68]=2)[CH:28]([NH:32][C:33](=[O:52])[C:34]([C:38]2[N:39]=[C:40]([NH:43][P:44]([O:49][CH2:50][CH3:51])([O:46][CH2:47][CH3:48])=[O:45])[S:41][CH:42]=2)=[N:35][O:36][CH3:37])[C:27]3=[O:53])=[O:55])=[CH:63][CH:62]=1
Reactant: CCOP(=O)(Nc1nc(C(=NOC)C(=O)NC2C(=O)N3C(C(=O)OCc4ccc(OC)cc4)=C(CCl)CSC23)cs1)OCC
Reactant: Sc1cnns1
Agent: CCOP(=O)(Nc1nc(/C(=N/OC)C(=O)O)cs1)OCC
Agent: [Na]
Solvent: O
Solvent: CC(C)=O
Product: CCOP(=O)(Nc1nc(C(=NOC)C(=O)NC2C(=O)N3C(C(=O)OCc4ccc(OC)cc4)=C(CSc4cnns4)CSC23)cs1)OCC
Yield: 76.8 %

Procedure:
[6R-[6-α, 7-β (Z)]]-3-(chloromethyl)-7-[[[2-[(diethoxyphosphinyl)amino]-4-thiazolyl]-(methoxy-imino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, (4-methoxyphenyl)methyl ester (0.8 g) and 0.4 g sodium 5-mercapto-1,2,3-thiadiazole were stirred in 30 ml acetone plus 15 ml water for 30 minutes. The solvent was evaporated to dryness and the residue was columned on Biosil A using methylene chloride containing 0.5 to 1.0% methanol to give 687 mg of product; MS ((+)FAB) 770 (M+H); IR (KBr,cm-1) 1786, 1720.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([OH:24])=O)=[C:15]3[N:14]=2)[CH:5]=[N:6][CH:7]=1.CN(C(ON1N=[N:40][C:35]2[CH:36]=[CH:37]C=N[C:34]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CC1(N)CC1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([NH:40][C:35]4([CH3:34])[CH2:37][CH2:36]4)=[O:24])=[C:15]3[N:14]=2)[CH:5]=[N:6][CH:7]=1
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cncc(F)c3)nc12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CC1(N)CC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1(NC(=O)c2cnn3ccc(N4CCC[C@@H]4c4cncc(F)c4)nc23)CC1
Reaction time: 0.17 h
Yield: 81.9 %

Procedure:
To a DMF (0.6 mL) solution of (R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation I, 10.5 mg, 0.0321 mmol) and HATU (14.6 mg, 0.0385 mmol) was added 1-methylcyclopropanamine hydrochloride (4.14 mg, 0.0385 mmol) and DIEA (0.0168 mL, 0.0962 mmol). After stirring for 10 minutes, the reaction mixture was directly purified by reverse-phase chromatography (5 to 50% acetonitrile/water) to yield the final product as white solid (10 mg, 82%). LCMS (apci) m/z=381.1 (M+H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5]([CH3:16])[CH:4]=1.[C-:17]#[N:18].[Na+]>CN(C)C=O.[Cl-].[Na+].O>[C:17]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5]([CH3:16])[CH:4]=1)#[N:18]
Reactant: Cc1cc(CCl)ccc1Sc1ccccc1
Reactant: [C-]#N
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(CC#N)ccc1Sc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Thus obtained 1-chloromethyl-3-methyl-4-phenylthiobenzene was dissolved in 56 ml of N,N-dimethylformamide, and 18.16 g of finely ground sodium cyanide was added, and the mixture was stirred overnight at room temperature. After adding 300 ml of saturated brine and 300 ml of ice water to the reaction mixture, it was extracted with ethyl acetate (300 ml×3). The extract was washed with saturated brine (200 ml×3), and dried with anhydrous sodium sulfate, concentrated in vacuo, and 1-cyanomethyl-3-methyl-4-phenylthiobenzene was obtained (45.95 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([O:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:20]=1[O:21][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[C:5]([NH:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][CH:9]=1)=[O:6]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([O:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:20]=1[O:21][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[CH:16][CH:17]=1)=[O:6]
Reactant: COC(=O)c1ccc(NC(=O)c2cc(Cl)c(OC3CCCC3)c(OC3CCCC3)c2)cc1
Solvent: C1COCCO1
Product: O=C(O)c1ccc(NC(=O)c2cc(Cl)c(OC3CCCC3)c(OC3CCCC3)c2)cc1
Yield: 77.4 %

Procedure:
4-(3-Chloro-4,5-bis(cyclopentyloxy)benzamido)benzoic acid (AAA-044) (55 mg, 72%) was prepared from methyl 4-(3-chloro-4,5-bis(cyclopentyloxy)benzamido)benzoate (7) (75 mg, 0.16 mmol) using a procedure essentially the same as in Step (ii) for AAA-001, except that 1,4-dioxane (2.5 mL) was used instead of THF: m/z 442 [M−H]− (ES−); 1H NMR (400 MHz, DMSO-d6) δ: 12.74 (1H, br s), 10.45 (1H, s), 7.94 (2H, d), 7.88 (2H, d), 7.69 (1H, d), 7.52 (1H, d), 4.97 (2H, m), 1.99-1.93 (2H, m), 1.73-1.48 (14H, m).
Reaction SMILES: [S:1]1(=[O:7])(=[O:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])CCC.[CH:13]([C:15]1[CH:20]=[CH:19][C:18]([CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=1)=[O:14]>O1CCCC1.CCCCCC>[O:6]=[S:1]1(=[O:7])[CH2:5][CH2:4][CH2:3][CH:2]1[CH:13]([OH:14])[C:15]1[CH:16]=[CH:17][C:18]([CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:19][CH:20]=1
Reactant: O=S1(=O)CCCC1
Reactant: CCOC(=O)C(C)c1ccc(C=O)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(C)c1ccc(C(O)C2CCCS2(=O)=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 33.7 %

Procedure:
Tetrahydrothiophene-1,1-dioxide (1.5 g) was dissolved in tetrahydrofuran (10 ml), and to the solution was added dropwise a 1.6 M solution of n-butyllithium in hexane (6.0 ml) at −60° C. The reaction mixture was gradually warmed to 0° C., stirred at the same temperature for 30 minutes, then a solution of ethyl 2-(4-formylphenyl)propionate (1.5 g) in tetrahydrofuran (2.0 ml) was added dropwise at 0° C., and the mixture was stirred at room temperature for 2 days. The reaction mixture was quenched with 10% aqueous citric acid, and then extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to give the title compound (800 mg, 39%).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[Cl-].C(C1C=CC=C(C(C)C)C=1[N+:27]1[CH:31]=[CH:30][N:29]([C:32]2[C:37]([CH:38](C)C)=[CH:36][CH:35]=[CH:34]C=2C(C)C)[CH:28]=1)(C)C.CC(C)([O-])C.[Na+]>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]>[C:8]1([C:5]2[N:4]=[N:3][C:2]([N:27]3[CH2:38][CH:37]4[CH2:32][N:29]5[CH2:28][CH:35]([CH2:34][CH:31]3[CH2:30]5)[CH2:36]4)=[CH:7][CH:6]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)c1cccc(C(C)C)c1-n1cc[n+](-c2c(C(C)C)cccc2C(C)C)c1
Reactant: Clc1ccc(-c2ccccc2)nn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: c1ccc(-c2ccc(N3CC4CC5CC3CN(C5)C4)nn2)cc1
Temperature: 90 °C

Procedure:
A solution of the product of Example 2 (0.10 g, 0.66 mmol) in dry toluene (10 mL) was treated with 3-chloro-6-phenylpyridazine (0.20 g, 1.0 mmol; Aldrich), tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3; 0.01 g, 0.013 mmol; Alfa Aesar), 1,3-bis(2,6-di-iso-propylphenyl)imidazolium chloride (0.017 g, 0.04 mmol; Strem), and sodium tert-butoxide (0.148 g, 1.32 mmol). The mixture was purged with nitrogen and heated to 90° C. for 8 hours. After cooling to room temperature, the reaction was quenched by pouring into a 5% aqueous NaHCO3 solution. The mixture was extracted with chloroform (3×), washed with brine, dried (MgSO4), filtered and concentrated. The crude product was purified by flash chromatography on silica gel, eluting with 2-10% methanol (containing 1% ammonium hydroxide)-chloroform to afford the title compound: MS (DCI/NH3) m/z 307 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:14]([F:17])([F:16])[F:15])=[N:8][N:9]([CH:11]2[CH2:13][CH2:12]2)[CH:10]=1)=O)C.CC(C[AlH]CC(C)C)C.Cl>C1(C)C=CC=CC=1>[CH:11]1([N:9]2[CH:10]=[C:6]([CH2:4][OH:3])[C:7]([C:14]([F:17])([F:16])[F:15])=[N:8]2)[CH2:13][CH2:12]1
Reactant: CCOC(=O)c1cn(C2CC2)nc1C(F)(F)F
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: OCc1cn(C2CC2)nc1C(F)(F)F
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of 1-Cyclopropyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (Preparation 101, 3.5 g, 14.11 mmol) in dry toluene (70 mL) was cooled to −78° C. and DIBAL-H (29.4 mL of a 1.2 M solution in toluene, 35.3 mmol) was added dropwise. The reaction mixture was stirred at −78° C. for 2 hours and then poured into 2N HCl (25 mL) followed by further stirring for 2 hours at room temperature. The mixture was extracted with EtOAc (2×50 mL) and the combined organic layers were washed with water (2×15 mL), brine (15 mL) and dried (Na2SO4) and evaporated in vacuo to afford the title compound as off white solid (100%, 3 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:23])[C:9]([C:15]2[CH:16]=[CH:17][C:18](=[O:22])[N:19]([CH3:21])[CH:20]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:24])[CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][C:27]=1[C:35]([O:37]CC)=[O:36]>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:23])[C:9]([OH:14])([C:15]3[CH:16]=[CH:17][C:18](=[O:22])[N:19]([CH3:21])[CH:20]=3)[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:24])[CH:3]=2)=[CH:28][C:27]=1[C:35]([OH:37])=[O:36]
Reactant: CCOC(=O)c1cc(B(O)O)ccc1Cl
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F
Product: CC(c1ccc(-c2ccc(Cl)c(C(=O)O)c2)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F

Procedure:
In analogy to Example 150, step 2, 5-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-methyl-1H-pyridin-2-one (Example 165, step 3) was reacted with 4-chloro-3-ethoxycarbonylphenylboronic acid. The product of this reaction was hydrolyzed in analogy to Example 141 to give the title compound as a colorless solid. MS (m/e, ISP neg. ion)=498.1 [M−H+].
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:12][C:13]1[CH:14]=[CH:15][C:16]([F:21])=[C:17]([CH:20]=1)[CH:18]=O>>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([F:21])=[C:17]([CH2:18][C:9]2[S:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:11][CH:10]=2)[CH:20]=1
Reactant: c1ccc(-c2cccs2)cc1
Reactant: O=Cc1cc(Br)ccc1F
Product: Fc1ccc(Br)cc1Cc1ccc(-c2ccccc2)s1

Procedure:
2-Phenylthiophene and 5-bromo-2-fluorobenzaldehyde were treated in a manner similar to Reference Example 7 to give the target compound. APCI-Mass m/Z 347/349 (M+H).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=2)[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=3)[C:10]3[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(C(F)(F)F)cc23)cc1OC
Reactant: c1nc[nH]n1
Product: COc1ccc(CNc2nc(-n3cncn3)nc3sc(C(F)(F)F)cc23)cc1OC

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with yields 2-chloro-6-trifluoromethyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-trifluoromethyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([OH:11])(=[O:10])[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)O.[CH2:12]([CH:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1O)[CH3:29])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>O>[C:4]1([CH:2]2[C:32]3[CH:33]=[CH:34][CH:35]=[C:30]([CH:28]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH3:29])[C:31]=3[O:11][C:1]2=[O:10])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)C(O)c1ccccc1
Reactant: CCCCCCCCCCCCCCCCC(C)c1ccccc1O
Solvent: O
Product: CCCCCCCCCCCCCCCCC(C)c1cccc2c1OC(=O)C2c1ccccc1

Procedure:
4.8 g (31.5 mmol) of mandelic acid and 10.4 g (30 mmol) of 1-hexadecylethylphenol are heated together at 190°-200° C. for approx. 8 hours under reduced pressure (13.3 mbar). In the course of this the water formed in the reaction is removed by distillation. When the reaction is complete, the reaction product is filtered over silica gel (hexane) and is then treated with cold hexane. The product has a melting point of 60°-62° C. and is in the form of a white powder. The yield is 7 g (=50% of theory).
Reaction SMILES: [C:1](O)(C(F)(F)F)=O.[O:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@H:11]([NH:18][C:19]2[C:24]([N+:25]([O-])=O)=[CH:23][N:22]=[C:21]([NH:28][C:29]3[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=3[NH:36][C:37](=O)OC(C)(C)C)[N:20]=2)[CH2:10][CH2:9]1>>[O:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@H:11]([N:18]2[CH:1]=[N:25][C:24]3[C:19]2=[N:20][C:21]([N:28]2[C:29]4[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=4[N:36]=[CH:37]2)=[N:22][CH:23]=3)[CH2:10][CH2:9]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)cc1Nc1ncc([N+](=O)[O-])c(N[C@@H]2CCOc3ccccc32)n1
Product: Fc1ccc2ncn(-c3ncc4ncn([C@@H]5CCOc6ccccc65)c4n3)c2c1

Procedure:
The title compound as a TFA salt was synthesized from (R)-tert-butyl 2-(4-(chroman-4-ylamino)-5-nitropyrimidin-2-ylamino)-4-fluorophenylcarbamate via the procedure described in Example 15. 1H NMR (300 MHz, CDCl3): δ 9.15 (s, 2H), 8.27 (dd, 1H), 7.89 (s, 1H), 7.78 (dd, 1H), 7.32 (td, 1H), 7.32 (td, 1H), 7.13 (td, 1H), 7.1-6.9 (m, 3H), 6.00 (t, 1H), 4.4-4.3 (m, 2H), 4.2-4.1 (m, 2H), 2.7-2.5 (m, 2H). 19F NMR: δ −116.4.
Reaction SMILES: C(O[C:12]([C:14]([O:20][C:21]([C:24]([C:27]([F:30])([F:29])[F:28])([F:26])[F:25])([F:23])[F:22])([C:16]([F:19])([F:18])[F:17])[F:15])=[O:13])(C(F)(F)F)(C(F)(F)F)F.C(OC(C(OC(C(C(F)(F)F)(F)F)(F)F)(C(F)(F)F)F)=O)(C(F)(F)F)C(F)(F)[F:33].[F-].[Na+]>>[F:33][C:12]([C:14]([O:20][C:21]([C:24]([C:27]([F:30])([F:28])[F:29])([F:25])[F:26])([F:23])[F:22])([C:16]([F:18])([F:17])[F:19])[F:15])=[O:13]
Reactant: O=C(OC(F)(C(F)(F)F)C(F)(F)F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Reactant: O=C(OC(C(F)(F)F)C(F)(F)F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Agent: [F-]
Agent: [Na+]
Product: O=C(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Temperature: 120 °C

Procedure:
2.1 g of a mixture of (CF3)2CFOCOCF(CF3)OCF2CF2CF3 and (CF3)2CHOCOCF(CF3)OCF2CF2CF3 obtained in Example 1-2, was charged into a flask together with 0.02 g of NaF powder and heated at 120° C. for 10 hours in an oil bath, while stirring vigorously. At an upper portion of the flask, a reflux condenser having the temperature adjusted at 20° C. and a gas bag were installed in series. After cooling, 1.5 g of a liquid sample and 0.4 g of a gas sample were recovered. The gas sample and the liquid sample were respectively analyzed by GC-MS, whereby from the gas sample, the above-identified compound was confirmed to be the main product, and from the liquid sample, FCOCF(CF3)OCF2CF2CF3 was confirmed to be the main product. The yield of the above-identified compound to (CF3)2CFOCOCF(CF3)OCF2CF2CF3, was 71.2%, as calculated by GC. Further, from the liquid sample, FCOCF(CF3)OCF2CF2CF3 (0.7 g) was obtained.