Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:19])[CH:9]([OH:18])[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:26](Cl)(=[O:34])[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:19])[CH:9]([O:18][C:26]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:34])[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCC(O)C(=O)c1ccc(F)cc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOC(=O)CCCC(OC(=O)Oc1ccccc1)C(=O)c1ccc(F)cc1
Yield: 92.6 %

Procedure:
To a mixture of ethyl 6-(4-fluorophenyl)-5-hydroxy-6-oxohexanoate (13.5 g), pyridine (4.40 g) and tetrahydrofuran (100 ml) was added dropwise phenyl chlorocarbonate (8.67 g) with stirring under ice-cooling. The mixture was stirred at room temperature for 16 hours. This reaction mixture was concentrated, diluted with ethyl acetate (400 ml) and washed with water (200 ml). The organic layer was dried over anhydrous magnesium sulfate, and concentrated to give ethyl 6-(4-fluorophenyl)-6-oxo-5-phenoxycarbonyloxyhexanoate as a yellow oil (18.1 g, 93%).
Reaction SMILES: [CH3:1][C:2]([C:6]1[C:11]([CH3:12])=[CH:10][C:9]([OH:13])=[C:8]([CH:14]([CH3:16])[CH3:15])[CH:7]=1)([CH3:5])[CH2:3][CH3:4].C=O.S(=O)(=O)(O)O.[O:24]1[CH2:29]COC[CH2:25]1>>[CH3:5][C:2]([C:6]1[CH:7]=[C:8]([CH:14]([CH3:15])[CH3:16])[C:9]2[O:13][CH2:25][O:24][CH2:29][C:10]=2[C:11]=1[CH3:12])([CH3:1])[CH2:3][CH3:4]
Reactant: CCC(C)(C)c1cc(C(C)C)c(O)cc1C
Reactant: C1COCCO1
Agent: C=O
Agent: O=S(=O)(O)O
Product: CCC(C)(C)c1cc(C(C)C)c2c(c1C)COCO2
Yield: 35 %

Procedure:
Reaction of 4-(1,1-dimethylpropyl)-2-(1-methylethyl)-5-methylphenol (22.02 g, 0.1 mol), which may be prepared as described by W. Koenigs and R. W. Carl, Chem. Ber., (1981) 25, 3892-3903, 40% formaldehyde solution (70 mL, 0.93 mol), p-dioxane (150 mL) and sulfuric acid (10 mL) according to the procedure described in Example 2, provided after chromatography and short-path distillation, 9.18 g (35% yield) of 6-(1,1-dimethylpropyl)-5-methyl-8-(1-methylethyl)-4H-1,3-benzodioxin (GLC purity 98%); 1H-NMR (CDCl3)δ 0.70 (3H, t, J=7 HZ), 1.20 (6H, d, J=7 Hz), 1.35 (6H, s), 1.78 (2H, q, J=7 Hz), 2.15(3H, s), 3.0-3.5 (1H, m), 4.80 (2H, s), 5.17(2H, s), 7.03 (1H, s); IR (film) νmax 2950, 1575, 1470 cm-1 ; MS m/e 262, 233, 217, 203, 175, 161; UVλmax (ethanol) 226 nm (ε=5530), 283 nm (ε=1520).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][C:10]([NH2:13])=[N:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1>C(O)C.Cl[Cu]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[CH:11][C:10]([NH2:13])=[N:9]2)=[CH:6][CH:7]=1
Reactant: NC1=NN(c2ccc(Cl)cc2)CC1
Agent: Cl[Cu]
Solvent: CCO
Solvent: c1ccncc1
Product: Nc1ccn(-c2ccc(Cl)cc2)n1
Reaction time: 10 h
Yield: 51.6 %

Procedure:
In the same apparatus and according to the same modalities as in Example 1, 1.95 g (0.01 mole) of 1-(p-chlorophenyl)-3-amino-2-pyrazoline were suspended in 12 ml of ethanol and 0.1 ml of pyridine with addition of 0.1 g of CuCl, under an oxygen head. Oxidation was completed after about 10 hours. The oxidized product was isolated as in Example 2, thus obtaining 1 g of 1-(p-chlorophenyl)-3-amino-pyrazole of melting point 107°-108° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][C:4]=1[C:14]([F:17])([F:16])[F:15].C1(C)C=CC=CC=1.[P:25]([O:30]C)([O:28][CH3:29])[O:26][CH3:27]>>[CH3:27][O:26][P:25]([CH2:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][C:4]=1[C:14]([F:17])([F:16])[F:15])([O:28][CH3:29])=[O:30]
Reactant: COP(OC)OC
Reactant: CCOC(=O)c1ccc(CBr)c(C(F)(F)F)c1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(CP(=O)(OC)OC)c(C(F)(F)F)c1

Procedure:
6.20 g of ethyl 4-(bromomethyl)-3-trifluoromethylbenzoate (Reference Example 2 (step 2)) was dissolved in 12 ml of trimethyl phosphite and the mixture was heated at reflux for 4 hours under an argon atmosphere. After the completion of the reaction, the operation of adding of toluene to the residue, followed by azeotropic removal of trimethyl phosphite was repeated three times. The residue was purified by silica gel column chromatography to obtain 4.96 g of the objective compound as a yellow oily product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[N:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=1[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19].[CH:22]1([CH:25]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH2:38]O)[CH:33]=2)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:24][CH2:23]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C1(C)C=CC=CC=1>[CH:22]1([CH:25]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH2:38][O:16][C:13]3[CH:14]=[N:15][C:10]([C:3]4[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=4[F:1])=[C:11]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=3)[CH:33]=2)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:24][CH2:23]1
Reactant: CCOC(=O)CC(c1ccnc(CO)c1)C1CC1
Reactant: COc1ccc(F)c(-c2ncc(O)cc2CC(C)(C)C)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CC(c1ccnc(COc2cnc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Reaction time: 14 h
Yield: 33.7 %

Procedure:
Under an argon atmosphere, to a solution of 6-(2-fluoro-5-methoxyphenyl)-5-neopentylpyridin-3-ol (300 mg), ethyl 3-cyclopropyl-3-(2-(hydroxymethyl)pyridin-4-yl)propanoate (259 mg) and triphenylphosphine (544 mg) in THF (5.0 mL) was added a 40% solution of diethyl azodicarboxylate in toluene (943 μL) at room temperature, and the mixture was stirred for 14 hr. The solvent of the reaction mixture was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (182 mg) as a pale-orange oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:11][CH:10]([CH2:12]Cl)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]([O-:17])(=[O:16])[CH3:15].[Na+]>CN(C)C=O>[CH2:1]([N:8]1[CH2:11][CH:10]([CH2:12][O:17][C:14](=[O:16])[CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCC1CN(Cc2ccccc2)C1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCC1CN(Cc2ccccc2)C1
Reaction time: 2.25 h

Procedure:
195.5 g of 1 was added, drop-by-drop over 45 minutes, to a stirred mixture of 164 g of anhydrous sodium acetate and 1.8 liters of dimethylformamide, at 130° C. The mixture was held at 130° C. for an additional 2.25 hours, then most of the solvent was evaporated under reduced pressure and the cooled residue and treated with sufficient of an ice/water mixture to dissolve the salts therein. The resulting mixture was extracted with ether, the extract was washed with water, and the solvent was evaporated to give 2, as a pale yellow oil, b.p.: 94° C., 0.1 Torr.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][C:23](O)=[O:24])[N:21]=1)=[CH:5]2.C(N(CC)CC)C.C(Cl)(=O)C(C)C.[BH4-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][CH2:23][OH:24])[N:21]=1)=[CH:5]2
Reactant: O=C(O)C[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1
Agent: CC(C)C(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: OCC[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-acetic acid (391 mg, 1 mmol) prepared in Example 4 was dissolved in DCM (10 mL). Triethylamine (280 ul, 2 mmol) and isobutyric acid chloride (106 mg, 1 mmol) were added thereto, and the mixture was stirred for 30 min at 0°. After completion of the reaction, the solvent was removed under reduced pressure. The residue was diluted with THF. NaBH4 (74 mg, 2 mmol) was added thereto, and the mixture was stirred for 12 h. The reaction was quenched with a small amount of water. Again, excess water was added to the reaction mixture, which was then stirred for 30 min, extracted with EtOAc, dried over MgSO4, and filtered. The solvent was removed under reduced pressure, and the residue was purified by column chromatography to give the title compound (272 mg, Yield 72%).
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:15]([O:23][CH2:24][CH3:25])(=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>CS(C)=O.CCOC(C)=O>[F:8][C:7]1[C:2]([CH:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:15]([O:23][CH2:24][CH3:25])=[O:22])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Fc1cccnc1F
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C(=O)OCC)c1ncccc1F
Temperature: 100 °C
Yield: 60.3 %

Procedure:
A mixture of 2,3-difluoropyridine (2.00 g, 17.4 mmol), Cs2CO3 (13.59 g, 41.7 mmol) and diethyl malonate (6.68 g, 41.7 mmol) in DMSO (19 mL) was heated at 100° C. for 4.5 h. The mixture was poured onto ice, diluted with EtOAc, and the organic phase was separated, washed sequentially with water and brine, and dried and concentrated. The residue was purified by column chromatography on silica gel (80 g), eluting with EtOAc-hexanes (sequentially 10%, 20% and 30%), to provide diethyl 2-(3-fluoropyridin-2-yl)malonate as a pale colored oil (2.68 g, 60% yield). 1H NMR (400 MHz, chloroform-d) δ 8.42 (dt, J=4.6, 1.3 Hz, 1H), 7.43 (ddd, J=9.4, 8.3, 1.4 Hz, 1H), 7.30 (dt, J=8.5, 4.3 Hz, 1H), 5.09 (d, J=1.1 Hz, 1H), 4.30 (q, J=7.0 Hz, 4H), 1.33-1.26 (m, 6H).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH2:15][CH2:14]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4]>[C:1]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[CH:14]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1cccc2c1NCC2
Agent: [Mn+4]
Agent: [O-2]
Product: O=C(c1ccccc1)c1cccc2cc[nH]c12

Procedure:
dehydrogenating the 7-benzoylindoline produced in step (1) with 1 to 5 molar equivalents of manganese dioxide in the presence of an inert solvent at a reflux temperature to produce 7-benzoylindole;
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][C@@H:14]2[CH2:19][N:18]([C:20](=[O:24])[CH:21]([F:23])[F:22])[CH2:17][CH2:16][O:15]2)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([C:38]2[CH:43]=[CH:42][C:41](B3OC(C)(C)C(C)(C)O3)=[CH:40][CH:39]=2)[CH2:34][CH2:33]1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:22][CH:21]([F:23])[C:20]([N:18]1[CH2:17][CH2:16][O:15][C@H:14]([CH2:13][NH:12][C:10]2[C:9]3[C:4](=[N:5][CH:6]=[CH:7][N:8]=3)[CH:3]=[C:2]([C:41]3[CH:40]=[CH:39][C:38]([N:35]4[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]4)=[CH:43][CH:42]=3)[N:11]=2)[CH2:19]1)=[O:24]
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: O=C(C(F)F)N1CCO[C@H](CNc2nc(Cl)cc3nccnc23)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CN1CCN(c2ccc(-c3cc4nccnc4c(NC[C@@H]4CN(C(=O)C(F)F)CCO4)n3)cc2)CC1
Temperature: 110 °C
Reaction time: 24 h

Procedure:
To a solution of (R)-1-(2-((7-chloropyrido[4,3-b]pyrazin-5-ylamino)methyl)morpholino)-2,2-difluoroethanone (72 mg, 0.2 mmol) in dioxane/H2O (5 mL/0.5 mL) was added Cs2CO3 (98 mg, 0.3 mmol), Pd (PPh3)4 (46.2 mg, 0.04 mmol) and 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (72.5 mg, 0.24 mmol). The mixture was stirred at 110° C. for 24 hours under N2. The reaction was filtered, concentrated and purified on column (CH2Cl2:MeOH=20:1) to give yellow solid. MS (m/z): 498 (M+H)+
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([C:12]1[CH:30]=[CH:29][C:15]([CH:16]=[CH:17][C:18]([NH:20][C:21]2[CH:27]=[CH:26][CH:25]=[C:23]([OH:24])[C:22]=2[OH:28])=[O:19])=[CH:14][CH:13]=1)[CH2:8][CH2:9][CH2:10][CH3:11].[CH3:31][O:32][C:33](=[O:38])[CH:34]=[CH:35][CH2:36]Br.O>CC(C)=O>[CH3:31][O:32][C:33](=[O:38])[CH2:34][CH:35]1[O:28][C:22]2[C:21]([NH:20][C:18](=[O:19])[CH:17]=[CH:16][C:15]3[CH:14]=[CH:13][C:12]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[CH:30][CH:29]=3)=[CH:27][CH:26]=[CH:25][C:23]=2[O:24][CH2:36]1
Reactant: COC(=O)C=CCBr
Reactant: CCCCCc1ccc(C=CC(=O)Nc2cccc(O)c2O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCCCCc1ccc(C=CC(=O)Nc2cccc3c2OC(CC(=O)OC)CO3)cc1

Procedure:
Potassium carbonate (509 mg) was added to a solution of 3-(p-pentylcinnamoyl)aminopyrocatechol (300 mg; synthesized by the same procedure as reference example 1) and 4-bromo-2-butenoic acid methyl ester in acetone (10 ml), and the mixture was refluxed for 10 min. The reaction mixture was poured into water. The mixture was extracted with ethyl acetate. The extract was purified by column chromatography on silica gel (hexane:ethyl acetate=5:1) to give the title compound (341 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].[C:9]1(=[O:14])O[CH2:12][CH2:11][CH2:10]1>>[N:1]1([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:14])[CH2:12][CH2:11][CH2:10][C:9]1=[O:14]
Reactant: NCCCCCCN
Reactant: O=C1CCCO1
Product: O=C1CCCN1CCCCCCN1CCCC1=O

Procedure:
11.62 g (0.1M) of 1,6-diaminohexane and 21.66 g (0.25M) of γ-butyrolactone were mixed and heated to 150°-165° for 22 hours. Excess γ-butyrolactone was then distilled off at reduced pressure (80°/2 mm). The light brown residue was poured into a crystallization dish where it immediately solidified. The solid was taken in chloroform, powdered, filtered and the tan powder was washed with chloroform. Yield 22.0 g (87%); melting point 101°-103°.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19](Br)[CH:18]=3)(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:24]([N:26]2[CH2:30][CH2:29][C:28]([F:32])([F:31])[CH2:27]2)=[O:25])=[O:8])[CH2:5][CH2:4]1)#[N:2].[CH3:33]B(O)O>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:18]=[C:19]([CH3:33])[CH:20]=[CH:21][CH:22]=3)(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:24]([N:26]2[CH2:30][CH2:29][C:28]([F:32])([F:31])[CH2:27]2)=[O:25])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: CB(O)O
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3cccc(Br)c3)C[C@H]2C(=O)N2CCC(F)(F)C2)CC1
Product: Cc1cccc(S(=O)(=O)[C@@H]2C[C@@H](C(=O)NC3(C#N)CC3)[C@H](C(=O)N3CCC(F)(F)C3)C2)c1

Procedure:
The title compound was prepared in analogy to example 196 using (1R,2R,4R)-4-(3-Bromo-benzenesulfonyl)-2-(3,3-difluoro-pyrrolidine-1-carbonyl)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (Example 188 step 4) and methylboronic acid. White solid (10%). MS (EI): 466.2 (M+H)+.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1.[Br:13][C:14]1[C:15](/[CH:20]=[N:21]/[S@:22]([C:24]([CH3:27])([CH3:26])[CH3:25])=[O:23])=[N:16][CH:17]=[CH:18][CH:19]=1>C1COCC1>[Br:13][C:14]1[C:15]([CH:20]([NH:21][S@:22]([C:24]([CH3:27])([CH3:26])[CH3:25])=[O:23])[C:3]2[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=2)=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: CC(C)(C)[S@](=O)/N=C/c1ncccc1Br
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(C)[S@](=O)NC(c1ccc(C(F)(F)F)cc1)c1ncccc1Br
Reaction time: 4 h

Procedure:
To a stirred suspension of magnesium (2.143 g, 88 mmol) in THF (50 mL), was added 4-bromobenzotrifluoride (5.06 mL, 36.2 mmol). Stirring was continued for 4 h (caution: slightly exothermic, cooled with a water bath if needed). The resulting mixture was added to a stirred solution of (S,E)-N-((3-bromopyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (5.1 g, 17.64 mmol) in THF (100 mL) at −78° C. in a dropwise fashion. The mixture was stirred for another hour after addition and the reaction was then quenched with saturated aqueous NH4Cl, extracted with Et2O (3×20 mL), dried over Na2SO4, concentrated, and purified by column chromatography using silica (100-200 mesh) with 5% EtOAc in hexane as eluent to give the title compound as a brown oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][N:7]([C:10]2[C:18]([Cl:19])=[C:13]3[CH2:14][CH2:15][CH2:16][CH2:17][N:12]3[N:11]=2)[C:8]=1[NH2:9])(=O)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1.O>C(COC)OC>[NH2:9][C:8]1[N:7]([C:10]2[C:18]([Cl:19])=[C:13]3[CH2:14][CH2:15][CH2:16][CH2:17][N:12]3[N:11]=2)[N:6]=[CH:5][C:4]=1[C:1](=[S:29])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(=O)c1cnn(-c2nn3c(c2Cl)CCCC3)c1N
Solvent: COCCOC
Solvent: O
Product: CC(=S)c1cnn(-c2nn3c(c2Cl)CCCC3)c1N

Procedure:
0.28 g (1 mmol) 4-Acetyl-5-amino-1-(3-chloro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)pyrazole was dissolved in 5 ml dimethoxyethane and treated with 0.28 (0.6 mmol) Lawesson's reagent. After heating under reflux for 2 hours with stirring, the reaction solution was poured into water and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography. (Hexane/ethyl acetate 1:1).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([NH:14][C:15](=[O:27])[C:16]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH3:18])[CH3:17])[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][N:29]1[CH:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:31]2([CH2:43][CH2:42][CH2:41][NH:40][CH2:39]2)[C:30]1=[O:44].CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C=O)C.O>[CH2:1]([O:8][CH2:9][C@@H:10]([NH:14][C:15](=[O:27])[C:16]([NH:19][C:20](=[O:21])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:18])[CH3:17])[C:11]([N:40]1[CH2:41][CH2:42][CH2:43][C:31]2([C:30](=[O:44])[N:29]([CH3:28])[CH:32]2[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:39]1)=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1C(=O)C2(CCCNC2)C1c1ccccc1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](COCc1ccccc1)C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CN1C(=O)C2(CCCN(C(=O)[C@@H](COCc3ccccc3)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C2)C1c1ccccc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture comprising (R)-3-(benzyloxy)-2-(2-(tert-butoxycarbonylamino)-2-methyl propanamido)propanoic acid (Intermediate 3A) (300 mg, 0.789 mmol), rac-2-methyl-3-phenyl-2,6-diazaspiro[3.5]nonan-1-one (Intermediate 2A) (182 mg, 0.789 mmol) and DIPEA (0.551 ml, 3.15 mmol) in DMF (4 ml) was treated with ®T3P (amide coupling agent 50% in DMF, 0.460 ml, 1.577 mmol) and stirred at RT for 17 hours. The reaction mixture was diluted with water (5 ml) and extracted with EtOAc. The organic portion was dried (MgSO4) and concentrated in vacuo. Purification of the crude product by chromatography on silica eluting with 1% MeOH in DCM afforded the title compound;
Reaction SMILES: [CH2:1]([NH:4][C:5]([N:7]1[C:11]([CH3:12])=[CH:10][C:9]([O:13][C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=2[Cl:25])=[N:8]1)=[O:6])[CH:2]=C.I([O-])(=O)(=O)=[O:27].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+].C(OCC)(=O)C>CCOCC.O.[Os](=O)(=O)(=O)=O>[CH:2]([CH2:1][NH:4][C:5]([N:7]1[C:11]([CH3:12])=[CH:10][C:9]([O:13][C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:22])([F:23])[F:24])=[CH:16][C:15]=2[Cl:25])=[N:8]1)=[O:6])=[O:27]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCNC(=O)n1nc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: Cc1cc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)nn1C(=O)NCC=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.1 %

Procedure:
N-allyl-3-(2,6-dichloro-4-trifluoromethylphenyloxy)-5-methylpyrazole-1-carboxamide (4.3 g, 10.9 mmol) was dissolved in a solution mixture of ether (50 ml) and water (50 ml), an aqueous solution (60 ml) of osmium tetraoxide (254 mg, 1.0 mmol) and sodium periodate (4.7 g, 21.8 mmol) were added, and the mixture was stirred at room temperature overnight. After completion of the reaction, a 10% sodium thiosulfate aqueous solution (100 ml) and ethyl acetate (100 ml) were added to the reaction solution, and an organic layer was separated and an aqueous layer was extracted with ethyl acetate (50 ml×2). These organic layers combined were washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and filtered to remove a desiccant. The solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/7→1/5), to give a white solid of N-formylmethyl-3-(2,6-dichloro-4-trifluoromethylphenyloxy)-5-methylpyrazole-1-carboxamide (2.12 g, yield: 49.1%). mp: 111-113° C.; 1H-NMR (CDCl3, TMS, ppm): δ 2.59 (d, J=0.8 Hz, 3H), 4.17 (d, J=5.5 Hz, 2H), 5.81 (q, J=0.8 Hz, 1H), 7.21 (br t, J=5.5 Hz, 1H), 7.67 (s, 2H), 9.66 (s, 1H).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].Br[C:13]1[S:21][C:20]2[C:19]([NH:22][C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[NH:28][CH:27]=[CH:26]4)=[N:18][CH:17]=[N:16][C:15]=2[CH:14]=1>>[NH:28]1[C:29]2[C:25](=[CH:24][C:23]([NH:22][C:19]3[C:20]4[S:21][C:13]([C:6]5[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=5)=[CH:14][C:15]=4[N:16]=[CH:17][N:18]=3)=[CH:31][CH:30]=2)[CH:26]=[CH:27]1
Reactant: Brc1cc2ncnc(Nc3ccc4[nH]ccc4c3)c2s1
Reactant: O=Cc1ccc(B(O)O)cc1
Product: O=Cc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1

Procedure:
The title compound was prepared from p-formylbenzeneboronic acid and (6-bromo-thieno[3,2-d]pyrimidin-4-yl)-(1H-indol-5-yl)-amine by a procedure analogous to example 2. 1H NMR (400 MHz, DMSO) d 11.2 (s, 1H), 9.95 (s, 1H), 8.85 (s, 1H), 7.90 (m, 6H), 7.75 (s, 1H), 7.46 (m, 3H), 7.20 (d, 1H), 6.49 (s, 1H), 2.28 (s, 3H), LC-MS: 371 (MH+); HPLC RT: 4.10 minutes.
Reaction SMILES: [S-:1][C:2]#[N:3].[NH4+].C(Cl)(=O)C1C=CC=CC=1.[NH2:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[CH2:21][CH2:20][CH2:19][CH2:18]2.[OH-].[NH4+]>CC(C)=O.C(O)C>[CH3:26][O:25][C:24]1[CH:23]=[C:22]2[C:17]([CH2:18][CH2:19][CH2:20][CH2:21]2)=[CH:16][C:15]=1[NH:14][C:2]([NH2:3])=[S:1]
Reactant: COc1cc2c(cc1N)CCCC2
Reactant: N#C[S-]
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CCO
Solvent: O=C(Cl)c1ccccc1
Product: COc1cc2c(cc1NC(N)=S)CCCC2
Yield: 80 %

Procedure:
1.45 g of ammonium thiocyanate are dissolved in 30 ml of acetone and after 2.2 ml of benzoyl chloride have been added, the reaction mixture is heated under reflux for 15 minutes. 2.6 g of 6-amino-7-methoxy-1,2,3,4-tetrahydronaphthalene (Compound 4-1) dissolved in 20 ml of acetone are added and then the mixture is heated under reflux for 30 minutes. It is evaporated to dryness, the residue obtained is taken up in a minimum of ethanol, 50 ml of 30% ammonium hydroxide are added and the mixture is heated under reflux for 20 hours. The thiourea obtained is cooled, filtered, washed with waer and then with an ethyl acetate/hexane 25/75 (v/v) mixture. 2.8 g of the expected product are obtained in the form of a beige powder; yield=80%.