Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.ON1C2C=CC=CC=2N=N1.[F:43][C:44]1[CH:49]=[C:48]([F:50])[CH:47]=[CH:46][C:45]=1[CH2:51][C:52]([OH:54])=O.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[F:43][C:44]1[CH:49]=[C:48]([F:50])[CH:47]=[CH:46][C:45]=1[CH2:51][C:52]([N:24]([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][S:18][C:9]1[NH:10][C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:54]
Reactant: O=C(O)Cc1ccc(F)cc1F
Reactant: CCCCCCCNCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCN(CCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1)C(=O)Cc1ccc(F)cc1F
Reaction time: 2.5 h
Yield: 88 %

Procedure:
To a solution of N-[5-(4,5-diphenyl-1H-imidazol-2-ylthio)pentyl]-1-heptanamine (2.2 g, 0.005 mol), 1-hydroxybenzotriazole hydrate (0.81 g, 0.006 mol), and 2,4-difluorophenylacetic acid (1.12 g, 0.0065 mol) in N,N-dimethylformamide (50 mL) at 0° was added, portionwise as a solid, dicyclohexylcarbodiimide (1.24 g, 0.006 mol). The reaction mixture was stirred at 0° for 2.5 hours, then at ambient temperature for 72 hours. The solids were filtered and washed with chloroform. The filtrate was concentrated under vacuum and the residue (5.2 g) was chromatographed with 7:3 hexane-ethyl acetate. The resulting solid was triturated with hexane to give the title compound (2.59 g, 0.0044 mol) as a yellow oil. 1H NMR (CDCl3) δ7.6-7.0(m,11H), 6.8-6.5(m,2H), 3.7(d,2H,J=13.7Hz), 3.5(t,2H,J=6.4Hz), 3.4-3.0(m,3H), 2.9(t,2 H,J=6.1Hz), 1.8-1.1(m,17H), 0.9(t,3H,J=6.6Hz).
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:23]=[CH:22][CH:21]=[N:20]3)=[CH:15][CH:14]=2)=[C:10]([CH3:24])[C:9]2[C:8]([OH:25])=[CH:7][CH:6]=[C:5]([F:26])[C:4]=2[N:3]=1.[C:27](B1OC(C)(C)C(C)(C)O1)([CH3:29])=[CH2:28].O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O>[F:26][C:5]1[C:4]2[N:3]=[C:2]([C:27]([CH3:29])=[CH2:28])[C:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH:23]=[CH:22][CH:21]=[N:20]4)=[CH:15][CH:14]=3)=[C:10]([CH3:24])[C:9]=2[C:8]([OH:25])=[CH:7][CH:6]=1
Reactant: Cc1c(Cc2ccc(-n3cccn3)cc2)c(Cl)nc2c(F)ccc(O)c12
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)c1nc2c(F)ccc(O)c2c(C)c1Cc1ccc(-n2cccn2)cc1
Temperature: 90 °C

Procedure:
A mixture of 2-chloro-8-fluoro-4-methyl-3-(4-pyrazol-1-ylbenzyl)quinolin-5-ol (0.22 g), 2-isopropenyl-4,4,5,5-tetramethyl[1,3,2]dioxaborolane (0.23 mL), potassium phosphate monohydrate (0.68 g) and N,N-dimethylformamide (3.0 mL) was purged with argon for 20 minutes, and then treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.048 g), and the mixture heated at 90° C. for 12 hours. The mixture was cooled to room temperature, filtered through Celite and concentrated under reduced pressure. The residue was diluted with saturated aqueous ammonium chloride solution (50 mL) and extracted with ethyl acetate (3×20 mL). The combined extracts were washed with water (5.0 mL) and saturated aqueous sodium chloride solution (5.0 mL), dried over magnesium sulfate and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (1:0 to 1:1 by volume) gave title compound as a white solid (0.082 g).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([OH:13])=O)[NH:6]2.Cl.Cl.Cl.[N:17]1([CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[N:17]1([CH2:24][CH2:25][N:26]2[CH2:27][CH2:28][CH:29]([NH:32][C:11]([C:5]3[NH:6][C:7]4[C:3]([CH:4]=3)=[C:2]([Br:1])[CH:10]=[CH:9][CH:8]=4)=[O:13])[CH2:30][CH2:31]2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: NC1CCN(CCN2CCCCCC2)CC1
Reactant: O=C(O)c1cc2c(Br)cccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CCN(CCN2CCCCCC2)CC1)c1cc2c(Br)cccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
4-Bromo-1H-indole-2-carboxylic acid (1.5 g, 3.1 mmol), 1-(2-azepan-1-yl-ethyl)-piperidin-4-ylamine tri-hydrochloride (5) (2.1 g, 3.1 mmol) and DIEA (4.3 ml, 12.4 mmol) are dissolved under argon atmosphere in DMF (25 ml). TBTU (2.3 g, 3.4 mmol) is added at room temperature. The reaction mixture is stirred for 2 h at r.t., evaporated under high vacuum, dissolved in ethyl acetate and washed twice with 5% aqueous NaHCO3 solution. The organic layers are dried over sodium sulfate. Evaporation under reduced pressure gave 1.3 g (93%) of a beige solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[C:5]([F:9])=[CH:4][C:3]=1[OH:10].C([O-])([O-])=O.[K+].[K+].Cl[CH2:18][C:19](Cl)=[O:20].O>CN(C=O)C>[Br:8][C:6]1[C:5]([F:9])=[CH:4][C:3]2[O:10][CH2:18][C:19](=[O:20])[NH:1][C:2]=2[CH:7]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1cc(Br)c(F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1COc2cc(F)c(Br)cc2N1
Temperature: 80 °C
Yield: 90.3 %

Procedure:
To a 0° C. mixture of 2-amino-4-bromo-5-fluorophenol (38.0 g, crude from previous step) and K2CO3 (76.0 g, 553 mmol) in DMF (100 mL) was added 2-chloroacetyl chloride (23.0 g, 15.3 mL, 203 mmol) drop-wise. The reaction mixture was heated at 80° C. overnight then cooled to ambient temperature and poured into water (300 mL). The precipitate was collected by filtration, washed with water and dried to give 6-bromo-7-fluoro-4H-benzo[1,4]oxazin-3-one (41.0 g, 90%). 1H NMR (DMSO-d6, 400 MHz): δ 7.13 (m, 2H), 4.62 (s, 2H). The amide proton was not observed.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.OO.Cl.C(=O)([O-])[O-:13].[Na+].[Na+]>C(O)(=O)C.N1C=CC=CC=1>[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][N:6]=1)=[O:13]
Reactant: Cc1ccc(O)cn1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: O=Cc1ccc(O)cn1
Temperature: 120 °C
Reaction time: 3 h
Yield: 32 %

Procedure:
To a stirred solution of 21.8 g of 5-hydroxy-2-picoline (0.2 mol) in 200 mL of glacial acetic acid was added 18 mL of 30% hydrogen peroxide (0.159 mol) in one portion. The mixture was heated in an oil bath at 80°-85° C. with stirring for 3 h. Then another 18 mL of hydrogen peroxide was added and the mixture was stirred for 3 h at the same temperature. Excess solvent was removed in vacuo followed by the addition of acetone, which caused the pyridine N-oxide to crystallize. Without further purification, 200 mL of acetic anhydride was added to the solid and the mixture was heated at 120° C. with stirring in an oil bath for 2 h. After cooling to room temperature, excess acetic anhydride was removed by high vacuum distillation. The oily material was again oxidized with 30% hydrogen peroxide twice and rearranged with acetic anhydride following the same procedure and amounts depicted above. The black oily material obtained was hydrolyzed with 200 mL of 1N HCl (0.2 mol) at room temperature for 3 weeks (hydrolysis at higher temperature may be harmful to the pyridine nucleus). The mixture was neutralized with anhydrous sodium carbonate, indicated by litmus paper and then extracted three times with 300 mL of diethylether. The combined ether extracts were dried (MgSO4), filtered and evaporated to leave a solid material in a small amount of oil. The pure product (7.8 g, 32%) was obtained by filtering the solid, followed by washing it with a small amount of ether. It is yellow in color and shows a sharp melting point at 186°-187° C. 1H NMR (d6 -DMSO) δ: 11.10 (br. s, 1H, OH); 9.87 (s, 1H, CHO); 8.35 (d, J=2 Hz, 1H); 7.58 (d, J=9 Hz, 1H); 7.35 (d of d, J=2 Hz, 9 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[N:20]1([CH2:25][CH2:26][O:27][C:28]2[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=2)[CH:24]=[CH:23][N:22]=[CH:21]1>>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([NH:9][C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)=[CH:3][C:2]=1[NH:1][C:32](=[O:33])[C:31]1[CH:30]=[CH:29][C:28]([O:27][CH2:26][CH2:25][N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)=[CH:36][CH:35]=1
Reactant: N#Cc1ccc(C(=O)Nc2ccc(Cl)c(N)c2)cc1
Reactant: O=C(O)c1ccc(OCCn2ccnc2)cc1
Product: N#Cc1ccc(C(=O)Nc2ccc(Cl)c(NC(=O)c3ccc(OCCn4ccnc4)cc3)c2)cc1
Yield: 75 %

Procedure:
Using an analogous procedure to that described in Example 14, N-(3-amino-4-chlorophenyl)-4-cyanobenzamide was reacted with 4-[2-(imidazol-1-yl)ethoxy]benzoic acid (J. Med. Chem., 1985, 28, 1427) to give the title compound in 75% yield; NMR Spectrum: (DMSOd6) 4.48 (t, 2H), 4.65 (m, 2H), 7.09 (d, 1H), 7.51 (d, 1H), 7.68 (m, 3H), 7.82 (s, 1H), 8.0 (m, 4H), 8.1 (m, 2H), 8.73 (d, 1H), 9.18 (s, 1H), 9.89 (s, 1H), 10.66 (s, 1H); Mass Spectrum: M−H− 484.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:21][O:22][C:23](=[O:31])[C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:19])([CH3:18])[CH:12]=[C:11]3[CH3:20])=[C:4]([O:32][CH3:33])[CH:3]=1.C(N(CC)CC)C.[C:41]1([C:46](Cl)=[O:47])[S:45][CH:44]=[CH:43][CH:42]=1>C(Cl)Cl>[CH3:33][O:32][C:4]1[CH:3]=[C:2]([O:1][C:46]([C:41]2[S:45][CH:44]=[CH:43][CH:42]=2)=[O:47])[CH:7]=[CH:6][C:5]=1[C:8]1[C:9]([CH2:21][O:22][C:23](=[O:31])[C:24]2[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=2)=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([CH3:19])([CH3:18])[CH:12]=[C:11]2[CH3:20]
Reactant: COc1cc(O)ccc1-c1ccc2c(c1COC(=O)c1ccc(C)cc1)C(C)=CC(C)(C)N2
Reactant: O=C(Cl)c1cccs1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(OC(=O)c2cccs2)ccc1-c1ccc2c(c1COC(=O)c1ccc(C)cc1)C(C)=CC(C)(C)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
6-(4-Hydroxy-2-methoxyphenyl)-5-(4-methylbenzoyloxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 3-1, 25.6 mg, 0.0577 mmol) was dissolved in anhydrous methylene dichloride (1 mL), and then triethylamine (19 μL, 0.14 mmol) and 2-thenoyl chloride (11.2 mg, 0.0764 mmol) were added thereto. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (28.8 mg) as a pale yellow amorphous product. (Yield 93%)
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][N:10]=2)=[C:4]([O:34][CH3:35])[CH:3]=1.[S:36]1[CH:40]=[N:39][N:38]=[C:37]1[NH2:41].C(=O)([O-])[O-].[Cs+].[Cs+].C(#N)C>CCOC(C)=O.Cl>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:41][C:37]4[S:36][CH:40]=[N:39][N:38]=4)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][N:10]=2)=[C:4]([O:34][CH3:35])[CH:3]=1
Reactant: COc1cc(Cl)c(F)cc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Reactant: Nc1nncs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cc(Cl)c(F)cc1-c1nccc2cc(S(=O)(=O)Nc3nncs3)ccc12
Reaction time: 8 h
Yield: 60.7 %

Procedure:
A vial was charged with perfluorophenyl 1-(4-chloro-5-fluoro-2-methoxyphenyl)isoquinoline-6-sulfonate (INTERMEDIATE GGGGG, 1.233 g, 2.310 mmol) 1,3,4-thiadiazol-2-amine (0.280 g, 2.77 mmol), and cesium carbonate (2.258 g, 6.93 mmol). Acetonitrile (11.55 ml) was added, and the mixture was stirred overnight. The mixture was diluted with EtOAc and 0.5 N aq. HCl. The layers were separated, and the aq. layer was extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (25-g SNAP Ultra column, 0-5% MeOH/DCM) to give 1-(4-chloro-5-fluoro-2-methoxyphenyl)-N-(1,3,4-thiadiazol-2-yl)isoquinoline-6-sulfonamide (632 mg, 1.402 mmol, 60.7% yield) as an off-white solid. m/z (ESI) 451.0 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][C@@H:14]([CH3:19])[C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH2:20][CH:21]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:22]#[N:23]>>[C:22]([CH:21]([NH:20][C:10]([C:7]1[CH:6]=[C:5]([O:13][C@@H:14]([CH3:19])[C:15]([F:18])([F:17])[F:16])[C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:9][N:8]=1)=[O:12])[C:24]([CH3:27])([CH3:26])[CH3:25])#[N:23]
Reactant: CC(C)(C)C(N)C#N
Reactant: C[C@H](Oc1cc(C(=O)O)ncc1C1CC1)C(F)(F)F
Product: C[C@H](Oc1cc(C(=O)NC(C#N)C(C)(C)C)ncc1C1CC1)C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-Cyclopropyl-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridine-2-carboxylic acid (Example 68a) and 2-Amino-3,3-dimethyl-butyronitrile (CAN 77425-86-6) as starting materials and isolated (2 g, 99%); MS (ESI, m/z): 370.6 (M+H+).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[NH2:11][C:12]1[N:17]=[C:16]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:15]=[CH:14][N:13]=1>C(OCC)(=O)C>[CH:1]([NH:11][C:12]1[N:17]=[C:16]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:15]=[CH:14][N:13]=1)=[O:3]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)Cc1ccnc(N)n1
Solvent: O=CO
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccnc(NC=O)n1
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
A mixture of acetic anhydride (32.7 g.) and formic acid (16.2 g.) was stirred at 50° to 60° C. for 30 minutes. The solution was added to a suspension of methyl 2-(2-aminopyrimidin-4-yl)acetate (17.93 g.) in ethyl acetate (300 ml.) at room temperature over 10 minutes, and the solution was stirred at room temperature for 3 hours. After removing the insoluble substance by filtration, water (300 ml.) was added to the filtrate, and then the mixture was adjusted to pH 7 with sodium bicarbonate. The aqueous layer was separated and extracted with ethyl acetate. The extract and the organic layer were combined, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, treated with activated charcoal, and then concentrated under reduced pressure. The residue was triturated with diethyl ether to give methyl 2-(2-formamidopyrimidin-4-yl)acetate (14.62 g.), mp 103° to 107° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[CH:10]([N:13]1[CH2:18][CH2:17][CH:16]([NH:19][S:20]([CH2:23][C:24]([NH2:27])([CH3:26])[CH3:25])(=[O:22])=[O:21])[CH2:15][CH2:14]1)([CH3:12])[CH3:11]>>[CH:10]([N:13]1[CH2:18][CH2:17][CH:16]([NH:19][S:20]([CH2:23][C:24]([NH:27][C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:9])([CH3:25])[CH3:26])(=[O:22])=[O:21])[CH2:15][CH2:14]1)([CH3:12])[CH3:11]
Reactant: CC(C)N1CCC(NS(=O)(=O)CC(C)(C)N)CC1
Reactant: O=C(O)c1ccc(Cl)s1
Product: CC(C)N1CCC(NS(=O)(=O)CC(C)(C)NC(=O)c2ccc(Cl)s2)CC1

Procedure:
5-Chloro-thiophene-2-carboxylic acid [2-(1-isopropyl-piperidin-4-ylsulfamoyl)-1,1-dimethyl-ethyl]-amide was prepared by an analogous procedure as described in example 26 viii) starting from 195 mg (1 equiv.) 5-chloro-thiophene-2-carboxylic acid and 332 mg (1.2 mmol) 2-amino-2-methyl-propane-1-sulfonicacid (1-isopropyl-piperidin-4-yl)-amide. Final purification by preparative RP-HPLC (CH3CN/H2O gradient+0.1% TFA) gave pure 5-chloro-thiophene-2-carboxylic acid [2-(1-isopropyl-piperidin-4-ylsulfamoyl)-1,1-dimethyl-ethyl]-amide. The title compound was obtained as its trifluoroacetate in form of a colorless amorphous material.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[O:4][CH:5]([CH3:9])[C:6](Cl)=[O:7].[Mg].[C:16]([O:24][CH2:25][CH3:26])(=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C(OCC)(=O)CC(OCC)=O>CCOCC>[CH2:21]([O:20][C:18](=[O:19])[CH:17]([C:6](=[O:7])[CH:5]([O:4][C:3]1[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:2]=1[Cl:1])[CH3:9])[C:16]([O:24][CH2:25][CH3:26])=[O:23])[CH3:22]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(Oc1ccc(Cl)cc1Cl)C(=O)Cl
Agent: [Mg]
Solvent: CCOCC
Product: CCOC(=O)C(C(=O)OCC)C(=O)C(C)Oc1ccc(Cl)cc1Cl
Yield: 76 %

Procedure:
A mixture of 25 g of 2-(2',4'-dichloro-phenoxy)-propionyl chloride and 30 ml of ether is added dropwise to a 35% etheral solution of magnesium-diethyl malonate prepared from 17.6 g of diethyl malonate. When the addition of the acid chloride is completed the reaction mixture is heated to boiling for an hour and worked up as described in Example 1. Thus 29 g of the desired compound are obtained in the form of a yellow oil, yield 76%, nD25 =1,355.
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[CH:9]=2)[CH2:4][C:3]21[CH2:26][C:25]1[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:19]2.[C:27](=[N:33][Si](C)(C)C)=[N:28][Si](C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:14]([C:13]1[CH:12]=[C:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[CH2:4][C:3]2([CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19]2)/[C:2]/3=[N:28]/[C:27]#[N:33])[CH:18]=[CH:17][CH:16]=1)#[N:15]
Reactant: N#Cc1cccc(-c2ccc3c(c2)C(=O)C2(Cc4ccccc4C2)C3)c1
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#C/N=C1\c2cc(-c3cccc(C#N)c3)ccc2CC12Cc1ccccc1C2
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 100.2 %

Procedure:
To a solution of 3-(1-oxo-1,1′,3,3′-tetrahydro-2,2′-spirobi[indene]-6-yl)benzonitrile (34 mg, 0.1 mmol) in DCM (5 mL) was added TiCl4 (76 mg, 0.4 mmol) dropwise, the mixture was stirred at 50° C. at Ar2 under microwave for 5 minutes, N,N′-methanediylidenebis(1,1,1-trimethylsilanamine) (74 mg, 0.4 mmol) was added dropwise. The mixture was stirred at 60° C. at Ar2 under microwave for 10 minutes and poured into ice-water (10 mL). The aqueous layer was extracted with CH2Cl2, which was combined with the organic layer. The organic layer was dried and concentrated to give crude ((Z)—N-(5-(3-cyanophenyl)-1′,3′-dihydro-2,2′-spirobi[indene]-3(1H)-ylidene) cyana mide (36 mg, 99%).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[C:8]([CH2:10]O)[CH:7]=[CH:6][C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[NH:22][N:21]([C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[NH:20][N:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:1][CH2:10][C:8]1[CH:7]=[CH:6][C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[NH:22][N:21]([C: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)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[NH:20][N:19]=2)=[C:4]([Cl:3])[CH:9]=1
Reactant: OCc1ccc(-c2ccccc2C2=NNN(C(c3ccccc3)(c3ccccc3)c3ccccc3)N2)c(Cl)c1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1cc(CBr)ccc1-c1ccccc1C1=NNN(C(c2ccccc2)(c2ccccc2)c2ccccc2)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.2 %

Procedure:
First 6.79 g of bromine (42.5 mmol) and then 20.4 g of the compound from Example XXXV in 300 ml of methylene chloride are added dropwise to a solution of 11.2 g of triphenylphosphine (42.5 mmol) in 100 ml of methylene chloride under argon in an ice-bath. After the reaction mixture has been stirred at room temperature for 1 hour, it is filtered through silica gel and eluted with methylene chloride. Concentration of the filtrate and digestion of the residue with hexane gives 15.8 g of white crystals [68.9% of theory; melting point 15°-60° C.; Rf 0.40 (hexane/ethyl acetate=3:1)].
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[CH:11][C:10]([N:13]([CH3:33])[C:14](=[O:32])[C:15]([C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=3)([CH3:17])[CH3:16])=[C:9]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=3[CH3:41])[CH:8]=2)[CH2:3]1.C(N(CC)C(C)C)(C)C.[CH3:51][S:52](Cl)(=[O:54])=[O:53]>ClCCl.CN(C1C=CN=CC=1)C>[F:27][C:24]([F:25])([F:26])[C:22]1[CH:23]=[C:18]([C:15]([CH3:16])([CH3:17])[C:14]([N:13]([C:10]2[CH:11]=[N:12][C:7]([N:4]3[CH2:5][CH2:6][C@H:2]([NH:1][S:52]([CH3:51])(=[O:54])=[O:53])[CH2:3]3)=[CH:8][C:9]=2[C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=2[CH3:41])[CH3:33])=[O:32])[CH:19]=[C:20]([C:28]([F:29])([F:30])[F:31])[CH:21]=1
Reactant: Cc1cc(F)ccc1-c1cc(N2CC[C@H](N)C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(F)ccc1-c1cc(N2CC[C@H](NS(C)(=O)=O)C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.3 %

Procedure:
To a solution of 600 mg (1.03 mmol) (S)—N-[6-(3-amino-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide in 6 ml dichloromethane were added 6 mg (0.05 mmol) 4-(N,N-dimethylamino)pyridine, 266 mg (2.06 mmol) N,N-diisopropylethylamine and 153 mg (1.34 mmol) methanesulfonyl chloride. After stirring at room temperature for 18 h the reaction mixture was diluted with 20 ml dichloromethane and washed with 20 ml of a saturated aqueous solution of sodium carbonate. The combined organic layers were dried over sodium sulfate, concentrated and purified by flash chromatography to give 553 mg (81%) of the title compound as an off-white foam.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:10]1[O:11][C:12](=[N:21][C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=2)[C:13]2[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1)[CH3:9])(C)(C)C>N1CCCCC1.Cl.O1CCOCC1>[NH2:7][CH:8]([C:10]1[N:21]([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=2)[C:12](=[O:11])[C:13]2[C:14](=[CH:16][CH:17]=[CH:18][C:19]=2[Cl:20])[N:15]=1)[CH3:9]
Reactant: CC(NC(=O)OC(C)(C)C)c1nc2cccc(Cl)c2c(=Nc2cc(F)cc(F)c2)o1
Agent: Cl
Solvent: C1CCNCC1
Solvent: C1COCCO1
Product: CC(N)c1nc2cccc(Cl)c2c(=O)n1-c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 98 %

Procedure:
A solution of compound 169 (1.68 mmol) in piperidine (2 mL) was stirred for 3 h at ambient temperature. Evaporation of the reaction mixture to dryness under high vacuum gave a yellow foam. This foam was dissolved in a 4M solution of hydrogen chloride in 1,4-dioxane (4 mL) and stirred for 17 h at ambient temperature. The reaction mixture was then concentrated to dryness, basified with 10% aqueous potassium carbonate (40 mL) and extracted with MTBE (3×20 mL). Combining the organic extracts, drying over sodium sulfate and concentrating to dryness afforded a solid residue. This residue was dissolved in d-chloroform (5 mL), and warmed for 15 h at 50° C. After cooling to ambient temperature, the reaction mixture was washed with water (3×10 mL), dried over sodium sulfate and evaporated to dryness, affording a 98% yield of compound 170 as a white solid. m.p. 200-202° C.; 1H NMR (CDCl3) δ (ppm) 7.65 (m, 2H), 7.49 (m, 1H), 7.01 (t, 1H, J=6.6 Hz), 6.89 (m, 2H), 3.68 (m, 1H), 1.33 (d, 3H, J=6.6 Hz), 1.25 (s, 2H); m/z=336 (M+H). The reaction described above and compound 170 are shown below.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1.[C:21](OC(=O)C)(=[O:23])C>C(O)=O>[CH2:14]([S:13][C:4]1[N:3]=[C:2]([NH:1][CH:21]=[O:23])[N:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:5]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc(SCc2ccccc2)nn1-c1ccccc1
Solvent: O=CO
Product: O=CNc1nc(SCc2ccccc2)nn1-c1ccccc1

Procedure:
5-Amino-3-benzylthio-1-phenyl-1,2,4-triazole (45 g) was suspended in acetic anhydride (31 ml) and formic acid (16.09 ml), and the mixture was stirred for 1 hour at 80° C. The solvents were then removed, and the residue was recrystallised from ethyl acetate to give 35.4 g of the desired product, mp 94° C.