Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C[Al](C)C.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]([CH3:24])([CH3:23])[C:21]#[N:22]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:21](=[NH:22])[C:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[F:13])([CH3:24])[CH3:23])=[CH:4][CH:3]=1
Reactant: CC(C)(C#N)c1ccccc1F
Reactant: Nc1ccc(Br)cc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC(C)(C(=N)Nc1ccc(Br)cc1)c1ccccc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 38.6 %

Procedure:
To an oven dried, N2 purged 250 mL round bottom flask attached with addition funnel was added 4-bromoaniline (7.31 g, 42.5 mmol) and anhydrous toluene (40 mL). To the reaction solution at 0° C. was added a 2.0 M Me3Al (32 mL, 1.5 molar equiv) solution. The reaction solution was stirred at 0° C. for 30 min, then a solution of 2-(2-fluorophenyl)-2-methylpropanenitrile (7.62 g, 46.7 mmol) in toluene (25 mL) was added to the reaction flask. The reaction solution was allowed to stir at 90° C. for 5 hr. The cooled reaction solution was quenched with an aq sodium potassium tartrate solution. After standing 20 min, the organic phase was partitioned and washed with sodium potassium tartrate solution. The organic solution was extracted with 1N aq HCl (100 mL×3). The combined aq HCl solution was neutralized by addition of 1N aq NaOH and extracted with dichloromethane (200 mL×2). The dichloromethane product solution was dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound (5.5 g, 39% yield). GCMS m/z=334, 336 [M]+.
Reaction SMILES: [C:1]([S-:3])#[N:2].[K+].[C:5](Cl)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH:14]1([NH2:17])[CH2:16][CH2:15]1>CC(C)=O>[CH2:5]([O:12][NH:2][C:1]([NH:17][CH:14]1[CH2:16][CH2:15]1)=[S:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N#C[S-]
Reactant: O=C(Cl)c1ccccc1
Reactant: NC1CC1
Agent: [K+]
Solvent: CC(C)=O
Product: S=C(NOCc1ccccc1)NC1CC1
Reaction time: 1.5 h

Procedure:
To a solution of the KSCN (4.60 g; 47.33 mmoL) in acetone (35 mL), at 0° C., was added dropwise benzoylchloride (5.0 mL; 43.03 mmoL). The milky solution was stirred in an ice bath for 1.5 h, then, cyclopropylamine (3.2 mL; 46.0 mmoL) was added dropwise. The reaction mixture was stirred for 1.5 h at 0° C., then, more cyclopropylamine (0.50 mL, 7.22 mmoL) was added and the reaction mixture stirred at R.T. for an additional 30 min. The reaction mixture was poured into ice/H2O (300 mL), stirred for 5 min. and the light yellow solid was filtered, washed several times with H2O and dried to provide N-benzyloxy-N′-cyclopropyl thiourea (6.62 g). This thiourea was suspended in a solution of 2N NaOH (50 mL) and heated at reflux for 15 min. The solution was cooled to R.T., saturated with solid NaCl and extracted with EtOAc (3×). The combined EtOAc extracts were washed with H2O (2×) and brine (1×), dried (MgSO4), filtered and evaporated to give the crude product as an off-white solid. The solid was triturated in hexane/EtOAc 5/5 to provide the N-cyclopropyl thiourea 8d as a white crystalline solid (2.5 g; 50% yield).
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:13][NH2:14].[CH:15]1([N:19]2[CH2:24][CH2:23][CH:22]([O:25][C:26]3[N:31]=[CH:30][C:29]([CH:32]=O)=[CH:28][N:27]=3)[CH2:21][CH2:20]2)[CH2:18][CH2:17][CH2:16]1>>[CH:15]1([N:19]2[CH2:24][CH2:23][CH:22]([O:25][C:26]3[N:31]=[CH:30][C:29]([C:32]4[N:14]([CH3:13])[C:4](=[O:6])[C:3]5[CH:7]=[CH:8][N:9]=[C:10]([O:11][CH3:12])[C:2]=5[N:1]=4)=[CH:28][N:27]=3)[CH2:21][CH2:20]2)[CH2:18][CH2:17][CH2:16]1
Reactant: O=Cc1cnc(OC2CCN(C3CCC3)CC2)nc1
Reactant: COc1nccc(C(=O)O)c1N
Reactant: CN
Product: COc1nccc2c(=O)n(C)c(-c3cnc(OC4CCN(C5CCC5)CC4)nc3)nc12

Procedure:
The entitled compound was obtained according to the method of Example 15 but starting from 3-amino-2-methoxyisonicotinic acid, methylamine and 2-[(1-cyclobutylpiperidin-4-yl)oxy]pyrimidine-5-carbaldehyde.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.N[C:10]1[CH:11]=[CH:12][C:13](C)=[C:14]([OH:16])[CH:15]=1>[OH-].[Na+]>[CH:7]1[C:2](=[N:1][C:11]2[CH:10]=[CH:15][C:14]([OH:16])=[CH:13][CH:12]=2)[CH:3]=[CH:4][C:5](=[O:8])[CH:6]=1
Reactant: Nc1ccc(O)cc1
Reactant: Cc1ccc(N)cc1O
Agent: [Na+]
Agent: [OH-]
Product: O=C1C=CC(=Nc2ccc(O)cc2)C=C1
Yield: 60.2 %

Procedure:
0.01 mole (1.09 g) of paraaminophenol is dissolved in 100 cm3 of a 0.1 N NaOH solution. A second solution of 0.01 mole (1.23 g) of 5-amino-2-methyl phenol in 100 cm3 of a 0.1N NaOH solution is also prepared. The two solutions are then mixed and air is bubbled in the resulting mixture for about 5 hours at ambient temperature. The reaction medium is then acidified with sufficient HCl to pH 5 to produce 1.2 g of said indophenol which is then filtered off and which, after recrystallization from a dimethylformamide-water mixture, melts at 215°.
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[NH2:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH3:19])[CH:14]=[CH:13]2.O.C(=O)([O-])[O-].[Na+].[Na+]>CN1CCCC1=O>[CH3:19][N:15]1[C:16]2[C:12](=[CH:11][C:10]([NH:9][C:3]3[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=3)=[CH:18][CH:17]=2)[CH:13]=[CH:14]1
Reactant: Cn1ccc2cc(N)ccc21
Reactant: Clc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cn1ccc2cc(Nc3ccncc3)ccc21
Yield: 53.3 %

Procedure:
4-Chloropyridine hydrochloride (8 g) was added to a solution of 5-amino-1-methylindole (7 g) in 75 ml 1 -methyl-2-pyrrolidinone preheated to 100° C. The addition of 4-chloropyridine hydrochloride (4 g) after one hour caused no further reaction as determined by TLC. After two hours the reaction mixture was cooled, stirred with water, basified with sodium carbonate and extracted with ethyl acetate. The dried (anhydrous magnesium sulfate) organic layer was filtered and evaporated to 12.7 g of an oil. The oil was eluted through silica with 10% methanol in dichloromethane via flash column chromatography to give the product which was triturated with ether to yield 5.7 g of a solid, m.p. 202°-203° C. Recrystallization from acetonitrile yielded 5 g of product as crystals, mp 209°-211° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[N:19]([Si](C)(C)C)=[N+:20]=[N-:21].C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1.CCOC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([C:8]([C:9]2[N:19]=[N:20][NH:21][N:10]=2)([CH3:12])[CH3:11])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C#N)c1ccc(-c2ccccc2)c(F)c1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(c1ccc(-c2ccccc2)c(F)c1)c1nn[nH]n1
Temperature: 150 °C

Procedure:
A mixture of 2-(2-fluoro-biphenyl-4-yl)-2-methyl-propionitrile (100 mg, 0.418 mmol), azidotrimethylsilane (222 μL, 1.672 mmol) and dibutyltin oxide (20 mg) in dry toluene (2.5 mL) was heated under microwave irradiation in a sealed vessel at 150° C. for 1000 seconds. The solution was then diluted with EtOAc, washed with water, the organics separated, dried (MgSO4), filtered and evaporated to dryness. The residue was purified by column chromatography (EtOAc) to afford the title compound, 5-[1-(2-Fluoro-biphenyl-4-yl)-1-methyl-ethyl]-2H-tetrazole as a colorless powder. 1H NMR (500 MHz, CD3OD) δ 7.50 (2H, m), 7.40-7.46 (3H, m), 7.35 (1H, m), 7.05-7.12 (2H, m), 1.87 (6H, s). LCMS(EI) 283.1 (M+H)+, 324.2 (M+Na+H3O)+.
Reaction SMILES: [CH3:1][C:2]([S-:5])([CH3:4])[CH3:3].[Na+].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10](Cl)[N:9]=1>CN(C=O)C.C(OCC)(=O)C>[C:2]([S:5][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([Cl:7])[N:9]=1)([CH3:4])([CH3:3])[CH3:1]
Reactant: Clc1cccc(Cl)n1
Reactant: CC(C)(C)[S-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)Sc1cccc(Cl)n1
Temperature: 80 °C
Reaction time: 12 h
Yield: 91.8 %

Procedure:
A suspension of sodium 2-methylpropane-2-thiolate (188 mg, 1.68 mmol) in DMF was treated with 2,6-dichloropyridine (4865 μl, 1.46 mmol) at ambient temperature in a vial. The vial was capped and heated to 80° C. with rapid stirring of the colorless solution. After 12 hours, the reaction was cooled to ambient temperature and diluted with ethyl acetate. The ethyl acetate solution was washed with brine solution, dried with sodium sulfate, filtered, concentrated and purified on silica gel. Elution with 2% to 10% ethyl acetate/hexanes provided the title compound (271 mg, 1.34 mmol, 92.0% yield) as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH2:16]([O:19][C:20]1[CH:25]=[N:24][CH:23]=[C:22](Cl)[N:21]=1)[CH:17]=[CH2:18]>>[CH2:16]([O:19][C:20]1[CH:25]=[N:24][CH:23]=[C:22]([N:13]2[CH:14]=[C:10]([C:9]#[C:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=3)[N:11]=[C:12]2[CH3:15])[N:21]=1)[CH:17]=[CH2:18]
Reactant: C=CCOc1cncc(Cl)n1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Product: C=CCOc1cncc(-n2cc(C#Cc3ccnc(Cl)c3)nc2C)n1

Procedure:
The title compound, light yellow viscous oil, MS: m/e=352.2, 354.2 (M+H+), was prepared in accordance with the general method of example 1b from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine (CAS: [802905-83-5]) and 2-Allyloxy-6-chloro-pyrazine (CAS: [107466-49-9].
Reaction SMILES: [CH:1](/[C:9]1[C:17]2[CH2:16][CH2:15][C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][C:12]=2[NH:11][N:10]=1)=[CH:2]\[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C1C2C(=CC=CC=2)CCC1.[Pd]>[CH:1](/[C:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:16]=2)[NH:11][N:10]=1)=[CH:2]\[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C1=C(Oc2ccccc2)CCc2c(/C=C/c3ccccc3)n[nH]c21
Agent: [Pd]
Solvent: c1ccc2c(c1)CCCC2
Product: C(=C/c1n[nH]c2cc(Oc3ccccc3)ccc12)\c1ccccc1
Temperature: 155 °C
Yield: 55 %

Procedure:
A suspension of 3-(E-styryl)-6-phenoxy-4,5-dihydro-1H-indazole (200 mg. 0.64 mmol) and 5% Pd/C (200 mg) in 10 mL of tetralin was heated at 155° C. for 18 h. The catalyst was removed by filtering the hot solution and washed with THF, EtOAc and MeOH. The filtrate was concentrated under reduced pressure and the residue was chromatographed on silica gel eluting hexanes/EtOAc (2:1) to provide 3-(E-styryl)-6-phenoxy-1H-indazole as an off-white solid (110 mg, 55%). 1H NMR (DMSO-d6) δ 6.96 (s, 2H), 7.10 (d, 2H, J=7.7 Hz), 7.20 (t, 1H, J=7.1 Hz), 7.30 (t, 1H, J=7.1 Hz), 7.44 (m, 6H), 7.71 (d, 2H, J=7.5 Hz), 8.20 (d, 1H, J=9.2 Hz), 12.90 (s, 1H). Anal. Calc. for C21H16N2O.0.1H2O: C, 80.28; H, 5.20; N, 8.92. Found: C, 80.20; H, 5.21; N, 8.93.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:7][O:8][C:9]=1[CH3:10])=[O:4].C([Li])CCC.[C:22](#[N:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Cl-].[NH4+]>CCCCCC.O1CCCC1.O>[NH2:29][C:22]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:10][C:9]1[O:8][N:7]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]=1[C:3]([NH:2][CH3:1])=[O:4]
Reactant: N#Cc1ccccc1
Reactant: CNC(=O)c1c(-c2ccccc2)noc1C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CNC(=O)c1c(-c2ccccc2)noc1C=C(N)c1ccccc1
Temperature: -5 °C
Reaction time: 1 h
Yield: 63.6 %

Procedure:
A mixture of 100 grams (0.463 mole) of N,5-dimethyl-3-phenyl-isoxazole-4-carboxamide and 1000 milliliters of dry tetrahydrofuran is cooled to -5° C. While maintaining the temperature at -5° to 0° C., there is added over a period of 1 hour a solution of 435 grams (0.95 mole) of 15% n-butyllithium in hexane. The resulting mixture is stirred for 1 hour and while maintaining the temperature at -5° to 0° C. a solution of 50 grams (0.485 mole) of benzonitrile in 100 milliliters of dry tetrahydrofuran is added over a period of 1 hour. The resulting mixture is stirred for an additional hour at which time 100 milliliters of saturated ammonium chloride is added dropwise over a period of 15 to 20 minutes. The resulting solution is then mixed for 1 hour and 40 minutes and then diluted with 200 milliliters of water. The solids are then filtered off and washed three times with tetrahydrofuran/hexane. The solids are then dried under vacuum to give 94 grams of 5-(2-amino-2-phenylethenyl)-N-methyl-3-phenyl-isoxazole-4-carboxamide; m.p. 181° to 183° C. Further extraction from the mother liquors provide a total of 104 grams or 70.3% of the desired title compound. After further recrystallization from chloroform/methanol, the purified product has a melting point of 187° to 190° C.
Reaction SMILES: O[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:3].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:50]([O:57][C:58]([N:60]1[CH2:64][CH2:63][CH2:62][C@H:61]1[C:65](=[O:79])[NH:66][C:67]1[S:68][CH:69]=[C:70]([C:72]2[CH:77]=[CH:76][C:75]([NH2:78])=[CH:74][CH:73]=2)[N:71]=1)=[O:59])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>CN(C=O)C>[CH2:50]([O:57][C:58]([N:60]1[CH2:64][CH2:63][CH2:62][CH:61]1[C:65](=[O:79])[NH:66][C:67]1[S:68][CH:69]=[C:70]([C:72]2[CH:73]=[CH:74][C:75]([NH:78][C:2](=[O:3])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]3[CH:16]4[CH:11]([NH:12][C:13](=[O:14])[NH:15]4)[CH2:10][S:9]3)=[CH:76][CH:77]=2)[N:71]=1)=[O:59])[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: Nc1ccc(-c2csc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)n2)cc1
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCCCC1SCC2NC(=O)NC21)Nc1ccc(-c2csc(NC(=O)C3CCCN3C(=O)OCc3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
70 mg (0.28 mmol) of biotin was dissolved in 5 mL of dry DMF. To this solution were added DIEA (0.34 mmol, 0.06 mL) and HATU (0.28 mmol, 0.1 g). This solution was stirred at room temperature for 2 hours. 80 mg (0.189 mmol) of Compound 5050 was then added to the reaction mixture and stirred at room temperature overnight. Reaction mixture was evaporated to dryness and redissolved in 5 mL of DMF and purified using reverse phase HPLC. MS: 649.2 (M+H+).
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[C:12]([F:13])=[C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:10]=[CH:9][N:8]=1.CCOCC>C(Cl)(Cl)Cl>[ClH:3].[Cl:3][CH2:6][C:7]1[C:12]([F:13])=[C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:10]=[CH:9][N:8]=1
Reactant: OCc1nccc(N2CCOCC2)c1F
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: Cl
Product: Fc1c(N2CCOCC2)ccnc1CCl

Procedure:
Thionyl chloride (1.8 ml) in chloroform (15 ml, alumina dried) was added dropwise to a stirred and cooled solution of 2-hydroxymethyl-3-fluoro-4-morpholinopyridine (1.74 g) in chloroform (20 ml). After 2 hours at room temperature the solution was reduced in volume and ether added. The precipitate was filtered off, washed and dried to give 2-chloromethyl-3-fluoro-4-morpholinopyridine hydrochloride (2.1 g) m.p. 203°-205°.
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].[Br:8][C:9]1[CH:10]=[C:11]([Cl:16])[C:12](Cl)=[N:13][CH:14]=1>CN(C=O)C.C(OCC)(=O)C.O>[Br:8][C:9]1[CH:10]=[C:11]([Cl:16])[C:12]([O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[N:13][CH:14]=1
Reactant: OCC1CC1
Reactant: Clc1cc(Br)cnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Clc1cc(Br)cnc1OCC1CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of cyclopropylmethanol (4.64 mL) in DMF (100 mL) was added sodium hydride (60% oil, 2.29 g), and the mixture was stirred at room temperature for 10 min. To the reaction mixture was added 5-bromo-2,3-dichloropyridine (10.0 g), and the mixture was stirred with heating at 70° C. for 30 min. The reaction mixture was allowed to cool to room temperature, and diluted with ethyl acetate and water, and the organic layer was separated. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (8.11 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[CH:10][CH2:11]O)[CH2:3]1.[Cl:14][C:15]([Cl:19])([Cl:18])[C:16]#[N:17].C([O:22]CC)C>>[Cl:14][C:15]([Cl:19])([Cl:18])[C:16]([NH:17][C:4]1([CH:10]=[CH2:11])[CH2:3][C:2]([CH3:13])([CH3:1])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5]1)=[O:22]
Reactant: CCOCC
Reactant: CC1(C)CC(=CCO)CC(C)(C)C1
Reactant: N#CC(Cl)(Cl)Cl
Product: C=CC1(NC(=O)C(Cl)(Cl)Cl)CC(C)(C)CC(C)(C)C1
Temperature: -10 °C
Yield: 66 %

Procedure:
To a solution of alcohol 3 (0.8 g, 4.7 mmol) in diethyl ether (5 ml) NaH (0.22 g of a 55% dispersion in mineral oil (0.22 mmol)) was added. The reaction mixture was cooled to −10° C. and a solution of trichloroacetonitrile (0.68 g, 4.7 mmol) in diethyl ether (3 ml) was added dropwise. The solution was allowed to warm to room temperature and the solvent evaporated. Pentane (8 ml) containing methanol (0.018 ml) was added to the residue. The resulting mixture was filtered through a pad of celite and evaporated. The residual oil was dissolved in xylene (10 ml) and refluxed for 10 h. Main amount of xylene was distilled off at reduced pressure (11 mm Hg) and the residue purified by flash chromatography on silica gel (hexane, hexane-ethyl acetate, 10:1) to give 4 (0.98 g, 66%) as an oil. 1H NMR (CDCl3, TMS): 0.95 (6H, s, 3,5-CH3); 1.18 (6H, s, 3,5-CH3); 1.1-1.5 (2H, m, 4-CH2); 1.32 (2H, d, 15 Hz, 2,6-CH2); 2.15 (2H, d, 15 Hz, 2,6-CH2); 5.08 (1H, d, 11 Hz, ═CH2); 5.13 (1H, d, 18 Hz, ═CH2); 5.85 (1H, dd, 18 and 11 Hz, —HC═) and 6.7 ppm (1H, br s, NH).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]([CH3:14])([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)[CH3:6])[CH3:2].[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.O.C(Cl)Cl.N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1>[CH2:1]([O:3][C:4](=[O:15])[C:5]([C:7]1[CH:8]=[CH:9][C:10]([CH2:13][Br:16])=[CH:11][CH:12]=1)([CH3:14])[CH3:6])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C(C)(C)c1ccc(C)cc1
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(C)(C)c1ccc(CBr)cc1
Yield: 97.7 %

Procedure:
To a solution of 2-methyl-2-p-tolyl-propionic acid ethyl ester (263 mg, 1.27 mmol) and N-bromosuccinimide (272 mg, 1.53 mmol) in CCl4 (15 mL) was added 1,1′-azobis(cyclohexanecarbonitrile) (15.5 mg, 0.06 mmol). The reaction was heated at reflux for 1 h and was diluted with water and CH2Cl2. The layers were separated and the aqueous layer was washed with CH2Cl2 (3×). The combined organic solutions were dried (MgSO4), filtered, and concentrated. Medium pressure chromatography (95:5 hexanes:EtOAc) provided 2-(4-bromomethyl-phenyl)-2-methyl-propionic acid ethyl ester (354 mg). 1H NMR (400 MHz, CDCl3) δ 7.31 (m, 4H), 4.47 (s, 2H), 4.10 (q, 2H), 1.54 (s, 6H), 1.17 (t, 3H).
Reaction SMILES: [N:1]1([NH2:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl.[Cl:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[F:19]>C(O)(C)C>[ClH:12].[F:19][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:13]=1[NH:10][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: Nn1ccc2ccccc21
Reactant: Fc1cnccc1Cl
Agent: Cl
Solvent: CC(C)O
Product: Fc1cnccc1Nn1ccc2ccccc21

Procedure:
The title compound was prepared from 1H-indol-1-amine and 4-chloro-3-fluoropyridine hydrochloride in isopropanol at 90° C. for 4 hours in substantially the same manner as in Example 17, m.p. >250° C.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH2:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=O)C.C(N(CC)CC)C.[C:35]1(=O)[CH2:39][CH2:38][CH2:37][CH2:36]1>ClC(Cl)C>[CH:35]1([NH:23][CH2:22][C:16]2([C:13]3[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:11][CH:12]=3)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: O=C1CCCC1
Reactant: NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: c1cc(C2(CNC3CCCC3)CCOCC2)ccc1OCCCN1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.3 %

Procedure:
To a solution of (4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl}methylamine (254 mg, 0.798 mmol) in dichloroethane (5 mL) under nitrogen atmosphere were added acetic acid (37 mg, 1.6 mmol), triethylamine (97 mg, 1.6 mmol) and cyclopentanone (10 mg, 1.19 mmol). The mixture was stirred for 30 min at ambient temperature and NaHB(OAc)3 (204 mg, 1.6 mmol) was added at 0° C. After stirring overnight, the reaction mixture was filtered over celite, concentrated in vacuo and purified by column chromatography on silica gel eluting with DCM:MeOH:NH3 (89:10:1) to give the title compound (226 mg, 58%). 1H NMR (400 MHz, CDCl3) δ 7.20 (d, 2H), 6.88H), 4.03 (t, 2H), 3.78-3.73 (m, 2H), 3.59-3.53 (m, 2H), 2.84 (q, 1H), 2.73 (t, 2H), 2.65-2.68 (m, 6H), 2.03-2.12 (m, 4H), 1.84-1.94 (m, 6H), 1.65-1.72 (m, 2H), 1.51-1.58 (m, 2H), 1.41-1.46 (m, 2H), 1.07-1.16 (m, 2H).
Reaction SMILES: [F:1][C:2]1[S:3][C:4]([CH3:10])=[C:5]([CH3:9])[C:6]=1[NH:7][NH2:8].[C:11]([CH2:13][C:14](Cl)=[O:15])#[N:12]>O1CCCC1>[NH2:12][C:11]1[N:7]([C:6]2[C:5]([CH3:9])=[C:4]([CH3:10])[S:3][C:2]=2[F:1])[N:8]=[C:14]([OH:15])[CH:13]=1
Reactant: Cc1sc(F)c(NN)c1C
Reactant: N#CCC(=O)Cl
Solvent: C1CCOC1
Product: Cc1sc(F)c(-n2nc(O)cc2N)c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Then, the obtained hydrazine derivative was dissolved in 50 mL of tetrahydrofuran, and to this solution, 5.1 g of cyanoacetyl chloride was added, followed by stirring at room temperature for 2 hours. Then, the solvent was distilled off under reduced pressure, the residue was dissolved in 50 mL of 1-propanol, and 3.1 g of methanesulfonic acid was added, followed by reflux with heating for 3 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure, followed by neutralization with sodium hydrogen carbonate to a pH of 7, and extraction with ethyl acetate was carried out. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 5.5 g of 5-amino-1-(2-fluoro-4-methyl-5-methylthiophenyl)-3-hydroxypyrazole in the form of yellow crystals (melting point: 230-232° C.).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([C:26]3([C:29]([F:32])([F:31])[F:30])[CH2:28][CH2:27]3)=[N:24][N:25]=[C:20]2[C@H:19]([NH2:33])[CH2:18][CH2:17]1.[C:34]([N:41]1[CH:45]=[CH:44]N=[CH:42]1)(N1C=CN=C1)=[O:35].[C:46]1(=[O:56])[C:50]2(CCNC[CH2:51]2)[CH2:49][CH2:48][NH:47]1>O1CCCC1.ClCCl>[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([C:26]3([C:29]([F:32])([F:30])[F:31])[CH2:27][CH2:28]3)=[N:24][N:25]=[C:20]2[C@H:19]([NH:33][C:34]([N:41]2[CH2:42][CH2:51][C:50]3([C:46](=[O:56])[NH:47][CH2:48][CH2:49]3)[CH2:44][CH2:45]2)=[O:35])[CH2:18][CH2:17]1
Reactant: O=C1NCCC12CCNCC2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c1nnc2C1(C(F)(F)F)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c1nnc2C1(C(F)(F)F)CC1)N1CCC2(CCNC2=O)CC1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 56.3 %

Procedure:
Triethylamine (16 μL, 0.112 mmol) was added to a solution of the bis hydrochloride salt of (6S,9R)-6-(2,3-difluorophenyl)-3-[1-(trifluoromethyl)cyclopropyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-9-amine (20 mg, 0.045 mmol) and 1,1′-carbonyldiimidazole (13 mg, 0.079 mmol) in tetrahydrofuran (1.0 mL) at 0° C. After 20 min, additional 1,1′-carbonyldiimidazole (7.3 mg, 0.045 mmol) was added. After 30 min, the hydrochloride salt of 2,8-diazaspiro[4.5]decan-1-one (11 mg, 0.056 mmol) and dichloromethane (1.0 mL) were added and the mixture was heated to 60° C. After 16 h, the reaction was concentrated. Purification by reverse phase HPLC (C-18, 10% acetonitrile/water→100% acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (14 mg). MS 553.2315 (M+1).