Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][C@H:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:5][CH2:4][C@@H:3]1[N:13]1[CH2:17][CH2:16][C@H:15]([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:14]1=[O:29].C(N(CC)CC)C.[C:37](OC(=O)C)(=[O:39])[CH3:38]>ClCCl>[C:37]([NH:1][C@@H:2]1[CH2:7][C@H:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:5][CH2:4][C@@H:3]1[N:13]1[CH2:17][CH2:16][C@H:15]([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:14]1=[O:29])(=[O:39])[CH3:38]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](N)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
A solution of benzyl (S)-1-((1S,2R,4R)-2-amino-4-(tert-butylamino)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (22 mg, 0.055 mmol) in dichloromethane (2 mL) was charged sequentially with triethylamine (11.1 mg, 2 eq) and acetic anhydride (6.1 mg, 1.1 eq). The reaction was stirred for 1.5 h at room temperature, diluted with dichloromethane (50 mL) and washed with saturated NaHCO3 (20 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give benzyl (S)-1-((1S,2R,4R)-2-acetamido-4-(tert-butylamino)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (22 mg, 90%). LC/MS found [M+H]=445.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([NH:10][C:11](=[O:13])[CH3:12])[CH2:4][C:3]1([CH3:15])[CH3:14].[C:16]1([CH3:23])[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=1>>[CH3:23][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=1)[CH2:22][O:1][N:2]1[C:7]([CH3:8])([CH3:9])[CH2:6][CH:5]([NH:10][C:11](=[O:13])[CH3:12])[CH2:4][C:3]1([CH3:15])[CH3:14]
Reactant: Cc1cccc(C)c1
Reactant: CC(=O)NC1CC(C)(C)N(O)C(C)(C)C1
Product: CC(=O)NC1CC(C)(C)N(OCc2cccc(C)c2)C(C)(C)C1
Temperature: 133 °C
Yield: 25.3 %

Procedure:
A mixture of 10.67 g (0.05 mol) of 1-oxyl-4-acetamido-2,2,6,6-tetramethylpiperidine and 106.17 g (1.0 mol) of m-xylene under a nitrogen atmosphere is heated at 133° C. for 67 hours. The reaction mixture is filtered to remove the hydroxylamine, and the filtrate is washed with 10 w/v % ascorbic acid (3×33 mL) and distilled water (2×50 mL). The organic phase is dried over anhydrous sodium sulfate and the volatiles are removed in vacuo. The residue is recrystallized from acetonitrile to give 4.03 g (51% yield) of a white solid melting at 163-164.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[C:15](Cl)[CH:14]=[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:12]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:12]=[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:14]=[C:15]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: C1CNCCN1
Reactant: COc1ccc(Nc2nc(Cl)cc(-c3ccccc3)n2)cc1Cl
Product: COc1ccc(Nc2nc(-c3ccccc3)cc(N3CCNCC3)n2)cc1Cl

Procedure:
(3-Chloro-4-methoxy-phenyl)-(4-chloro-6-phenyl-pyrimidin-2-yl)-amine compound (1 g, 2.8 mmol) on treatment with piperazine (0.24 g, 2.8 mmol), as described above yielded the desired compound.
Reaction SMILES: [CH:1]1([NH:5][C@H:6]2[CH2:11][CH2:10][CH2:9][CH2:8][C@H:7]2[NH:12][C:13](=[O:30])[C:14]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:17]([C:24]([F:27])([F:26])[F:25])=[CH:16][C:15]=2[O:28][CH3:29])[CH2:4][CH2:3][CH2:2]1.C=O.[C:33](=O)([O-])[O-].[Na+].[Na+]>C(O)=O>[CH:1]1([N:5]([CH3:33])[CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]2[NH:12][C:13](=[O:30])[C:14]2[C:19]([C:20]([F:21])([F:22])[F:23])=[CH:18][C:17]([C:24]([F:25])([F:26])[F:27])=[CH:16][C:15]=2[O:28][CH3:29])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C([O-])[O-]
Reactant: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@@H]1CCCC[C@@H]1NC1CCC1
Agent: C=O
Agent: [Na+]
Solvent: O=CO
Product: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)NC1CCCCC1N(C)C1CCC1
Temperature: 110 °C
Yield: 38 %

Procedure:
cis-N-(2-Cyclobutylamino-cyclohexyl)-2-methoxy-4,6-bis-trifluoromethyl-benzamide (example 16, 118 mg, 0.27 mmol) was dissolved in 2 mL formic acid. Formaldehyde (36% in water, 0.06 mL, 0.81 mmol) was added and the reaction mixture was stirred at 110° C. over night. The reaction mixture was basified by slow addition of 10 ml 1N sodium carbonate solution. The mixture was extracted three times with ethyl acetate. The combined organic phases were dried on sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography on silica gel (dichloromethane/methanol/ammonia 100:0:0->110:10:1) yielded the title compound as a white solid (46 mg, 38%), MS: m/e=453.2 [(M+H)+].
Reaction SMILES: FC(F)(F)C([O-])=O.[C:8]([CH2:11][N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[NH+:14]=[CH:13]1)([OH:10])=O.[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[F:29])[NH2:25]>C(Cl)(=O)C(Cl)=O.ClCCl.C1COCC1>[N:12]1([CH2:11][C:8]([NH:25][C:24]2[CH:26]=[CH:27][C:28]([F:29])=[C:22]([Cl:21])[CH:23]=2)=[O:10])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[CH:13]1
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: O=C(O)Cn1c[nH+]c2ccccc21
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])C(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(Cn1cnc2ccccc21)Nc1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.8 %

Procedure:
3-Carboxymethyl-3H-benzoimidazol-1-ium trifluoro-acetate (128 mg, 0.44 mmol) was dissolved in a mixture of oxalyl chloride (0.6 mL) and dichloromethane (3.4 mL). The reaction mixture was stirred for 30 min at ambient temperature and the solvent was evaporated. The residue was dissolved in a mixture of dichloromethane (2.5 mL) and anhydrous TBF (2.5 mL) and added to a mixture of 3-chloro4-fluoro-aniline (17 mg, 0.12 mmol) and N,N-(diisopropyl)aminomethylpolystyrene resin (140 mg, Argonaut Technologies, Inc) in anhydrous THF (3 mL). The mixture was shaken overnight. The resin was filtered off, the solvents were evaporated and the crude product was purified on a preparative LC/MS (XTerra Cs column 19×100mm, 0.1 M aqueous NH4Ac/CH3CN). The pooled fractions were lyophilized to afford 7.2 mg (20%) of the title compound. Calculated for C15H11ClFN3O m/z: 303.7, found 304.7 [M+H]+. 1H NMR (400 M, MeOD) δ ppm 5.2 (s, 2H), 7.2 (t, J=9.1 Hz, 1H), 7.3 (m, 2H), 7.5 (m, 1H), 7.5 (d, J=7.1 Hz, 1H), 7.7 (d, J=7.1 Hz, 1H), 7.8 (dd, J=6.6, 2.5 Hz, 1H), 8.2 (s, 1H).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]([F:29])([F:28])[CH:25]1[O:27][CH2:26]1>>[O:1]([C:8]1[CH:9]=[C:10]([N:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:26][CH:25]([OH:27])[C:24]([F:29])([F:28])[F:23])[CH:17]=2)[CH2:26][CH:25]([OH:27])[C:24]([F:29])([F:28])[F:23])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(CNc2cccc(Oc3ccccc3)c2)c1
Reactant: FC(F)(F)C1CO1
Product: OC(COc1cccc(CN(CC(O)C(F)(F)F)c2cccc(Oc3ccccc3)c2)c1)C(F)(F)F
Temperature: 95 °C
Yield: 74.4 %

Procedure:
The N-(3-phenoxyphenyl)[[3-hydroxyphenyl]methyl]amine (400 mg, 1.35 mmol) product from EX-655A and 1,1,1-trifluoro-2,3-epoxypropane (348 mg, 3 mmol) were placed in a sealed vial, then stirred and heated to 95° C. for 15 h under an atmosphere of nitrogen. The vial was cooled, and more 1,1,1-trifluoro-2,3-epoxypropane (112 mg, 1 mmol) was added. The vial was sealed, then stirred and heated to 95° C. for a further 20 h under an atmosphere of nitrogen. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate in hexane (1:6) to give 518 mg (77%) of the desired 3-[(3-phenoxyphenyl)[[3-(2-hydroxy-3,3,3-trifluoro-n-propoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a light amber oil, 98% pure by HPLC analysis. 1H NMR (CDCl3) δ 7.20-7.32 (m, 3H), 7.14 (t, 1H), 7.07 (t, 1H), 6.95 (d, 2H), 6.80 (m, 2H), 6.74 (s, 1H), 6.48 (dd, 1H), 6.38 (m, 2H), 4.59 (ABq, 2H), 4.31 (m, 1H), 4.18 (dd, 1H), 4.10 (dd, 1H), 3.83 (dd, 1H), 3.54 (dd, 1H), 2.92 (d, 1H), 2.61 (d, 1H). 19F NMR (CDCl3) δ −78.0 (d, 3F), −79.2 (d, 3F). HRMS calcd. for C25H23F6 NO4:516.1611 [M+H]+, found: 516.1618.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=O)[N:13]=1.C(N(CC)CC)C.Cl.[NH:27]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[NH2:28]>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[OH:9])[N:27]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[N:28]=1
Reactant: O=c1nc(-c2ccccc2O)oc2ccccc12
Reactant: CCOC(=O)CNN
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)Cn1nc(-c2ccccc2O)nc1-c1ccccc1O

Procedure:
51.5 g of 2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one, 30.5 ml of triethylamine and 33.4 g of ethyl hydrazinoacetate hydrochloride are boiled under reflux for 0.5 h in 450 ml of ethanol. On cooling, the product precipitates in crystalline form. It is filtered off and washed with ethanol. After drying, ethyl [3,5-bis(2-hydroxyphenyl)-(1,2,4]triazol-1-yl]acetate remains as colorless crystals of m.p. 172-174° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]([O:22]CC)=[O:21])[CH2:16][C@H:15]1[NH:25][C:26]([C:28]1[S:29][C:30]3[CH2:31][N:32]([CH3:37])[CH2:33][CH2:34][C:35]=3[N:36]=1)=[O:27])=[O:12])=[CH:5]2.C(O)C.[OH-].[Na+].Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]([OH:22])=[O:21])[CH2:16][C@H:15]1[NH:25][C:26]([C:28]1[S:29][C:30]3[CH2:31][N:32]([CH3:37])[CH2:33][CH2:34][C:35]=3[N:36]=1)=[O:27])=[O:12])=[CH:5]2
Reactant: CCOC(=O)[C@H]1CC[C@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)[C@H](NC(=O)c2nc3c(s2)CN(C)CC3)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CN1CCc2nc(C(=O)N[C@@H]3C[C@@H](C(=O)O)CC[C@@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Reaction time: 12 h
Yield: 78.4 %

Procedure:
The compound (1.6 g) obtained in Example 50 was suspended in a mixed solvent of ethanol (20 ml) and tetrahydrofuran (15 ml), and a 1N aqueous solution (5.9 ml) of sodium hydroxide was added at room temperature to stir the mixture for 12 hours at the same temperature. After adding 1N hydrochloric acid (5.9 ml), the solvent was distilled off under reduced pressure, and the residue was washed with water and diethyl ether to obtain the title compound (1.19 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)=[O:4].[CH3:21][C:22]1[CH:26]=[CH:25][S:24][C:23]=1[C:27](O)=[O:28]>>[F:20][C:16]1[CH:15]=[C:14]([CH:6]([NH:5][C:3]([CH2:2][NH:1][C:27]([C:23]2[S:24][CH:25]=[CH:26][C:22]=2[CH3:21])=[O:28])=[O:4])[C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: Cc1ccsc1C(=O)O
Reactant: NCC(=O)NC(c1cccc(F)c1)c1cccc(F)c1
Product: Cc1ccsc1C(=O)NCC(=O)NC(c1cccc(F)c1)c1cccc(F)c1

Procedure:
Prepared in analogy to example 1.12 from 2-amino-N-[bis-(3-fluoro-phenyl)-methyl]-acetamide (example 3.4) and 3-methyl-thiophene-2-carboxylic acid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:26]=[CH:25][C:24]4[CH:27]=[C:28]([C:30]5[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=5)[S:29][C:23]=4[C:22]3=[O:37])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:36][C:33]1[CH:32]=[CH:31][C:30]([C:28]2[S:29][C:23]3[C:22](=[O:37])[N:21]([C:18]4[CH:17]=[N:16][C:15]([O:14][CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)=[CH:20][CH:19]=4)[CH:26]=[CH:25][C:24]=3[CH:27]=2)=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(-n3ccc4cc(-c5ccc(Cl)cc5)sc4c3=O)cn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1c2sc(-c3ccc(Cl)cc3)cc2ccn1-c1ccc(OC2CCNCC2)nc1
Yield: 73.4 %

Procedure:
Combine 4-{5-[2-(4-chloro-phenyl)-7-oxo-7H-thieno[2,3-c]pyridin-6-yl]-pyridin-2-yloxy}-piperidine-1-carboxylic acid tert-butyl ester (1.67g, 3.10 mmol) with trifluoroacetic acid (2.31 mL, 31.04 mmol) in dichloromethane (20 mL) and stir at RT overnight. Load the mixture onto an SCX column and wash with methanol and dichloromethane. Elute the product with 2M NH3 in methanol and concentrate in vacuo. Chromatograph the residue (silica gel, eluting with 0-10% 2M NH3 in MeOH:dichloromethane) to yield 996 mg (73%) of 2-(4-chloro-phenyl)-6-[6-(piperidin-4-yloxy)-pyridin-3-yl]-6H-thieno[2,3-c]pyridin-7-one. Add ammonium chloride (45 mg, 0.85 mmol) to a solution of the free base (350 mg, 0.80 mmol) in 15 mL of methanol/dichloromethane (1:1) and sonicate the solution until complete dissolution of NH4Cl. Concentrate in vacuo to yield 379 mg (100%) of the title compound. MS/ES m/z (35C1) 438.0 [M+H]+.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]1[C:9]([C:18]([O:20]CC)=O)=[N:10][C:11]2[C:16]([N:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2.[C:23](#[N:25])[CH3:24].O>C1(C)C=CC=CC=1>[CH3:7][C:8]1[C:9]([C:18](=[O:20])[CH2:24][C:23]#[N:25])=[N:10][C:11]2[C:16]([N:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2
Reactant: CC#N
Reactant: CCOC(=O)c1nc2ccccc2nc1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1nc2ccccc2nc1C(=O)CC#N
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a suspension of potassium tert-butoxide (72.7 g, 647 mmol) in toluene (810 mL) was added a solution of ethyl 3-methylquinoxaline-2-carboxylate (70.0 g, 324 mmol) and acetonitrile (38.3 mL, 809 mmol) in toluene (270 mL) dropwise over 50 min at 5° C. After being stirred for 5 min at 0° C., water (585 mL) was added. The organic layer was extracted with water (100 mL) and the aqueous layer was combined and acidified to pH 3-4 with 10% aqueous hydrochloric acid. The resulting precipitate was collected and dissolved to tetrahydrofuran. And then the organic layer was dried over sodium sulfate, filtrated and concentrated in vacuo. The crude solid was purified by silica gel column chromatography (silica gel 2.2 kg, chloroform to chloroform:ethyl acetate=19:1) to give 3-(3-methylquinoxalin-2-yl)-3-oxopropanenitrile. MS (APCI): m/z 212 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:14])=[C:5]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.[C:15]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3]1[C:4]([CH3:14])=[C:5]([N:9]([CH3:15])[S:10]([CH3:13])(=[O:12])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cccc(NS(C)(=O)=O)c1C
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(N(C)S(C)(=O)=O)c1C
Reaction time: 0.17 h
Yield: 106.4 %

Procedure:
A slurry of N-(3-methoxy-2-methylphenyl)methanesulfonamide 7a (Blondet, D.; Pascal, J. -C. Tetrahedron Lett. 1994, 35, 2911) (4.5 g, 20.9 mmol), K2CO3 (4.33 g, 31.4 mmol) and Mel (6.52 mL, 105 mmol) in DMF (100 mL) was stirred vigorously for 5 days. The reaction was poured onto H2O (250 mL), stirred for 10 minutes and then extracted with ether. The combined organic extracts were washed with water and brine and dried over MgSO4 to give 7b (5.10 g) after removal of the solvent.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:3]=1[C:4]([NH:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]2)=[O:15])[CH2:10][CH2:9]1)=[O:5].C1C[O:36][CH2:35]C1>>[C:22]([N:19]1[CH2:18][CH2:17][N:16]([C:14]([C@H:11]2[CH2:12][CH2:13][C@H:8]([CH2:7][N:6]3[C:4](=[O:5])[C:3]4[C:2](=[CH:30][CH:29]=[C:28]([O:31][CH3:32])[CH:27]=4)[NH:1][C:35]3=[O:36])[CH2:9][CH2:10]2)=[O:15])[CH2:21][CH2:20]1)(=[O:26])[CH:23]([CH3:25])[CH3:24]
Reactant: C1CCOC1
Reactant: COc1ccc(N)c(C(=O)NC[C@H]2CC[C@H](C(=O)N3CCN(C(=O)C(C)C)CC3)CC2)c1
Product: COc1ccc2[nH]c(=O)n(C[C@H]3CC[C@H](C(=O)N4CCN(C(=O)C(C)C)CC4)CC3)c(=O)c2c1

Procedure:
A solution of 2-amino-N-[trans-4-(4-isobutyryl-piperazine-1-carbonyl)-cyclohexylmethyl]-5-methoxy-benzamide (156 mg, 0.35 mmol) and 1,1-carbonyldiimidazole (130 mg, 0.8 mmol) in THF (4 mL) was irradiated with microwave at 150° C. (250 W) for 20 minutes. The desired product precipitated from the reaction mixture and was filtered. 85 mg of the titled compound were obtained (yield 52%).
Reaction SMILES: [CH3:1][Si:2]([CH3:45])([CH3:44])[CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:11]=[CH:10][C:9]=1[C:23]1[C:24](=[O:43])[O:25][C:26]2[C:31]([C:32]=1[CH3:33])=[CH:30][CH:29]=[C:28]([O:34][CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[CH:27]=2.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:56][CH2:57][C:58](Cl)=[O:59]>C1COCC1.C(OCC)C>[CH3:45][Si:2]([CH3:44])([CH3:1])[CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:20])([CH3:21])[CH3:22])[CH:11]=[CH:10][C:9]=1[C:23]1[C:24](=[O:43])[O:25][C:26]2[C:31]([C:32]=1[CH2:33][C:58](=[O:59])[CH2:57][Cl:56])=[CH:30][CH:29]=[C:28]([O:34][CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[CH:27]=2
Reactant: O=C(Cl)CCl
Reactant: Cc1c(-c2ccc(OCOCC[Si](C)(C)C)cc2OCOCC[Si](C)(C)C)c(=O)oc2cc(OCOCC[Si](C)(C)C)ccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCOc1ccc(-c2c(CC(=O)CCl)c3ccc(OCOCC[Si](C)(C)C)cc3oc2=O)c(OCOCC[Si](C)(C)C)c1
Temperature: -20 °C
Reaction time: 0.17 h

Procedure:
At room temperature, 3-[2,4-Bis-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-4-methyl-7-(2-trimethylsilanyl-ethoxymethoxy)-chromen-2-one (1.6 g, 2.37 mmol) in THF (10 mL) was added LiHMDS (2.9 mL, 2.84 mmol) slowly. The reaction mixture was stirred for 10 min and then added into chloroacetyl chloride (0.28 mL, 1.5 equiv.) in THF (20 mL) at −20° C. The reaction mixture was maintained at −20° C. for 1 hour, then diluted with diethyl ether (200 mL), washed with aqueous NH4Cl (100 ml), brine and organic layer was dried over anhydrous MgSO4. The resulting product was then concentration by vacuum to dryness and purified by silica gel column chromatography to yield the title compound as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:16](=[C:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[CH2:9][CH2:8][C:7]=2[CH:23]=1)#[N:2].[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:16](=[C:17]3[CH2:22][CH2:21][N:20]([C:24](=[O:26])[CH3:25])[CH2:19][CH2:18]3)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[CH2:9][CH2:8][C:7]=2[CH:23]=1)#[N:2]
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1ccc2c(c1)CCc1cccnc1C2=C1CCNCC1
Solvent: c1ccncc1
Product: CC(=O)N1CCC(=C2c3ccc(C#N)cc3CCc3cccnc32)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66 %

Procedure:
Pyridine (4 ml) was added to 0.4 g of 8-cyano-11-(4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine to dissolve the latter, followed by the addition of 8 ml of acetic anhydride. At the room temperature, the resulting mixture was stirred for 4 hours. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure. Water was added to the residue, followed by extraction with chloroform. The extract was next dried over anhydrous Na2SO4 and the chloroform was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column and, from relevant fractions eluted with chloroform:methanol (100:1), 0.3 g of 8-cyano-11-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine was obtained (yield: 66%).
Reaction SMILES: C([O:3][C:4](=[O:8])[C@@H:5]([OH:7])[CH3:6])C.N1C=CC=CC=1.[C:15]1([C:21]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)Cl)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C1C=CN=CC=1.C(#N)C>[C:21]([O:7][C@@H:5]([CH3:6])[C:4]([OH:3])=[O:8])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)[C@H](C)O
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: c1ccncc1
Product: C[C@H](OC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Reaction time: 16 h
Yield: 51.6 %

Procedure:
To a solution of 38.6 g of (S)-2-hydroxy-propionic acid ethyl ester, 8.21 g of 4-dimethylamino-pyridine and 25.9 g of pyridine in 97 g of acetonitrile were added 92.0 g of triphenylchloromethane, and the mixture was heated at reflux for 16 h. The reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was successively washed with 1M potassium hydrogensulfate solution, saturated potassium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residual oil was taken up in a solution of 22 g of sodium hydroxide in 200 ml of methanol, and the mixture was stirred for 16 h. The reaction mixture was filtered and the filtrate was diluted with 0.5 l of water. The resulting mixture was first concentrated in vacuo to a volume of about 0.5 l and then extracted with tert-butyl methyl ether and the organic phase was discarded. The pH of the aqueous phase was adjusted to 3 by the addition of 2N potassium hydrogensulfate solution and again extracted with tert-butyl methyl ether. The organic phase was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residual oil was taken up in hexane to afford 56.0 g of (S)-2-trityloxy-propionic acid as off white crystals, m.p. 100°-106° C. Recrystallization from hexane/tert-butyl methyl ether afforded white crystals, m.p. 117.5°-119° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([CH:17]2[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:20](=[O:28])[NH:19][CH2:18]2)=[O:16])[CH2:11][CH2:10]1.[H-].[Na+].[F:31][C:32]([F:40])([F:39])[CH2:33][CH2:34][S:35](Cl)(=[O:37])=[O:36]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([CH:17]2[CH2:18][N:19]([S:35]([CH2:34][CH2:33][C:32]([F:40])([F:39])[F:31])(=[O:37])=[O:36])[C:20](=[O:28])[N:21]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:16])[CH2:11][CH2:10]1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CNC(=O)N3c3ccccc3)CC2)c1
Reactant: O=S(=O)(Cl)CCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)CCC(F)(F)F)C(=O)N3c3ccccc3)CC2)c1

Procedure:
In analogy to example 33, (RS)-5-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-1-phenyl-imidazolidin-2-one (example 33, step 1) was reacted with sodium hydride and 3,3,3-trifluoropropane-1-sulfonyl chloride to give the title compound as an off-white solid. MS: 539.0 ([M+H]+)
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[N:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH:16]=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH2:14][CH2:13]3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1>[Pd].CO>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([CH:15]2[CH2:16][CH2:17][N:12]([C:9]3[CH:10]=[CH:11][C:6]4[N:7]([C:3]([C:2]([F:25])([F:1])[F:24])=[N:4][N:5]=4)[N:8]=3)[CH2:13][CH2:14]2)[CH:19]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CC=C(c4cccnc4)CC3)nn12
Agent: [Pd]
Solvent: CO
Product: FC(F)(F)c1nnc2ccc(N3CCC(c4cccnc4)CC3)nn12
Reaction time: 72 h
Yield: 28.7 %

Procedure:
A mixture of 1′-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]-1′,2′,3′,6′-tetrahydro-3,4′-bipyridine (obtained as described in Example 605) (82 mg, 0.24 mmol) and 10% palladium on carbon (25.2 mg, 0.02 mmol) in MeOH (10 mL) was stirred under an atmosphere of hydrogen at atmospheric pressure for 3 days. The catalyst was removed by filtration and the solvent evaporated to give crude product, which was purified by flash silica chromatography, elution gradient 0 to 3% MeOH in DCM. Fractions containing the desired product were evaporated to dryness to give 6-(4-pyridin-3-ylpiperidin-1-yl)-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (24 mg, 29%).