Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][NH:7]1)=[O:5].Cl[C:12]1[O:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1>C(Cl)Cl>[O:13]1[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=[C:12]1[N:7]1[CH2:8][CH2:9][CH2:10][C@H:6]1[C:4]([O:3][CH3:2])=[O:5]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: Clc1nc2ccccc2o1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCCN1c1nc2ccccc2o1
Temperature: 120 °C
Yield: 93 %

Procedure:
A mixture of 1.66 G (S)-pyrrolidine-2-carboxylic acid methyl ester, hydrochloride salt and 1.15 mL of 2-chlorobenzoxazole in 6 mL CH2Cl2 was subjected to microwave heating at 120° C. for 0.5 h. Solvent was evaporated. Purification by chromatography (SiO2, EtOAc/heptane) provided 2.283 g (93% yield) of (S)-1-benzooxazol-2-yl-pyrrolidine-2-carboxylic acid, methyl ester as a waxy white solid, m/z 247.16 (MH+). A mixture of 2.0 g of (S)-1-benzooxazol-2-yl-pyrrolidine-2-carboxylic acid, methyl ester and 1.02 G LiOH H2O in 15 mL MeOH and 15 mL water was stirred overnight at room temperature. The reaction was acidified with 1N HCl, was extracted three times with MeOH/CH2Cl2, was dried over Na2SO4 and was evaporated to provide the title compound. m/z 233.17 (MH+).
Reaction SMILES: [C:1]1([C:7]2([CH2:13][O:14][CH2:15][C:16]3[CH:17]=[C:18]([C:25]([F:28])([F:27])[F:26])[CH:19]=[C:20]4[C:24]=3[NH:23][N:22]=[CH:21]4)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:29]([BH3-])#N.[Na+].C=O.C(O)(=O)C>C(#N)C.C(O)(=O)C>[CH3:29][N:10]1[CH2:11][CH2:12][C:7]([CH2:13][O:14][CH2:15][C:16]2[CH:17]=[C:18]([C:25]([F:27])([F:26])[F:28])[CH:19]=[C:20]3[C:24]=2[NH:23][N:22]=[CH:21]3)([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9]1
Reactant: [BH3-]C#N
Reactant: FC(F)(F)c1cc(COCC2(c3ccccc3)CCNCC2)c2[nH]ncc2c1
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CN1CCC(COCc2cc(C(F)(F)F)cc3cn[nH]c23)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 7-(((4-phenylpiperidin-4-yl)methoxy)methyl)-5-(trifluoromethyl)-1H-indazole (62 mg, 0.159 mmol) and sodium cyanoborohydride (10 mg, 0.159 mmol) in acetonitrile (1 mL) at room temperature was added formalin (25 μL). To this was added 1 drop of acetic acid. After 5 min, a second drop of acetic acid was added and the reaction stirred at room temperature for 15 min. The reaction was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was washed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated. The product was purified by preparative HPLC. The trifluoroacetic acid salt was loaded onto a strong cation exchange cartridge in methanol. The cartridge was washed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated to give 37 mg (58%). 1H-NMR (CDCl3, 500 MHz) δ 9.60 (bs, 1H), 8.02 (s, 1H), 7.91 (s, 1H), 7.49 (m, 2H), 7.41 (m, 3H), 7.25 (s, 1H), 4.71 (s, 2H), 3.61 (s, 2H), 2.57 (m, 2H), 2.10-2.40 (m, 4H), 2.22 (s, 3H), 1.96 (m, 2H); 13C-NMR (CDCl3, 126 MHz) δ 143.9, 139.5, 135.2, 129.0, 127.1, 126.9, 124.7 (q, J=272 Hz), 123.2 (q, J=32 Hz), 121.9, 120.1, 118.3, 80.8, 72.0, 52.0, 46.3, 40.7, 32.9. Mass spec.: 404.01 (MH)+. Accurate mass spec.: m/z [MH]+, Δ=4.4 ppm.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][N:25]=1>CC#N>[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6](=[O:15])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:29])=[CH:26][N:25]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Reactant: O=C(O)c1ccc(Cl)nc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.7 %

Procedure:
To solution of (2-amino-phenyl)-carbamic acid tert-butyl ester (22) (Seto, C. T.; Mathias, J. P.; Whitesides, G. M.; J. Amer. Chem. Soc., (1993), 115, 1321-1329.) (1.56 g, 7.49 mmol) in MeCN (40 mL) is added triethylamine (2.60 mL, 18.7 mmol) and 6-chloronicotinic acid (1.42 g 8.99 mmol). The mixture is stirred for 18 h at r.t. Upon completion of the reaction, the solvent is removed in vacuo and the residue is partitioned between EtOAc and an NH4Cl solution. The organic phase is collected and the aqueous layer is then extracted with EtOAc; the combined organic layers are washed with brine, dried over MgSO4 and evaporated. The residue is purified by flash chromatography using EtOAc/Hexane (a gradient of 20:80 to 50:50) as an eluent, to afford the title compound 94 (2.39 g, 92% yield). 1H NMR (DMSO-d6) δ(ppm): 10.01 (s, 1H), 8.96 (d, J=2.0 Hz, 1H), 8.71 (s, 1H), 8.35 (dd, J=8.4, 2.4 Hz, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.48 (d, J=7.6 Hz, 1H), 7.22 (td, J=7.8, 1.4 Hz, 1H), 7.13 (t, J=7.6 Hz, 1H), 1.44 (s, 9H). LRMS (ESI): (calc) 347.10 (found) 370.1 (M+Na+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[C:14]([CH3:22])[CH:15]=[N:16][C:17]=3[O:19][CH2:20][CH3:21])[NH:12][C:11]([CH3:23])=[C:10]2[C:24]([O:26]CCC#N)=[O:25])=[C:5]([O:31][CH3:32])[CH:4]=1)#[N:2].[OH-].[Na+].C(OCC)C.Cl>COCCOC.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[C:14]([CH3:22])[CH:15]=[N:16][C:17]=3[O:19][CH2:20][CH3:21])[NH:12][C:11]([CH3:23])=[C:10]2[C:24]([OH:26])=[O:25])=[C:5]([O:31][CH3:32])[CH:4]=1)#[N:2]
Reactant: CCOc1ncc(C)c2c1C(c1ccc(C#N)cc1OC)C(C(=O)OCCC#N)=C(C)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Solvent: CCOCC
Product: CCOc1ncc(C)c2c1C(c1ccc(C#N)cc1OC)C(C(=O)O)=C(C)N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.75 g (4.05 mmol) of the compound from Example 29A are dissolved in 60 ml of 1,2-dimethoxyethane/water (2:1 v/v), 8.09 ml (8.09 mmol) of 1 N sodium hydroxide solution are added, and the mixture is stirred at room temperature for one hour. 30 ml of diethyl ether are then added to the mixture, and the aqueous phase is acidified with 6 N hydrochloric acid. The resulting precipitate is filtered off and washed with water and a little diethyl ether. Drying in a vacuum drying oven at 40° C. results in 1.47 g (96% of theory) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[C:5]([NH:7][C:8]1[CH:13]=[C:12]([C:14]2[N:15]=[C:16]3[N:21]([CH:22]=2)[N:20]=[C:19]([C:23]2[C:24]([C:29]([F:32])([F:31])[F:30])=[N:25][CH:26]=[CH:27][CH:28]=2)[CH:18]=[CH:17]3)[CH:11]=[CH:10][C:9]=1[CH3:33])=[O:6].[C:37]([O:41][CH2:42][CH3:43])(=[O:40])[CH:38]=[CH2:39].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(C(C)C)C(C)C>CN(C=O)C.CN(P(N(C)C)(N(C)C)=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:42]([O:41][C:37](=[O:40])[CH:38]=[CH:39][C:2]1[CH:36]=[CH:35][CH:34]=[C:4]([C:5](=[O:6])[NH:7][C:8]2[CH:13]=[C:12]([C:14]3[N:15]=[C:16]4[N:21]([CH:22]=3)[N:20]=[C:19]([C:23]3[C:24]([C:29]([F:32])([F:31])[F:30])=[N:25][CH:26]=[CH:27][CH:28]=3)[CH:18]=[CH:17]4)[CH:11]=[CH:10][C:9]=2[CH3:33])[CH:3]=1)[CH3:43]
Reactant: Cc1ccc(-c2cn3nc(-c4cccnc4C(F)(F)F)ccc3n2)cc1NC(=O)c1cccc(Br)c1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1cccc(C(=O)Nc2cc(-c3cn4nc(-c5cccnc5C(F)(F)F)ccc4n3)ccc2C)c1
Temperature: 100 °C
Reaction time: 24 h
Yield: 106.1 %

Procedure:
To a mixture of 3-bromo-N-[2-methyl-5-[6-[2-(trifluoromethyl)-3-pyridyl]imidazo[2,1-f]pyridazin-2-yl]phenyl]benzamide (0.442 g, 0.8 mmol), ethyl acrylate (0.872 mL, 8 mmol), palladium(II) acetate (9 mg, 0.04 mmol), tri(o-tolyl)phosphine (0.049 g, 0.16 mmol) in DMF (4.6 mL) and HMPA (0.4 mL) is added DIPEA (0.557 mL, 3.2 mmol). The mixture is degassed with N2 then sealed and heated at 100° C. for 15 hours. The reaction is not complete, and is stirred at 100° C. for another 24 hours. The mixture is poured into saturated aqueous NaHCO3 and extracted with EtOAc (2×). Organic layers are combined, dried and concentrated to give the title compound as a solid (485 mg), which is used without further purification. LCMS (m/z)=572.5 [M+H]+, tR=3.14 min.
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11](=[O:13])[CH3:12])=[CH:4][C:3]=1[O:14]C.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(O)(=O)C.Br>[OH:14][C:3]1[CH:4]=[C:5]([C:11](=[O:13])[CH3:12])[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[OH:1]
Reactant: COc1cc(C(C)=O)cc([N+](=O)[O-])c1O
Agent: Br
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)c1cc(O)c(O)c([N+](=O)[O-])c1
Reaction time: 8 h

Procedure:
A solution containing 19.9 g of the product obtained in Example 18 in 200 ml of acetic acid and 200 ml of 48% hydrobromic acid was refluxed for 5 h. 500 ml of a saturated solution of sodium sulfate was added to the reaction mixture and the same was let stand overnight at 5° C. The solution was extracted with ether. The ether phase was washed with 200 ml of water, dried and the solvent evaporated in vacuo. The residue was crystallized from isopropanol. Yield 10.2 g (55 m.p. 155°-159° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].C[O-].[Na+].Cl[CH2:10][C:11]1[N:15]=[C:14]([CH3:16])[O:13][N:12]=1>CO>[CH3:16][C:14]1[O:13][N:12]=[C:11]([CH2:10][S:5][CH2:4][CH2:3][NH2:2])[N:15]=1
Reactant: Cc1nc(CCl)no1
Reactant: NCCS
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1nc(CSCCN)no1
Reaction time: 1.17 h
Yield: 121.9 %

Procedure:
Cysteamine hydrochloride (3.03 g; 26.7 mmoles) was added in several portions over a period of 10 minutes to a stirred solution of sodium methylate (2.89 g; 53.4 mmoles) in 50 ml of methanol at 0°. After stirring for 70 minutes at 0°, a solution of 3-chloromethyl-5-methyl-1,2,4-oxadiazole (3.54 g; 26.7 mmoles) in 15 ml of methanol was added dropwise over a period of 15 minutes, and the reaction mixture was allowed to stir at ambient temperature for 16 hours. The mixture was filtered, evaporated and redissolved in isopropyl alcohol, then filtered and evaporated under reduced pressure to give the title compound (5.64 g) as a yellow oil. The NMR spectrum (60 MHz) in CDCl3 gave the following resonances δ: 3.77 (s, 2H); 2.77 (m, 4H); 2.63 (s, 3H).
Reaction SMILES: C([C:3]([CH2:14][CH3:15])(P(=O)=O)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])C.[H-].[Na+].O=C1C[CH2:23][CH:22]([C:25]2[CH:35]=[CH:34][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1>CN(C)C=O>[C:7]([O:6][C:4]([CH:3]=[C:14]1[CH2:15][CH2:23][CH:22]([C:25]2[CH:26]=[CH:27][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:34][CH:35]=2)[CH2:21][CH2:20]1)=[O:5])([CH3:8])([CH3:9])[CH3:10]
Reactant: CCC(CC)(C(=O)OC(C)(C)C)P(=O)=O
Reactant: CCOC(=O)c1ccc(C2CCC(=O)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(C2CCC(=CC(=O)OC(C)(C)C)CC2)cc1
Temperature: 4 °C
Reaction time: 0.5 h
Yield: 72.1 %

Procedure:
5.63 g of tert-butyl diethylphosphoacetate (20.3 mmol, 1 eq.) are placed in 20 mL of dimethylformamide with stirring. The solution is cooled to a temperature of 4° C. by placing it in an ice bath, and 0.536 g of sodium hydride (22.33 mmol, 1.1 eq.) is then added portionwise. After 30 minutes, 5 g of ethyl 4-(4-oxo-cyclohexyl)benzoate (20.3 mmol, 1 eq.) are added and the ice bath is removed. After stirring for 1 hour, the flask is placed in an ice bath to cool the reaction medium to a temperature of 4° C., and 0.049 g of sodium hydride (2.04 mmol, 0.1 eq.) is added. The ice bath is removed and, after 30 minutes, the mixture is poured into 200 mL of 1N potassium hydrogen sulfate and extracted with 300 mL of ethyl ether. The organic phase is washed 4 times with brine. The organic phase is dried over sodium sulfate and evaporated. The residue is chromatographed on silica gel, eluting with a gradient of methanol in dichloromethane ranging from 0% to 5%. 5.04 g of ethyl 4-(4-tert-butoxycarbonylmethylenecyclohexyl)benzoate are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:37]=[CH:36][C:6]([C:7]([O:22][CH2:23][C:24]2[CH:25]=[C:26]([CH:31]=[C:32]([CH2:34][F:35])[CH:33]=2)[CH2:27][N:28]=[N+]=[N-])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]([O:22][CH2:23][C:24]2[CH:25]=[C:26]([CH:31]=[C:32]([CH2:34][F:35])[CH:33]=2)[CH2:27][NH2:28])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6]2[CH:36]=[CH:37][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:9][CH:10]=1
Reactant: COc1ccc(C(OCc2cc(CF)cc(CN=[N+]=[N-])c2)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(OCc2cc(CN)cc(CF)c2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.2 %

Procedure:
To a solution of 3-(4,4′-dimethoxytrityloxy)methyl-5-fluoromethylbenzylazide (39) (247 mg, 0.50 mmol) in THF (5.00 mL) were added water (0.20 mL) and then triphenylphosphine (264 mg, 1.01 mmol). The air was evacuated from the reaction system, and then Ar was charged therein. The reaction mixture was stirred for 15 hours at a room temperature. TLC was used to confirm the progress of the reaction. Then, the reaction mixture was extracted with EtOAc. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to remove the solvent. The residue was purified by neutral silica gel column chromatography (EtOAc, then EtOAc: MeOH=2:1) to isolate 3-(4,4′-dimethoxytrityloxy)methyl-5-fluoromethylbenzylamine (40) (234 mg, 100%) as a white opaque oil.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH:22]3[CH2:24][CH2:23]3)[CH2:17][CH2:16]2)[CH2:11][CH2:10]1)C1C=CC=CC=1.C(O)(=O)C.[H][H].[O-2].[Al+3].[O-2].[O-2].[Al+3]>CO.[Pd]>[CH:22]1([CH2:21][N:18]2[CH2:19][CH2:20][N:15]([C@H:12]3[CH2:13][CH2:14][C@H:9]([NH2:8])[CH2:10][CH2:11]3)[CH2:16][CH2:17]2)[CH2:23][CH2:24]1
Reactant: [H][H]
Reactant: c1ccc(CN(Cc2ccccc2)[C@H]2CC[C@H](N3CCN(CC4CC4)CC3)CC2)cc1
Agent: [Pd]
Agent: [Al+3]
Agent: [O-2]
Solvent: CC(=O)O
Solvent: CO
Product: N[C@H]1CC[C@H](N2CCN(CC3CC3)CC2)CC1

Procedure:
(trans)-N,N-Dibenzyl-4-[4-(cyclopropylmethyl)piperazin-1-yl]cyclohexanamine 16a (1.41 g, 3.38 mmol) was dissolved in 15 mL of methanol followed by the addition of palladium/carbon (706 mg, 10%) and 0.1 mL of acetic acid, filled with hydrogen three times. The reaction mixture was reacted for 12 hours at 3 atmosphere of hydrogen, added with 3 g alkaline aluminum oxide (200-300 mesh) and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (trans)-4-[4-(cyclopropylmethyl)piperazin-1-yl]cyclohexanamine 16b (900 mg, yield: 100%) as a colorless solid.
Reaction SMILES: ClC1C=CC2SC=[C:8]([CH2:9][N:10]3[CH2:14][CH2:13][N:12](C4SC(C(O)=O)=C(C)N=4)C3=O)[C:4]=2[CH:3]=1.[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:39][C:40]([C:44](O)=[O:45])=[C:41]([CH3:43])[N:42]=3)[C:34]2=[O:47])=[CH:30][CH:29]=1.N1C=CC=CC=1CN>>[F:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:39][C:40]([C:44]([NH:12][CH2:13][C:14]4[CH:3]=[CH:4][CH:8]=[CH:9][N:10]=4)=[O:45])=[C:41]([CH3:43])[N:42]=3)[C:34]2=[O:47])=[CH:48][CH:49]=1
Reactant: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)O
Agent: NCc1ccccn1
Product: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1ccccn1
Yield: 54 %

Procedure:
Following the procedure as described in Example 32, making variations as required to replace 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with pyridin-2-ylmethanamine, the title compound was obtained as a colorless solid in 54% yield: mp 183-185° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.60-8.56 (m, 2H), 7.85-7.80 (m, 1H), 7.45-7.23 (m, 6H), 4.55 (d, J=6.0 Hz, 2H), 4.49 (s, 2H), 4.07 (t, J=9.0 Hz, 2H), 3.52 (t, J=9.0 Hz, 2H) 2.55 (s, 3H); MS (ES+) m/z 426.2 (M+1).
Reaction SMILES: C([O:3][C:4]([N:6]1[CH2:12][CH2:11][N:10]([O:13][CH3:14])[CH2:9][CH2:8][N:7]1[C:15](=[O:27])[CH2:16][C:17]1[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=1[CH2:25][CH3:26])=O)C.C[O-].[Na+].Cl>CN(C)C=O>[CH2:25]([C:18]1[CH:19]=[C:20]([CH3:24])[CH:21]=[C:22]([CH3:23])[C:17]=1[CH:16]1[C:15](=[O:27])[N:7]2[CH2:8][CH2:9][N:10]([O:13][CH3:14])[CH2:11][CH2:12][N:6]2[C:4]1=[O:3])[CH3:26]
Reactant: CCOC(=O)N1CCN(OC)CCN1C(=O)Cc1c(C)cc(C)cc1CC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cc(C)cc(C)c1C1C(=O)N2CCN(OC)CCN2C1=O
Reaction time: 0.33 h

Procedure:
To a solution of 2-[2-(2-ethyl-4,6-dimethyl-phenyl)-acetyl]-5-methoxy-[1,2,5]triazepane-1-carboxylic acid ethyl ester (550 mg, 1.46 mmol) in absolute dimethylformamide (5 ml) at 80° C. was added sodium methoxide (240 mg, 4.44 mmol) in one portion and stirring continued at 80° C. for 20 minutes. The cooled reaction mixture was poured on ice, the aqueous alkaline phase was acidified to pH 5 by addition of a 6N HCl solution, the resulting suspension was filtered, the obtained solid dissolved in dichloromethane, the organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel (ethyl acetate/methanol 20:1). Yield: 220 mg of 8-(2-ethyl-4,6-dimethyl-phenyl)-3-methoxy-tetrahydro-pyrazolo[1,2-a][1,2,5]triazepine-7,9-dione (compound P2.14) as a pale brown solid, mp 213-215° C.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[NH:34]1[CH2:39][CH2:38][CH:37]([NH:40][C:41](=[O:43])[CH3:42])[CH2:36][CH2:35]1>>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:34]4[CH2:39][CH2:38][CH:37]([NH:40][C:41](=[O:43])[CH3:42])[CH2:36][CH2:35]4)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: CC(=O)NC1CCNCC1
Product: CC(=O)NC1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CC1

Procedure:
N-(1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidin-4-yl)-acetamide was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and N-Piperidin-4-yl-acetamide following General Procedure B.
Reaction SMILES: [C:1]1([CH:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:8][C:9]2[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][OH:17])[N:11]([CH2:18][CH:19]([O:22][CH3:23])[O:20][CH3:21])[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[O-2].[O-2].[Mn+4]>[C:24]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][C:9]2[C:14](=[O:15])[CH:13]=[C:12]([CH:16]=[O:17])[N:11]([CH2:18][CH:19]([O:20][CH3:21])[O:22][CH3:23])[CH:10]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(Cn1cc(OC(c2ccccc2)c2ccccc2)c(=O)cc1CO)OC
Agent: [Mn+4]
Agent: [O-2]
Product: COC(Cn1cc(OC(c2ccccc2)c2ccccc2)c(=O)cc1C=O)OC

Procedure:
Starting from 2.052 g of 3-diphenylmethoxy-1-(2,2-dimethoxyethyl)-6-hydroxymethyl-4-pyridone and 12.0 g of manganese dioxide, the title compound is obtained in the same manner as in Synthesis Example 2 as colorless crystal in a yield of 1.582 g.
Reaction SMILES: C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[N:20]1([CH2:27][CH2:28][O:29][C:30]2[CH:56]=[CH:55][C:33]([O:34][C:35]3[C:44]4[C:39](=[CH:40][C:41]([O:45][CH3:46])=[CH:42][CH:43]=4)[CH:38]=[CH:37][C:36]=3OS(C(F)(F)F)(=O)=O)=[CH:32][CH:31]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.[F-].[Cs+].[F:59][C:60]1[CH:61]=[C:62](B(O)O)[CH:63]=[CH:64][C:65]=1[F:66]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Pd].C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C(#N)C>[F:59][C:60]1[CH:61]=[C:62]([C:36]2[CH:37]=[CH:38][C:39]3[C:44](=[CH:43][CH:42]=[C:41]([O:45][CH3:46])[CH:40]=3)[C:35]=2[O:34][C:33]2[CH:55]=[CH:56][C:30]([O:29][CH2:28][CH2:27][N:20]3[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]3)=[CH:31][CH:32]=2)[CH:63]=[CH:64][C:65]=1[F:66]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Agent: [Pd+2]
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: CC#N
Product: COc1ccc2c(Oc3ccc(OCCN4CCCCCC4)cc3)c(-c3ccc(F)c(F)c3)ccc2c1
Temperature: 90 °C
Yield: 85.7 %

Procedure:
Combine palladium acetate (33 mg, 0.15 mmol), tricyclohexyl phosphine (61 mg, 0.22 mmol) and acetonitrile (6 mL). Sonicate the mixture for 5 minutes. Combine trifluoromethanesulfonic acid 1-[4-(2-azepan-1-yl-ethoxy)-phenoxy]-6-methoxy-naphthalen-2-yl ester (787 mg, 1.46 mmol), cesium fluoride (2.00 g, 13.2 mmol), 3,4-difluorophenylboronic acid (692 mg, 4.38 mmol) and acetonitrile (16 mL). Add the sonicated Pd/Pcy3 suspension to reaction vessel and heat to 90° C. for 30 minutes. Cool to room temperature and filter through pad of Celite and evaporate the solvent. Dissolve residue in ethyl acetate (40 mL) and wash with saturated NaHCO3 (10 mL). Separate the layers, wash the organic layer with brine (10 ml), dry with MgSO4, filter, and concentrate in vacuo. Chromatograph the residue on a SiO2 column eluting the material with methanol in dichloromethane (0 to 5%) to give 630 mg (86%) of the title compound: mass spectrum (ion spray) m/z=504.2 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1I.C([Sn](CCCC)(CCCC)[S:20][CH3:21])CCC>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[S:20][CH3:21]
Reactant: CCCC[Sn](CCCC)(CCCC)SC
Reactant: COC(=O)c1nc(Cl)c(F)c(N)c1I
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1nc(Cl)c(F)c(N)c1SC
Temperature: 80 °C
Reaction time: 18 h

Procedure:
Methyl 4-amino-6-chloro-5-fluoro-3-iodopicolinate (1.5 g, 4.6 mmol), tri-n-butylmethylthiostannane (2.5 g, 7.3 mmol), his (triphenylphosphine) palladium (II) chloride (320 mg, 0.46 mmol) and copper (I) iodide (90 mg, 0.46 mmol) were combined 15 ml dry, deaerated DMF and heated to 80° C. After 3 h another 2.5 g portion of the stannane were added and heating was continued for 18 h. After cooling, the mixture was stirred with 25 ml 10% potassium bifluoride solution for 20 ml. The heterogeneous mixture was stirred with 100 ml ethyl acetate and filtered through diatomaceous earth to remove curdy solids. The separated organic phase was washed twice with 15 ml water, 15 ml sat. NaCl, dried (Na2SO3) and evaporated. The product was purified by silica gel chromatography eluting with a 0-25% ethyl acetate-DCM gradient. The gummy residue was stirred with hexane to produce the written product as a white solid, 800 mg. Mp: 75-77° C. 1H NMR (400 MHz, CDCl3) δ 5.35 (s, 2H), 3.96 (s, 3H), 2.33 (s, 3H). 19F NMR (376 MHz, CDCl3) δ −138.81. EIMS m/z 250.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4]#[N:5].[CH2:11]1[O:21][C:15]2([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[O:14][CH:12]1[CH3:13]>ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>[CH2:11]1[O:21][C:15]2([CH2:20][CH2:19][N:18]([C:2]3[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=3[C:4]#[N:5])[CH2:17][CH2:16]2)[O:14][CH:12]1[CH3:13]
Reactant: N#Cc1cc(F)ccc1F
Reactant: CC1COC2(CCNCC2)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC1COC2(CCN(c3ccc(F)cc3C#N)CC2)O1
Temperature: 25 °C
Reaction time: 264 h

Procedure:
A mixture of 2,5-difluorobenzonitrile (2.272 g, 16.33 mmol) and 4-piperidone propylene ketal (2.570 g, 16.34 mmol) was stirred at room temperature (11 d). The resulting mixture was diluted with dichloromethane and sodium carbonate solution and the aqueous layer was extracted with two additional portions of dichloromethane. The combined organic extracts were washed with brine and dried over Na2SO4. The solvent was removed in vacuo. PCTLC (SiO2, 6 mm, 20% EtOAc-80% hexane) afforded the title compound (39).