Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:6]([CH:7]([CH3:9])[CH3:8])[NH:5][C:4](=[O:10])[CH:3]=1.[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH2:28][CH2:29][NH:30][C:31](=[O:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:20]1>>[OH:1][C:2]1[CH:6]([CH:7]([CH3:9])[CH3:8])[NH:5][C:4](=[O:10])[C:3]=1[CH:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:20]1[NH:19][C:27]2[C:22]([C:21]=1[CH2:28][CH2:29][NH:30][C:31](=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[CH:23][CH:24]=[CH:25][CH:26]=2
Reactant: O=Cc1ccccc1
Reactant: CC(C)C1NC(=O)C=C1O
Reactant: O=C(NCCc1c[nH]c2ccccc12)c1ccccc1
Product: CC(C)C1NC(=O)C(C(c2ccccc2)c2[nH]c3ccccc3c2CCNC(=O)c2ccccc2)=C1O

Procedure:
Using general procedure C, 4-hydroxy-5-isopropyl-1,5-dihydro-pyrrol-2-one (Lit. 11) was reacted with benzaldehyde and N-[2-(1H-indol-3-yl)-ethyl]-benzamide to give the title compound as a grey solid. MS: 494.3 ([M+H]+).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[C:5]([OH:8])(=O)[CH3:6].[CH:9](=O)[C:10]1[C:11](=[CH:13][CH:14]=[CH:15][CH:16]=1)[OH:12]>C1(C)C=CC=CC=1>[CH:9](=[N:3][CH2:2][CH2:1][N:4]=[CH:13][C:11]1[C:5](=[CH:6][CH:15]=[CH:16][CH:10]=1)[OH:8])[C:10]1[C:11](=[CH:13][CH:14]=[CH:15][CH:16]=1)[OH:12]
Reactant: NCCN
Reactant: O=Cc1ccccc1O
Reactant: CC(=O)O
Solvent: Cc1ccccc1
Product: Oc1ccccc1C=NCCN=Cc1ccccc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethylenediamine (5.71 g, 0.095 mmol) was dissolved into toluene (60 ml). To it, a catalytic amount of acetic acid was added. Then, salicylaldehyde (23.20 g, 0.190 mmol) dissolved into toluene (60 ml) was dropwise added into the above solution. The resulting solution was then stirred at room temperature overnight. A yellowish crystalline product was precipitated. It was filtered, washed with ethanol, and dried. The yield was 23.7 g (93%). 1H NMR (300 MHz, CDCl3): δ=3.84 ppm (s, 4H), 6.85 ppm (t, 2H), 6.92 ppm (d, 2H), 7.17 ppm (m. 2H), 7.19 ppm (m, 2H), 8.28 ppm (s, 2H), 12.77 (s, broad, 2×OH); ESI MS: calcd. for C16H16N2O2, 268.3, found 269.2 (M+1); UV/Vis (λmax, nm, in methanol): 212, 255, 316, 400; IR (cm−1, nujol mull): 1610 (m, —C═N—).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][N:18]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[F:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:30]4[CH:29]=[CH:28][CH:27]=[C:26]([F:25])[CH:31]=4)=[CH:19][N:18]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1
Reactant: OB(O)c1cccc(F)c1
Reactant: COC(=O)CC1CCC(c2ccc(-c3ccc(N)cn3)cc2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)CC1CCC(c2ccc(-c3ccc(Nc4cccc(F)c4)cn3)cc2)CC1
Reaction time: 18 h

Procedure:
To a solution of {4-[4-(5-amino-pyridin-2-yl)-phenyl]-cyclohexyl}-acetic acid methyl ester (0.10 g, 0.3 mmol, 1.0 equiv) and 3-fluorophenyl boronic acid (0.086 g, 0.61 mmol, 2.0 equiv) in 5 Ml dichloromethane was added pyridine (0.05 Ml, 0.61 mmol, 2.0 equiv), copper (II) acetate (0.084 g, 0.46 mmol, 1.5 equiv) and 4 Å molecular sieves. The heterogeneous mixture was allowed to stir open to atmosphere for 18 h. Purification by silica gel chromatography (20-45% EtOAc in hexanes) afforded the title compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12-1.27 (m, 2 H) 1.47 (br. S., 1 H) 1.53 (dd, J=12.51, 2.65 Hz, 1 H) 1.67 (br. S., 1 H) 1.85 (d, J=12.38 Hz, 4 H) 2.29 (d, J=6.57 Hz, 2 H) 3.34 (s, 2 H) 3.64 (s, 3 H) 6.69 (td, J=8.46, 2.53 Hz, 1 H) 6.89 (dt, J=11.62, 2.15 Hz, 1 H) 6.96 (dd, J=7.83, 1.77 Hz, 1 H) 7.33 (d, J=8.34 Hz, 2H) 7.63 (dd, J=8.59, 2.78 Hz, 1 H) 7.84 (d, J=8.59 Hz, 1 H) 7.95 (d, J=8.34 Hz, 2 H) 8.47 (s, 1 H) 8.71 (s, 1H); (M+H)+ 419.3.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[CH3:15][O:16][C:17]1[C:27]([O:28][CH3:29])=[CH:26][C:20]2[CH2:21][CH2:22][NH:23][CH2:24][CH2:25][C:19]=2[CH:18]=1.[C:30]([OH:35])(=[O:34])[C:31]([OH:33])=[O:32].CO>C(OCC)(=O)C>[C:30]([OH:35])(=[O:34])[C:31]([OH:33])=[O:32].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:23]3[CH2:24][CH2:25][C:19]4[CH:18]=[C:17]([O:16][CH3:15])[C:27]([O:28][CH3:29])=[CH:26][C:20]=4[CH2:21][CH2:22]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: COc1cc2c(cc1OC)CCNCC2
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc2c(cc1OC)CCN(C[C@H](O)COc1cccc3[nH]ccc13)CC2

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 48% overall yield. FDMS m/e=396 (M+ of free base). α[D]589 =-9.34 (c=0.47, methanol).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=O)=[CH:4][CH:3]=1.Cl.[NH2:14][OH:15].C([O-])(=O)C.[Na+]>C(O)C.O>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[N:14][OH:15])=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C1CCCc2ccc(O)cc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=C1CCCc2ccc(O)cc21
Temperature: 80 °C
Yield: 94.1 %

Procedure:
7-Hydroxy-3,4-dihydronaphthalen-1(2H)-one (0.75 g, 4.2 mmol) was dissolved in ethanol (30 mL) and water (10 mL), then the hydroxylamine hydrochloride (0.59 g, 8.5 mmol) and sodium acetate (0.70 g, 8.5 mmol) were added. The reaction was heated to 80° C. for 2 h. The reaction was allowed to cool to r.t., concentrated under reduced pressure and the residue was partitioned between ethyl acetate and 1 N HCl. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give the crude product as oil. The oil was purified by flash chromatography on a silica gel column eluting hexane: ethyl acetate gradient to give 7-hydroxy-3,4-dihydronaphthalen-1(2H)-one oxime (0.70 g, 95%) as a yellow green oil. Analytical LCMS (M+H)+: m/z=178.1.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][S:8]([NH:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][CH2:27][CH2:28][N:29](C(OC(C)(C)C)=O)[CH2:30][C@@H:31]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=3)[OH:32])=[CH:22][CH:21]=2)=[CH:16][C:15]=1[O:47][CH2:48][CH:49]([CH3:51])[CH3:50])=[O:13])(=[O:10])=[O:9])(=O)C.[OH-].[Na+]>CO.O1CCCC1>[ClH:39].[ClH:39].[Cl:39][C:35]1[CH:34]=[C:33]([C@@H:31]([OH:32])[CH2:30][NH:29][CH2:28][CH2:27][NH:26][C:23]2[CH:22]=[CH:21][C:20]([C:17]3[CH:18]=[CH:19][C:14]([C:12]([NH:11][S:8]([CH2:7][CH2:6][CH2:5][OH:4])(=[O:10])=[O:9])=[O:13])=[C:15]([O:47][CH2:48][CH:49]([CH3:50])[CH3:51])[CH:16]=3)=[CH:25][CH:24]=2)[CH:38]=[CH:37][CH:36]=1
Reactant: CC(=O)OCCCS(=O)(=O)NC(=O)c1ccc(-c2ccc(NCCN(C[C@H](O)c3cccc(Cl)c3)C(=O)OC(C)(C)C)cc2)cc1OCC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)COc1cc(-c2ccc(NCCNC[C@H](O)c3cccc(Cl)c3)cc2)ccc1C(=O)NS(=O)(=O)CCCO
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 241.2 %

Procedure:
To a solution of 3-[[[[4′-[[2-[(tert-butoxycarbonyl)-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]amino]-3-isobutoxy-4-biphenylyl]carbonyl]amino]sulfonyl]propyl acetate (34.0 mg) in methanol (0.340 ml) and tetrahydrofuran (0.170 ml) was added 1N aqueous sodium hydroxide solution (0.228 ml) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted with ethyl acetate, washed with water and brine and dried over magnesium sulfate. The solvent was concentrated under reduced pressure. To a solution of the resulting residue in 1,4-dioxane (0.340 ml) was added 4N hydrogen chloride in 1,4-dioxane (0.340 ml) and the mixture was stirred at room temperature overnight. The solvent was concentrated under reduced pressure and to the residue was added ethyl acetate. The precipitate was collected by filtration and dried in vacuo to give 4′-[[2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]amino]-N-[(3-hydroxypropyl)sulfonyl]-3-isobutoxy-4-biphenylcarboxamide dihydrochloride (24.8 mg) as a yellow powder.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6]1[CH2:12][CH2:11][C:9](=[O:10])[CH2:8][CH2:7]1)=[O:5].[CH2:13](O)[CH2:14][OH:15].CCOCC>C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:15]1[C:9]2([CH2:11][CH2:12][CH:6]([C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH2:7][CH2:8]2)[O:10][CH2:13][CH2:14]1
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
This compound was prepared from ethyl cyclohexanone-4-carboxylate by following the procedure of Pearson et al. (J. Org. Chem., 1997, 62, 5284). A mixture of ethylene glycol (131 mL, 2350 mmol), ethyl 4-oxocyclohexanecarboxylate (100 g, 588 mmol), and p-toluene sulfonic acid monohydrate (2.012 g, 10.58 mmol) in benzene (125 mL) was stirred overnight at room temperature, under N2. The solution was poured into Et2O (1 L) and the mixture washed with water (3×300 mL), sat. NaHCO3 (100 mL) followed by brine (100 mL). The organic layer was then dried (MgSO4), filtered, and concentrated to yield the title compound (125.5 g, 586 mmol, 100% yield) as a clear oil: LCMS m/z 215.13 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[C:5]([C:13]([F:16])([F:15])[F:14])[CH:4]=1.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:63]=[CH:62][C:27]([C:28]([N:30]([CH2:54][C:55]([O:57]C(C)(C)C)=[O:56])[CH2:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]3[N:42]=[C:41]([NH:43][S:44]([C:47]4[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][CH:48]=4)(=[O:46])=[O:45])[O:40][N:39]=3)=[CH:34][CH:33]=2)=[O:29])=[CH:26][CH:25]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:23][C:24]2[CH:63]=[CH:62][C:27]([C:28]([N:30]([CH2:54][C:55]([OH:57])=[O:56])[CH2:31][C:32]3[CH:33]=[CH:34][C:35]([C:38]4[N:42]=[C:41]([NH:43][S:44]([C:47]5[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][CH:48]=5)(=[O:46])=[O:45])[O:40][N:39]=4)=[CH:36][CH:37]=3)=[O:29])=[CH:26][CH:25]=2)=[O:12])=[C:5]([C:13]([F:16])([F:15])[F:14])[CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2nc(-c3ccc(CN(CC(=O)OC(C)(C)C)C(=O)c4ccc(N)cc4)cc3)no2)cc1
Reactant: COc1ccc(CC(=O)O)c(C(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)O)Cc3ccc(-c4noc(NS(=O)(=O)c5ccc(C)cc5)n4)cc3)cc2)c(C(F)(F)F)c1
Yield: 18 %

Procedure:
Prepared using General Procedures 7 and 8: To a stirring suspension of 2-(4-methoxy-2-(trifluoromethyl)phenyl)acetic acid (26.4 mg, 0.113 mmol) in DCM (1 mL) and DMF (10 μL) was added oxalyl chloride (9.85 μL, 0.113 mmol) at room temperature. After 1 h the reaction mixture was added to a solution of tert-butyl 2-(4-amino-N-(4-(5-(4-methylphenylsulfonamido)-1,2,4-oxadiazol-3-yl)benzyl)benzamido)acetate INT-69 (13 mg, 0.023 mmol) in DCM (0.5 mL) and TEA (6.27 μL, 0.045 mmol). After stirring at room temperature for 2 h TFA (0.5 mL) was added. The reaction mixture was concentrated in vacuo and purified by preparative HPLC to afford 3.2 mg (18%) of 2-(4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(5-(4-methylphenylsulfonamido)-1,2,4-oxadiazol-3-yl)benzyl)benzamido)acetic acid 480 as an off-white solid. LCMS-ESI (m/z) calculated for C35H30F3N5O8S: 737; found 738 [M+H]+, tR=5.74 min (Method 9).
Reaction SMILES: FC1C=C(F)C=C(F)C=1C(NC1C=CC=C([C:13]([CH:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)=[O:14])N=1)=O.C[N:29]1[CH2:34][CH2:33]C(C(O)=O)[CH2:31][CH2:30]1.S(Cl)(Cl)=O.C(NCC)C>>[CH2:30]([N:29]([CH2:34][CH3:33])[C:13]([CH:15]1[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]1)=[O:14])[CH3:31]
Reactant: CN1CCC(C(=O)O)CC1
Reactant: CN1CCC(C(=O)c2cccc(NC(=O)c3c(F)cc(F)cc3F)n2)CC1
Solvent: O=S(Cl)Cl
Solvent: CCNCC
Product: CCN(CC)C(=O)C1CCN(C)CC1

Procedure:
The present invention relates to a process for preparing 2,4,6-trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide or salt thereof, further comprising the step of: reacting 1-methylpiperidine-4-carboxylic acid with thionyl chloride and diethyl amine to yield N,N-diethyl-1-methylpiperidine-4-carboxamide.
Reaction SMILES: [CH:1]1([C:5](Cl)=O)[CH2:4][CH2:3][CH2:2]1.C1(P(=[CH:27][C:28](=[O:30])[CH3:29])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=CC=CC=1>O1CCCC1.[Pd]>[CH:1]1([CH:5]=[CH:27][C:28](=[O:30])[CH3:29])[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(Cl)C1CCC1
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: CC(=O)C=CC1CCC1

Procedure:
10 parts of cyclobutylcarboxylic acid chloride in tetrahydrofuran is hydrogenated over 10% palladium on carbon catalyst, to provide cyclobutylcarboxaldehyde. 25 parts of triphenylphosphoranylidene-2-propanone and 6.3 parts of the cyclobutylcarboxaldehyde in 60 parts by volume of benzene under nitrogen are refluxed for 8 hours. The solvent is removed by evaporation under reduced pressure to provide 4-cyclobutyl-3-buten-2-one.
Reaction SMILES: Cl.C([N:9]([CH2:23][C@H:24]([OH:33])[CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:10]1[CH2:16][CH2:15][CH2:14][C:13]2[CH:17]=[C:18]([OH:22])[C:19]([Cl:21])=[CH:20][C:12]=2[CH2:11]1)C1C=CC=CC=1.[H][H]>ClC1C=CC=CC=1.CO.[Pd]>[ClH:21].[Cl:21][C:19]1[C:18]([OH:22])=[CH:17][C:13]2[CH2:14][CH2:15][CH2:16][CH:10]([NH:9][CH2:23][C@H:24]([OH:33])[CH2:25][O:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:11][C:12]=2[CH:20]=1
Reactant: [H][H]
Reactant: Oc1cc2c(cc1Cl)CC(N(Cc1ccccc1)C[C@H](O)COc1ccccc1)CCC2
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: Clc1ccccc1
Product: Oc1cc2c(cc1Cl)CC(NC[C@H](O)COc1ccccc1)CCC2
Yield: 150 %

Procedure:
A mixture of (2S)-1-[N-benzyl-N-(3-chloro-6,7,8,9-tetrahydro-2-hydroxy-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol hydrochloride (121 mg) and 10% Pd/C (50% wet, 18 mg) in chlorobenzene (1.8 ml) and MeOH (0.4 ml) was stirred at room temperature in the presence of hydrogen at an atmospheric pressure for 1 hour and filtered. The filtrate was evaporated in vacuo, and the residue was partitioned between ethyl acetate and a saturated aqueous solution of sodium bicarbonate. The organic layer was separated, washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed (dichloromethane-methanol) over silica gel (2.0 g). The eluate was treated with 4N hydrogen chloride in ethyl acetate and evaporated in vacuo. The residue was triturated in diisopropyl ether, and the precipitated powder was collected by filtration to afford (2S)-1-(3-chloro-6,7,8,9-tetrahydro-2-hydroxy-5H-benzocyclohepten-6-yl)amino-3-phenoxy-2-propanol hydrochloride (74 mg, 75%) as a colorless powder.
Reaction SMILES: O[C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C1(N=C=NC2CCCCC2)CCCCC1.[O:27]1CCCC1>>[CH:10]1[CH:9]=[C:8]([OH:11])[C:7]([OH:27])=[C:3]([C:4]([OH:6])=[O:5])[CH:2]=1
Reactant: C1CCOC1
Reactant: O=C(O)c1cc(O)ccc1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: O=C(O)c1cccc(O)c1O
Reaction time: 12 h

Procedure:
2,5-dihydroxy benzoic acid (DHBA) is first activated by treatment with dicyclohexylcarbodiimide (DCC) and NHS in tetrahydrofurane (THF). To a stirred solution of 9.25 g (60 mmole) DHBA in 450 ml of THF was added 7.14 g (62 mmole) NHS and 12.8 g (62 mmole) DCC. After filtering off the formed dicyclohexylurea, the solution was concentrated by vacuum evaporation until crystallisation of the DHBA-MHS ester started. The solution was stored at 5° C. for 12 hrs and the resulting DHBA-NHS precipitate was collected by filtration. After drying the yield of the synthesis was 70%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[O:11])=[CH:4][CH:3]=1.C1C(=O)N(Br)C(=O)C1.[NH2:28][C:29]([NH2:31])=[S:30]>C(O)C>[NH2:31][C:29]1[S:30][C:9]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[O:11])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:28]=1
Reactant: NC(N)=S
Reactant: O=C(CC(=O)c1ccc(F)cc1)c1ccc(F)cc1
Agent: O=C1CCC(=O)N1Br
Solvent: CCO
Product: Nc1nc(-c2ccc(F)cc2)c(C(=O)c2ccc(F)cc2)s1
Temperature: 25 °C

Procedure:
1,3-Bis-(4-fluoro-phenyl)-propane-1,3-dione and NBS (1.05 eq) were heated neat at 60° C. for 10 minutes then cooled. The resulting mixture was dissolved in ethanol (0.2 M) and treated with thiourea (1.5 eq). It was heated at reflux for 15 hours and cooled to room temperature. It was evaporated to dryness and the residue was partioned between EtOAc and saturated NaHCO3. Organic fraction was dried over MgSO4, filtered and concentrated. The title compound was collected by trituration with heptanes. 1H NMR (400 MHz, DMSO-d6) 6.86-7.01 (m, 4H) 7.22-7.32 (m, 2H) 7.35-7.45 (m, 2H) 8.11 (br. s., 2H). LCMS Method A Rt=1.18 m/z 317.0 (M+1), 315 (M−1).
Reaction SMILES: N1C2C(=CC=CC=2)C(=O)C1=O.[Cl:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[C:15](=[O:23])[C:16](=[O:22])[NH:17]2.BrCCC1CC1.Br[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[Cl:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[C:15](=[O:23])[C:16](=[O:22])[N:17]2[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: CCOC(=O)CBr
Reactant: O=C1Nc2cccc(Cl)c2C1=O
Agent: BrCCC1CC1
Agent: O=C1Nc2ccccc2C1=O
Product: CCOC(=O)CN1C(=O)C(=O)c2c(Cl)cccc21

Procedure:
Following the procedure as described in PREPARATION 2A, and making non-critical variations to replace isatin with 4-chloro-1H-indole-2,3-dione, and (2-bromoethyl)cyclopropane with ethyl bromoacetate, the title compound was obtained (95%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.48 (t, 1H), 7.08 (d, 1H), 6.67 (d, 1H), 4.47 (s, 2H), 4.23 (q, 2H), 1.27 (t, 3H); MS (ES+) m/z 268.6 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][C:18]2[NH:22][C:21]([C:23]3C=CC=CN=3)=[N:20][N:19]=2)=[CH:4][CH:3]=1.[Cl:29]C1C=CC2N(C(CC(NN)=O)=C(C3C=CC=CC=3)N=2)C=1.Cl.C(=N)(N)C>>[Cl:29][C:13]1[CH:14]=[CH:15][C:10]2[N:11]([C:16]([CH2:17][C:18]3[NH:22][C:21]([CH3:23])=[N:20][N:19]=3)=[C:8]([C:5]3[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=3)[N:9]=2)[CH:12]=1
Reactant: Clc1ccc(-c2nc3ccccn3c2Cc2nnc(-c3ccccn3)[nH]2)cc1
Reactant: NNC(=O)Cc1c(-c2ccccc2)nc2ccc(Cl)cn12
Agent: CC(=N)N
Agent: Cl
Product: Cc1nnc(Cc2c(-c3ccccc3)nc3ccc(Cl)cn23)[nH]1

Procedure:
The title compound was prepared according to the experimental described for compound 230 from 2-(6-chloro-2-phenylimidazo[1,2-a]pyridin-3-yl)acetohydrazide and acetimidamide hydrochloride. M/e− 324 for C17H15ClN5 (M+H)+; 1H-NMR (400 MHz, CD3OD) δ 8.43 (s, 1H), 7.74 (d, J=8.4 Hz, 2H), 7.63 (m, 1H), 7.57 (d, J=9.9 Hz, 1H), 7.46 (d, J=8.4 Hz, 2H), 7.39 (m, 2H), 4.46 (s, 2H), 2.38 (s, 3H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=2)=[N:6][CH:7]=1.[CH3:25][C:26]1([NH2:30])[CH2:29][O:28][CH2:27]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:30][C:26]3([CH3:25])[CH2:29][O:28][CH2:27]3)=[O:22])=[CH:18][N:17]=2)=[N:6][CH:7]=1
Reactant: Cn1nnc(-c2ccc(F)cn2)c1COc1ccc(C(=O)O)cn1
Reactant: CC1(N)COC1
Product: Cn1nnc(-c2ccc(F)cn2)c1COc1ccc(C(=O)NC2(C)COC2)cn1
Yield: 91 %

Procedure:
As described for example 35b, 6-[5-(5-fluoro-pyridin-2-yl)-3-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-nicotinic acid (80 mg, 0.24 mmol) was converted, using 3-methyl-3-oxetanamine instead of 4-aminotetrahydropyran, to the title compound (88 mg, 91%) which was obtained as a white solid. MS: m/e=399.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][C:3]=1[O:10][CH2:11][CH2:12][CH2:13][CH3:14].S(Cl)([Cl:17])=O>C(Cl)Cl>[CH2:11]([O:10][C:3]1[CH:4]=[C:5]([CH2:8][Cl:17])[CH:6]=[CH:7][C:2]=1[Br:1])[CH2:12][CH2:13][CH3:14]
Reactant: O=S(Cl)Cl
Reactant: CCCCOc1cc(CO)ccc1Br
Solvent: ClCCl
Product: CCCCOc1cc(CCl)ccc1Br
Reaction time: 8 h
Yield: 92 %

Procedure:
To a stirred solution of 20.2 (659.3 mg, 2544 μmol) in DCM (15 mL) at 23° C., was added thionyl chloride (371 μL, 5088 μmol). The resulting mixture was stirred overnight. The reaction was concentrated and then purified by combiflash (0 to 10% EtOAc/Hexanes) to provide 20.3 (650 mg, 92.0% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20]([CH2:28][OH:29])[N:19]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:29][CH2:28][C:20]2[N:19]=[CH:18][C:27]3[C:22]([CH:21]=2)=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-n2cccn2)c1C#N
Reactant: OCc1cc2ccccc2cn1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(OCc2cc3ccccc3cn2)nc(N)nc1-n1cccn1

Procedure:
From 2-amino-4-methanesulfinyl-6-pyrazol-1-yl-pyrimidine-5-carbonitrile, isoquinolin-3-yl-methanol and DBU in DME. ES-MS m/e (%): 366 (M+Na+, 60), 344 (M+H+, 100).
Reaction SMILES: O1CCCC1.[F:6][C:7]1[CH:24]=[CH:23][C:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19](Cl)=[N:20][OH:21])=[CH:14][CH:13]=2)=[CH:9][CH:8]=1.[C:25]([C:27]1[C:28]([NH2:34])=[N:29][C:30]([NH2:33])=[CH:31][CH:32]=1)#[CH:26].C(N(CC)CC)C>O>[F:6][C:7]1[CH:24]=[CH:23][C:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]3[CH:26]=[C:25]([C:27]4[C:28]([NH2:34])=[N:29][C:30]([NH2:33])=[CH:31][CH:32]=4)[O:21][N:20]=3)=[CH:14][CH:13]=2)=[CH:9][CH:8]=1
Reactant: ON=C(Cl)Cc1ccc(Oc2ccc(F)cc2)cc1
Reactant: C#Cc1ccc(N)nc1N
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1ccc(-c2cc(Cc3ccc(Oc4ccc(F)cc4)cc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.7 %

Procedure:
To a tetrahydrofuran (5.00 mL) solution of (4-(4-fluoro-phenoxy)-phenyl)acetohydroximoyl chloride (290 mg, 1.04 mmol) described in Manufacturing Example 141-1-3 and 3-ethynyl-pyridine-2,6-diamine (40.0 mg, 0.300 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (105 μL, 0.750 mmol) under nitrogen atmosphere at room temperature, which was stirred for 16 hours at room temperature. Water was added at room temperature to the reaction solution at room temperature, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=3:1→ethyl acetate) to obtain the title compound (38.1 mg, 33.7%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:7]([C:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)=[O:8].CN(C)C=O.[F:29][C:30]([F:40])([F:39])[C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH2:33]Br>C(#N)C>[CH3:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:7]([C:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:33][C:32]2[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=2[C:30]([F:29])([F:39])[F:40])[CH:10]=1)=[O:8]
Reactant: Cc1ccc(C(=O)c2c[nH]c3ccccc3c2=O)cc1C
Reactant: FC(F)(F)c1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: Cc1ccc(C(=O)c2cn(Cc3ccccc3C(F)(F)F)c3ccccc3c2=O)cc1C

Procedure:
Compound 4kk was prepared following the procedure outlined in Step 3 of Example 1 using 26 mg (0.65 mmol) of sodium hydride (60%), 138.6 mg (0.50 mmol) of 3-(3,4-Dimethyl-benzoyl)-2,3-dihydro-1H-quinolin-4-one 3a, 3 mL of anhydrous dimethylformamide, and 155.4 mg (0.65 mmol) of 2-trifluoromethylbenzylbromide. The crude product was purified by flash chromatography to yield 96 mg of 4kk as a colorless solid: LC-MSD, m/z for C26H20F3NO2, [M+H]+=436.5, [M+2H]+=437.5; Reverse phase HPLC (gradient acetonitrile 0.1% TFA 20-95% in 4 min) retention time=2.709 min; 1H NMR (400 MHz, CDCl3/HCl): δ 2.32 (d, 6H), 5.60 (s, 2H), 6.92 (m, 1H), 7.17 (t, 2H), 7.39-7.47 (m, 3H), 7.54-7.60 (m, 2H), 7.65 (s, 1H), 7.79 (m, 1H), 8.22 (s, 1H), 8.50 (m, 1H).