Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][N:10]([CH3:23])[C:11]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=2)[C:16]([O:18][CH3:19])=[O:17])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:24][C:25]([O:28][C:29]([N:31]1[CH2:36][CH2:35][N:34]([CH2:37][C:38]2[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][CH:43]=2)[CH2:33][C@@H:32]1[CH3:47])=[O:30])([CH3:27])[CH3:26].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:9][N:10]([CH3:23])[C:11]([C:13]2[CH:22]=[CH:21][CH:20]=[C:15]([C:16]([O:18][CH3:19])=[O:17])[CH:14]=2)=[O:12])=[CH:3][C:2]=1[C:40]1[CH:41]=[CH:42][CH:43]=[C:38]([CH2:37][N:34]2[CH2:35][CH2:36][N:31]([C:29]([O:28][C:25]([CH3:27])([CH3:26])[CH3:24])=[O:30])[C@@H:32]([CH3:47])[CH2:33]2)[CH:39]=1
Reactant: C[C@H]1CN(Cc2cccc(B(O)O)c2)CCN1C(=O)OC(C)(C)C
Reactant: COC(=O)c1cccc(C(=O)N(C)Cc2ccc(F)c(Br)c2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cccc(C(=O)N(C)Cc2ccc(F)c(-c3cccc(CN4CCN(C(=O)OC(C)(C)C)[C@@H](C)C4)c3)c2)c1
Temperature: 130 °C
Yield: 69.3 %

Procedure:
To a solution of methyl 3-{[[(3-bromo-4-fluorophenyl)methyl](methyl)amino]carbonyl}benzoate (0.20 g, 0.526 mmol) in p-dioxane/H2O (4.5/1.5 mL) was added {3-[((3S)-4-{[(1,1-dimethylethyl)oxy]carbonyl}-3-methyl-1-piperazinyl)methyl]-phenyl}boronic acid (0.264 g, 0.789 mmol), Pd(PPh3)4 (0.030 g, 0.026 mmol), and K2CO3 (0.29 mL, 2.1 mmol). The mixture was heated with z microwave at 130° C. for 15 min. The mixture was then filtered, and the filtrate concentrated and purified by CombiFlash chromatograph to afford the title compound 0.215 g (69%). LC-MS m/z 590 (M+H)+.
Reaction SMILES: C(OC([C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][Br:19])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)=O)C.[CH2:20]([O:22][C:23](C1C=CC(C2C=CC(C)=CC=2)=CC=1)=[O:24])[CH3:21].BrN1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[CH2:20]([O:22][C:23]([C:11]1[CH:6]=[CH:7][C:8]([C:12]2[CH:13]=[CH:14][C:15]([CH2:18][Br:19])=[CH:16][CH:17]=2)=[CH:9][CH:10]=1)=[O:24])[CH3:21]
Reactant: CCOC(=O)c1cccc(-c2ccc(CBr)cc2)c1
Reactant: CCOC(=O)c1ccc(-c2ccc(C)cc2)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(-c2ccc(CBr)cc2)cc1
Yield: 83 %

Procedure:
4′-Bromomethyl-biphenyl-4-carboxylic acid ethyl ester was prepared as described for 4′-bromomethyl-biphenyl-3-carboxylic acid ethyl ester. 4′-Methyl-biphenyl-4-carboxylic acid ethyl ester (3.4 g, 14.15 mmol, 1 eq.) was reacted with N-bromosuccinimide (3.27 g, 18.4 mmol, 1.3 eq.) and 2,2′-azobisisobutyronitrile (0.12 g, 0.71 mmol, 5 mol %) in carbon tetrachloride (150 mL). When complete, the reaction was worked up as described to produce 4′-bromomethyl-biphenyl-4-carboxylic acid ethyl ester (3.74 g, 83% yield) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([OH:9])=[CH:7][CH:6]=[C:5](/[CH:10]=[CH:11]/[C:12]([CH2:14][C:15](/[CH:17]=[CH:18]/[C:19]2[CH:27]=[C:24]([O:25][CH3:26])[C:22]([OH:23])=[CH:21][CH:20]=2)=[O:16])=[O:13])[CH:4]=1.[C:28](O)(=[O:48])/[CH:29]=[CH:30]\[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=[CH:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl.O>[C:28]([O:9][C:8]1[CH:7]=[CH:6][C:5]([CH:10]=[CH:11][C:12](=[O:13])[CH2:14][C:15](=[O:16])[CH:17]=[CH:18][C:19]2[CH:20]=[CH:21][C:22]([OH:23])=[C:24]([O:25][CH3:26])[CH:27]=2)=[CH:4][C:3]=1[O:2][CH3:1])(=[O:48])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=[CH:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]
Reactant: CCCCCCCCCC=CC=CC=CC=C/C=C\C(=O)O
Reactant: COc1cc(/C=C/C(=O)CC(=O)/C=C/c2ccc(O)c(OC)c2)ccc1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCCC=CC=CC=CC=CC=CC(=O)Oc1ccc(C=CC(=O)CC(=O)C=Cc2ccc(O)c(OC)c2)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.4 %

Procedure:
To a solution of curcumin (300 mg, 0.81 mmol), cis-eicosapentaenoic acid (250 mg, 0.83 mmol) and catalytic amount of 4-(dimethylamino)pyridine in dichloromethane (10 mL) was added a solution of N,N′-dicyclohexylcarbodiimide (252 mg, 1.2 mmol) in dichloromethane (5 mL) for 5 min at ice cold temperature. The mixture was stirred at rt for 16 h and diluted with water. The dichloromethane layer was separated and the aqueous layer was extracted with dichloromethane (3×100 mL). The combined dichloromethane layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and the residue was chromatographed over silica gel column using hexane-ethyl acetate (90:10) mixture as an eluent to give the product as an oil (235 mg, 44%). IR (neat) νmax 3013, 2961, 2929, 1762, 1630, 1593, 1268, 1123, 1032, 970 cm−1; 1H NMR (CDCl3) δ 7.61 (1H, d, J=16.0 Hz, H-1), 7.60 (1H, d, J=15.6 Hz, H-7), 7.03-7.16 (5H, m, H-2′, 2″, 5′, 6′, 6″), 6.93 (1H, d, J=8.4 Hz, H-5″), 6.55 (1H, d, J=16 Hz, H-2), 6.49 (1H, d, J=16 Hz, H-6), 5.89 (1H, br s, Ar—OH), 5.83 (1H, s, H-4), 5.38-5.39 (10H, m, H-5′″, 6′″, 8′″, 9′″, 11′″, 12′″, 14′″, 15′″, 17′″, 18′″), 3.95 (3H, s, Ar—OCH3), 3.87 (3H, s, Ar—OCH3), 2.84-2.86 (8H, m, H-7′″, 10′″, 13′″, 16′″), 2.58-2.66 (2H, m, H-2′″), 2.22-2.23 (2H, m, H-19′″), 2.05-2.09 (2H, m, H-4′″), 1.82-187 (2H, m, H-3′″), 0.97 (3H, t, J=7.4 Hz, H-20′″); LCMS (ESI, negative ion mode): m/z 651 (M-H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][CH:13]([CH3:23])[CH2:14][CH2:15][CH2:16][N:17]([CH2:21][CH3:22])[CH2:18][CH2:19][OH:20])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:24](Cl)(=[O:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]/[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41].CO>ClCCl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][CH:13]([CH3:23])[CH2:14][CH2:15][CH2:16][N:17]([CH2:21][CH3:22])[CH2:18][CH2:19][O:20][C:24](=[O:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]/[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCN(CCO)CCCC(C)Nc1ccnc2cc(Cl)ccc12
Reactant: CCCCCCCC/C=C/CCCCCCCC(=O)Cl
Solvent: CO
Solvent: ClCCl
Product: CCCCCCCC/C=C/CCCCCCCC(=O)OCCN(CC)CCCC(C)Nc1ccnc2cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 20.9 %

Procedure:
To a solution of 7-chloro-4-[4-[ethyl(2-hydroxyethyl)amino]1-methylbutylamino]-quinoline (hydroxychloroquine) (3.17 g, 9.4 mmol) in 30 ml dichloromethane was added elaidic acid chloride (2.82 g, 9.4 mmol) and the reaction mixturewas stirred at ambient temperature for 48 hours. A small amount of methanol was added, and the solvents were evaporated at high vacuum. The residue was repeatedly purified on a column of silica gel (first run: chloroform/methanol 9:1, second run: chloroform/methanol 95:5). Homogenous fractions were evaporated to give 1.18 g (21%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:12])([C:8]([F:11])([F:10])[F:9])[C:3]([O:5]CC)=[O:4].C[Si](C)(C)[O-].[K+:18]>CCOCC>[F:1][C:2]([F:12])([C:8]([F:11])([F:10])[F:9])[C:3]([O-:5])=[O:4].[K+:18]
Reactant: CCOC(=O)C(F)(F)C(F)(F)F
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Product: O=C([O-])C(F)(F)C(F)(F)F
Yield: 93 %

Procedure:
The procedure of Example 1 was followed using ethyl perfluoropropionate (4.8 g, 25 mmol), potassium trimethylsilanolate (3.2 g, 25 mmol), and dry ether (150 mL). Potassium perfluoropropionate (4.7 g, 93% yield) was isolated as a white solid: 19F NMR (D2O) δ -79.5 (m, CF3, 3F), -117.5 (m, CF2, 2F). Anal. Calcd. for C3F5KO2 : C, 17.83; F, 47.00; K, 19.35. Found: C, 17.52; F, 46.83; K, 19.24.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:13]([O:15][CH3:16])=[O:14])=[C:4]([CH3:12])[C:5]([O:8][CH:9]([CH3:11])[CH3:10])=[N:6][CH:7]=1.Br[CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24].C([O-])([O-])=O.[K+].[K+]>CC#N>[C:23]([O:22][C:21]([NH:20][CH2:19][CH2:18][O:1][C:2]1[C:3]([C:13]([O:15][CH3:16])=[O:14])=[C:4]([CH3:12])[C:5]([O:8][CH:9]([CH3:10])[CH3:11])=[N:6][CH:7]=1)=[O:27])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: COC(=O)c1c(O)cnc(OC(C)C)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1c(OCCNC(=O)OC(C)(C)C)cnc(OC(C)C)c1C
Yield: 64.8 %

Procedure:
A mixture of methyl 5-hydroxy-3-methyl-2-(propan-2-yloxy)pyridine-4-carboxylate (131c, 0.70 g, 3.1 mmol), tert-butyl (2-bromoethyl)carbamate (0.76 g, 3.4 mmol) and K2CO3 (0.86 g, 6.2 mmol) in CH3CN (24 mL) was degassed with N2 and refluxed for 15 hours. To the reaction mixture was added brine (40 mL) and EtOAc (40 mL). The aqueous layer was extracted with EtOAc (20 mL). The combined organic layers were washed with brine (60 mL), dried over Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether/EtOAc, 10/1) to give methyl 5-{2-[(tert-butoxycarbonyl)amino]ethoxy}-3-methyl-2-(propan-2-yloxy)pyridine-4-carboxylate (131d, 0.74 g, 65%) as yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[N:7]([C@H:9]([C:11](=[O:37])[NH:12][C@H:13]1[C@H:19]([CH3:20])[N:18]([C:21](=[O:31])[C:22]2[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][CH:23]=2)[C:17]2[CH:32]=[CH:33][CH:34]=[CH:35][C:16]=2[NH:15][C:14]1=[O:36])[CH3:10])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[Br:45][C:46]1[CH:55]=[CH:54][CH:53]=[C:52]2[C:47]=1[CH:48]=[CH:49][C:50]([O:58][CH3:59])=[C:51]2[CH2:56]Cl.[I-].[Na+]>CN(C)C=O.O>[C:1]([O:5][C:6](=[O:38])[N:7]([C@H:9]([C:11](=[O:37])[NH:12][C@H:13]1[C@H:19]([CH3:20])[N:18]([C:21](=[O:31])[C:22]2[CH:23]=[CH:24][C:25]([C:28](=[O:30])[CH3:29])=[CH:26][CH:27]=2)[C:17]2[CH:32]=[CH:33][CH:34]=[CH:35][C:16]=2[N:15]([CH2:56][C:51]2[C:52]3[C:47](=[C:46]([Br:45])[CH:55]=[CH:54][CH:53]=3)[CH:48]=[CH:49][C:50]=2[O:58][CH3:59])[C:14]1=[O:36])[CH3:10])[CH3:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1ccc2c(Br)cccc2c1CCl
Reactant: CC(=O)c1ccc(C(=O)N2c3ccccc3NC(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@@H]2C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(Br)cccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@H](C)N(C(=O)c2ccc(C(C)=O)cc2)c2ccccc21
Reaction time: 2 h
Yield: 45.1 %

Procedure:
To a solution of {(S)-1-[(2S,3S)-1-(4-acetyl-benzoyl)-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamoyl]-ethyl}-methyl-carbamic acid tert-butyl ester (60 mg, 0.115 mmol) in N,N-dimethylformamide (1.0 mL) was added cesium carbonate (94 mg, 0.287 mmol), 5-bromo-1-chloromethyl-2-methoxy-naphthalene (39.3 mg, 0.138 mmol) and sodium iodide (17.2 mg, 0.115 mmol) and the reaction was stirred for 2 h. The reaction mixture was diluted with water (10 ml) and extracted with ethyl acetate (2×15 mL). The organic layers were combined, washed with brine (1×10 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatography over silica gel gradient eluted with 10 to 70% v/v ethyl acetate hexanes to give {(S)-1-[(2S,3S)-1-(4-acetyl-benzoyl)-5-(5-bromo-2-methoxy-naphthalen-1-ylmethyl)-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamoyl]-ethyl}-methyl-carbamic acid tert-butyl ester (40 mg, 45%).
Reaction SMILES: Cl[C:2]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[OH-].[Na+].[C:20]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([SH:30])=[CH:26][CH:25]=1)(=[O:22])[CH3:21]>>[C:20]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([S:30][C:2]2[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[N+:15]([O-:17])=[O:16])=[CH:26][CH:25]=1)(=[O:22])[CH3:21]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Reactant: CC(=O)Nc1ccc(S)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Nc1ccc(Sc2c([N+](=O)[O-])cc(C(=O)O)cc2S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The starting material is prepared as follows: The mixture of 19.6 g of 4-chloro-3-nitro-5-sulfamoylbenzoic acid, 280 ml of N aqueous sodium hydroxide and 11.8 g of 4-acetamidothiophenol is stirred for 24 hours at room temperature under nitrogen. It is filtered, the filtrate made strongly acidic with concentrated hydrochloric acid, the precipitate formed filtered off and recrystallized from 50% aqueous ethanol, to yield the 4-(4-acetamidophenylmercapto)-3-nitro-5-sulfamoylbenzoic acid, meltingat 168°.
Reaction SMILES: [N+:1]([C:4]1[C:5]([S:10]([NH2:13])(=[O:12])=[O:11])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O.[Cl-].[NH4+].C(OCC)(=O)C>C(O)C.[Fe]>[NH2:1][C:4]1[C:5]([S:10]([NH2:13])(=[O:12])=[O:11])=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: NS(=O)(=O)c1ncccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1cccnc1S(N)(=O)=O
Temperature: 105 °C
Reaction time: 1.5 h
Yield: 76.3 %

Procedure:
3-Nitro-pyridine-2-sulfonic acid amide (3 g, 14.77 mmol) and iron powder (5 g, <10 micron) were suspended in ethanol (100 mL). Saturated aqueous ammonium chloride solution (60 mL) was added and the mixture stirred at 105° C. for 1.5 h. Upon cooling to 25° C., ethyl acetate (200 mL) was added and the mixture was shaken vigorously. The entire mixture was filtered through a plug of Celite. The resulting filtrate was diluted with ethyl acetate (100 mL) and the layers were separated. The aqueous layer was back-extracted with ethyl acetate (3×200 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo to dryness. The resulting solid was triturated with a 3:1 mixture of hexanes and ethyl acetate (˜10 mL). The solid was collected by vacuum filtration and dried in vacuo for 16 h to afford the desired product, 3-amino-pyridine-2-sulfonic acid amide (1.95 g, 11.27 mmol, 76%), as an off-white powder. 1H NMR (400 MHz, DMSO-d6) δ: 5.98 (2H, bs), 7.19-7.21 (1H, m), 7.32 (2H, bs), 7.79-7.80 (1H, m), 7.90-7.91 (1H, m).
Reaction SMILES: [N:1]1([CH2:5][C:6]2[CH:7]=[C:8]([C:21]3[N:26]=[C:25]([CH3:27])[N:24]=[C:23]([N:28](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)[N:22]=3)[C:9]([NH:12][C:13]3[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)=[N:10][CH:11]=2)[CH2:4][CH2:3][CH2:2]1.FC(F)(F)S(O)(=O)=O>C(O)(C(F)(F)F)=O>[N:1]1([CH2:5][C:6]2[CH:7]=[C:8]([C:21]3[N:26]=[C:25]([CH3:27])[N:24]=[C:23]([NH2:28])[N:22]=3)[C:9]([NH:12][C:13]3[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)=[N:10][CH:11]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCC4)cnc3Nc3ccc(OC)nc3)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2ncc(CN3CCC3)cc2-c2nc(C)nc(N)n2)cn1
Temperature: 80 °C
Reaction time: 1 h
Yield: 12 %

Procedure:
A solution of 4-(5-(azetidin-1-ylmethyl)-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (150 mg, 0.242 mmol) in TFA (2424 μL) was treated with trifluoromethanesulfonic acid (63.5 μL, 0.727 mmol) and stirred at 80° C. for 1 h. The reaction mixture was concentrated and diluted with 100 mL of DCM, added to a separatory funnel, partitioned with sodium bicarbonate (saturated, aqueous), washed 2 times with 75 mL of sodium bicarbonate (saturated, aqueous), separated, diluted with a small amount of methanol to make the solution clear, dried over sodium sulfate, and concentrated to give crude product. The crude product was purified via flash chromatography (silica gel) with 100% DCM to 8% 2 M ammonia in MeOH/DCM to give 4-(5-(azetidin-1-ylmethyl)-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (11 mg, 11.99% yield). 1H NMR (400 MHz, CDCl3) δ 11.75 (s, 1H); 8.90 (d, J=2.35Hz, 1H); 8.37 (d, J=2.74 Hz, 1H); 8.17 (d, J=2.35 Hz, 1H); 8.08 (dd, J=8.90, 2.64 Hz, 1H); 6.77 (d, J=8.80 Hz, 1H); 3.94 (s, 3H); 3.76 (s, 2H); 3.53 (t, J=7.34 Hz, 4H); 2.53 (s, 3H); 2.28 (quin, J=7.38 Hz, 2H). m/z (ESI, +ve ion) 379.1 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:40]=[CH:39][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:29]=[CH:30][C:31]([CH3:38])=[C:32]([CH:37]=4)[C:33]([O:35][CH3:36])=[O:34])[O:25][C:26]=3[CH3:27])=[C:18]([O:41][CH3:42])[CH:17]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1)=O.[CH2:43]([P:52](=[O:59])([O:56][CH2:57][CH3:58])[O:53][CH2:54][CH3:55])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[CH2:57]([O:56][P:52](/[CH:43]=[CH:1]/[C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:40]=[CH:39][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:29]=[CH:30][C:31]([CH3:38])=[C:32]([CH:37]=4)[C:33]([O:35][CH3:36])=[O:34])[O:25][C:26]=3[CH3:27])=[C:18]([O:41][CH3:42])[CH:17]=2)=[N:5][N:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1)([O:53][CH2:54][CH3:55])=[O:59])[CH3:58]
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: COC(=O)c1cc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4C=O)cc3OC)c(C)o2)ccc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccc(C)c(C(=O)OC)c3)oc2C)c(OC)c1)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.8 %

Procedure:
To a mixture of methyl 5-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}-2-methylbenzoate (1.13 g), tetraethyl methylenediphosphonate (0.63 g) and N,N-dimethylformamide (30 mL) was added sodium hydride (60% in oil, 0.10 g) at room temperature. The mixture was stirred at room temperature for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give methyl 5-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]-2-methylbenzoate as colorless crystals (0.57 g, yield 41%) from a fraction eluted with ethyl acetate-hexane (4:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 121-122° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[N:32][NH:33][CH:34]=2)O1>>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:8]2([C:5]3[CH:6]=[CH:7][C:2]([C:30]4[CH:31]=[N:32][NH:33][CH:34]=4)=[CH:3][CH:4]=3)[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:16][CH:17]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CN1CCC(c2ccc(Cl)cc2)(c2ccc(Br)cc2)CC1
Product: CN1CCC(c2ccc(Cl)cc2)(c2ccc(-c3cn[nH]c3)cc2)CC1

Procedure:
4-(4-Bromo-phenyl)-4-(4-chloro-phenyl)-1-methyl-piperidine was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure set out in Example 1 to give the title compound. LC/MS: (PS-B3) Rt 2.90 [M+H]+ 352. 1H NMR (Me-d3-OD) δ 2.41-2.53 (2H, m), 2.82 (3H, d), 2.97-3.12 (4H, m), 3.56-3.59 (2H, m), 7.28 (2H, s), 7.34 (1H, m), 7.42 (1H, d), 7.49 (1H, d), 7.54 (1H, d), 7.61 (1H, d), 7.75 (1H, d), 8.52 (2H, d).
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([OH:13])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:16][O:17][C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([NH2:26])[CH:20]=1.C(=O)(O)[O-].[Na+]>C[Si](OP(=O)=O)(C)C>[CH3:16][O:17][C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([NH:26][C:11](=[O:13])[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:15][CH:14]=2)[CH:20]=1
Reactant: COC(=O)c1ccc(O)c(N)c1
Reactant: CC(C)(C)c1ccc(OCC(=O)O)cc1
Agent: C[Si](C)(C)OP(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)c1ccc(O)c(NC(=O)COc2ccc(C(C)(C)C)cc2)c1
Yield: 102 %

Procedure:
(4-tert-butyl-phenoxy)-acetic acid (200 mg, 0.96 mmol) and 3-amino-4-hydroxy-benzoic acid methyl ester (240.7 mg, 1.44 mmol) were dissolved in PPSE (3 mL), and reacted for 2.5 h at 140° C. After saturated sodium bicarbonate aqueous solution was added, organic phase was washed with 10% HCl and brine. The organic phase was dried (MgSO4 anh), and concentrated. The residue was purified by silica gel column chromatography (n-Hexane:Ethyl acetate:MeOH=15:3:1) to give 3-[2-(4-tert-butyl-phenoxy)-acetyl-amino]-4-hydroxy-benzoic acid methyl ester as an orange solid (350 mg, 89% yield).
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:9]=2[C:10]=1[NH:11][C:12](OCC)=[O:13])=O)C.O.[NH2:23][NH2:24]>C(O)C>[NH2:23][N:24]1[C:4](=[O:3])[C:6]2[O:7][C:8]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:9]=3[C:10]=2[NH:11][C:12]1=[O:13]
Reactant: CCOC(=O)Nc1c(C(=O)OCC)oc2ccc(Cl)cc12
Reactant: NN
Solvent: CCO
Solvent: O
Product: Nn1c(=O)[nH]c2c(oc3ccc(Cl)cc32)c1=O

Procedure:
To a solution of 5-chloro-3-ethoxycarbonylamino-benzofuran-2-carboxylic acid ethyl ester (3.6 g, 11.6 mmol) in ethanol (50 mL) was added hydrazine hydrate (6.2 mL, 127 mmol). After heating at reflux for 4 h, the title compound was collected by filtration (2.9 g) and was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]#[N:12])=[C:6]2[N:5]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:3]=1[CH2:18][CH2:19]Cl.[CH:21]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]3[N:27]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)[CH2:19][CH2:18][C:3]=3[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:5][C:6]=12)#[N:12]
Reactant: NC1CCCCC1
Reactant: CCOC(=O)c1nc2c(C#N)cnn2c(Cl)c1CCCl
Product: CCOC(=O)c1nc2c(C#N)cnn2c2c1CCN2C1CCCCC1
Yield: 96.5 %

Procedure:
The intended compound was obtained in 96.5% yield in the same manner as in Synthesis Example (5) using ethyl 7-chloro-6-(2-chloroethyl)-3-cyanopyrazolo[1,5-a]-pyrimidine-5-carboxylate and cyclohexylamine.
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=O)[CH2:3][CH:4]([CH3:6])[CH3:5].[NH:17]([CH3:29])[C@H:18]([C:26]([NH2:28])=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CN1CCOCC1>O1CCCC1>[NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([N:17]([CH3:29])[C@H:18]([C:26]([NH2:28])=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:9])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CN[C@@H](Cc1ccccc1)C(N)=O
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)[C@@H](Cc1ccccc1)C(N)=O
Yield: 48 %

Procedure:
Condensation of Boc-Leu-OH (liberated from 5.0 g. of the monohydrate by heating at 45° C. under vacuum) and H-MePhe-NH2 and H-MepheNH2 (mixture of isomers) hydrobromide salt (4.92 g.) and N-methylmorpholine (two 2.31 g. portions) in tetrahydrofuran (50 ml.) for 45 min. at 25° C. and then overnight at room temperature, isolation of the crude product (5.94 g.) by ethyl acetate extraction, and purification by HPLC on silica gel gave Boc-Leu-MePhe-NH2 and Boc-Leu-Mephe-NH2 (mixture of isomers) as a colorless foam (3.8 g., 48% yield).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8]2=[O:15])(=[O:3])[CH3:2].Cl.[CH:17]([N:20]([CH:24]([CH3:26])[CH3:25])[CH2:21][CH2:22]Cl)([CH3:19])[CH3:18]>>[C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:22][CH2:21][N:20]([CH:24]([CH3:26])[CH3:25])[CH:17]([CH3:19])[CH3:18])[C:9](=[O:14])[C:8]2=[O:15])(=[O:3])[CH3:2]
Reactant: CC(C)N(CCCl)C(C)C
Reactant: CC(=O)Nc1ccc2c(c1)C(=O)C(=O)N2
Agent: Cl
Product: CC(=O)Nc1ccc2c(c1)C(=O)C(=O)N2CCN(C(C)C)C(C)C
Yield: 77 %

Procedure:
By using 5-acetamidoisatin and 2-diisopropylaminoethyl chloride hydrochloride, a method analogous to that described in Reference Example 7 was carried out to obtain 5-acetamido-1-(2-diisopropylaminoethyl)isatin having a melting point of 187°-190° C. (yield: 77.0%, recrystallizing solvent: ethyl acetate-hexane).