Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:8]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][C:32]=1[C:41](Cl)=[O:42].C(=O)(O)[O-].[Na+]>ClCCl>[CH:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][C:32]=1[C:41]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:8]=2)=[CH:22][CH:23]=1)=[O:42]
Reactant: CCOC(=O)Cn1nc(Cc2ccc(N)cc2)c2ccccc21
Reactant: O=C(Cl)c1ccc2ccccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cn1nc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)c2ccccc21
Yield: 89.9 %

Procedure:
630 mg (2.04 mmol) ethyl 2-[3-(4-aminobenzyl)-1H-indazol-1-yl]acetate was dissolved in 20 mL dichloromethane. 0.85 mL (6.11 mmol) triethylamine was added, and in an ice bath a dichloromethane solution dissolving 428 mg (2.25 mmol) 2-naphthoyl chloride was added slowly, and reacted in an ice bath for 3 h. An aqueous solution of sodium bicarbonate was added to quench, extracted with ethyl acetate, rotate evaporated to dryness, chromatographed on a column to obtain a white solid 850 mg, at a yield of 89.7%.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:20]([C@H:23]2[C@H:28]([O:29]CC3C=CC=CC=3)[C@@H:27]([O:37]CC3C=CC=CC=3)[C@H:26]([O:45]CC3C=CC=CC=3)[C@@H:25]([CH2:53][O:54]CC3C=CC=CC=3)[O:24]2)=[CH:19][C:3]=1[CH2:4][C:5]1[N:6]=[N:7][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:10]=1.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C[O-].[Na+].[H][H]>C(OC(=O)C)(=O)C.CO>[Cl:1][C:2]1[CH:22]=[CH:21][C:20]([CH:23]2[CH:28]([OH:29])[CH:27]([OH:37])[CH:26]([OH:45])[CH:25]([CH2:53][OH:54])[O:24]2)=[CH:19][C:3]=1[CH2:4][C:5]1[N:6]=[N:7][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:10]=1
Reactant: Clc1ccc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(C#Cc2ccccc2)nn1
Reactant: [H][H]
Agent: C[O-]
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)OC(C)=O
Product: OCC1OC(c2ccc(Cl)c(Cc3ccc(C#Cc4ccccc4)nn3)c2)C(O)C(O)C1O
Temperature: 25 °C
Yield: 20 %

Procedure:
To a solution of 3-(2-chloro-5-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-tetrahydro-2H-pyran-2-yl)benzyl)-6-(phenylethynyl)pyridazine (0.5 mmol) from step 1 at −30° C. in acetic anhydride (10 mL) was slowly added a solution of trimethylsilyl trifluoromethanesulfonate (0.73 mL, 4.0 mmol) in acetic anhydride (5 mL). The resulting mixture was stirred with gradual warming to ambient temperature over 15 h, cooled to 0° C., and quenched with saturated sodium bicarbonate. After dilution with ethyl acetate, the organic layer was washed with sodium bicarbonate and brine prior to drying over magnesium sulfate. Filtration and removal of volatiles under reduced pressure yielded peracetylated compound as a brown amorphous solid. Deacetylation was achieved by addition of sodium methoxide (25 wt % in methanol, 1 mL) to a solution of this residue in methanol (10 mL). The reaction mixture was stirred at ambient temperature for 2 h. Amberlite® IR120 hydrogen form was then added to neutralize the reaction mixture. The resin was filtered off and the filtrate was concentrated in vacuo. Purification by reverse phase preparative HPLC (Gilson®, SunFire™ Prep, 5 to 50% acetonitrile in water gradient) provided the title compound (41 mg, 0.10 mmol, 25%) as a white solid.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[CH2:22]=[O:23].[OH-].C([N+](CC)(CC)CC)C1C=CC=CC=1>O>[C:8]([C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:22][OH:23])#[N:9]
Reactant: N#CC(c1ccccc1)c1ccccn1
Reactant: C=O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: N#CC(CO)(c1ccccc1)c1ccccn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To an ice cold stirred solution of phenyl-2-pyridyl acetonitrile* (50 g., 0.26 mole) in 350 ml. of pyridine containing a suspension of paraformaldehyde (31 g., 1.0 mole) is added 1 ml. of benzyl triethylammonium hydroxide. The mixture is stirred under nitrogen at room temperature for 24 hours. The reaction mixture is poured into water and extracted with ether. The combined ether extracts are washed with water, saturated sodium chloride solution and dried over magnesium sulfate. The solvent is evaporated to give a thick oil 58 g, which is identified by nmr.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=O)(C)(C)C.Cl>O1CCOCC1>[O:21]([C:18]1[CH:19]=[CH:20][C:15]([NH:14][CH2:13][C@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[CH:16][CH:17]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CNc1ccc(Oc2ccccc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc(Oc2ccc(NC[C@H]3CCCN3)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 119.8 %

Procedure:
To the product from step 1 (155 mg, 0.42 mmol) was added 4M HCl in dioxane (6 mL) and the resulting mixture was stirred at rt for 3 h. The solvent was removed in vacuo to obtain the product as a solid (135 mg, 94%). The solid was dried under vacuum oven at 50° C. for 15 h: MS; m/z 269 (M+H): LCMS (UV) 99.6%: Elemental analysis: Calc C, 59.83; H, 6.50; N, 8.21. Found C, 59.69; H, 6.55; N, 7.97. 1H NMR (400 MHz, DMSO-d6) δ 1.64-1.70 (m, 1H), 1.88-1.98 (m, 2H), 2.07-2.12 (m, 1H), 3.16-3.20 (m, 2H), 3.30-3.37 (m, 2H), 3.57 (s, 1H), 3.66-374 (m, 1H), 6.76 (d, 2H, J=8.8 Hz), 6.88 (t, 4H, J=18 Hz), 7.03 (t, 1H, J=16 Hz), 7.30-7.34 (m, 2H), 9.0 (s, 1H), 9.4 (s, 1H).
Reaction SMILES: [CH2:1]([N:5]([CH2:15][CH2:16][CH2:17][CH3:18])[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[C:8]([OH:14])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN1CCCC1=O.C(OCC)(=O)C>[CH2:19]([O:14][C:8]1[CH:7]=[C:6]([N:5]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:1][CH2:2][CH2:3][CH3:4])[CH:13]=[CH:12][C:9]=1[CH:10]=[O:11])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: CCCCN(CCCC)c1ccc(C=O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCN(CCCC)c1ccc(C=O)c(OCc2ccccc2)c1
Temperature: 50 °C
Yield: 91.2 %

Procedure:
In 20 ml of 1-methyl-2-pyrrolidone were dissolved 1.86 g (7.46 mmol) of 4-dibutylamino-2-hydroxybenzaldehyde and 1.66 g (9.71 mmol) of benzyl bromide. To this mixture was added 2.06 g (14.9 mmol) of anhydrous potassium carbonate and the mixture was stirred with heating at 50° C. for 2 hours. After the reaction mixture was added to water, extraction with ethyl acetate, washing with a saturated saline solution, drying over anhydrous sodium sulfate, and concentration were performed. The residue was purified by silica gel column chromatography to give 2.31 g of a pale yellow crystal (yield: 91.3%).
Reaction SMILES: [BH4-].[Na+].CO.[CH3:5][O:6][C:7](=[O:30])[CH2:8][CH2:9][CH2:10][C:11]#[C:12][CH2:13][N:14]1[C@@H:19](/[CH:20]=[CH:21]/[C:22](=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:18][CH2:17][CH2:16][C:15]1=[O:29]>C(Cl)Cl>[CH3:5][O:6][C:7](=[O:30])[CH2:8][CH2:9][CH2:10][C:11]#[C:12][CH2:13][N:14]1[C:15](=[O:29])[CH2:16][CH2:17][CH2:18][C@@H:19]1/[CH:20]=[CH:21]/[CH:22]([OH:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[OH:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[C:12][CH2:13][N:14]1[C@@H:19](/[CH:20]=[CH:21]/[CH:22]([OH:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:18][CH2:17][CH2:16][C:15]1=[O:29]
Reactant: CCCCCC(=O)/C=C/[C@H]1CCCC(=O)N1CC#CCCCC(=O)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCCCCC(O)/C=C/[C@H]1CCCC(=O)N1CC#CCCCC(=O)OC
Product: CCCCCC(O)/C=C/[C@H]1CCCC(=O)N1CC#CCCCCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 8 %
Yield: 38 %

Procedure:
Sodium borohydride (35 mg, 0.93 mmol), followed by MeOH (0.25 mL), was added to a solution of 7-[(R)-2-oxo-6-((E)-3-oxo-oct-1-enyl)-piperidin-1-yl]-hept-5-ynoic acid methyl ester (68 mg, 0.19 mmol) in CH2Cl2 (1.0 mL) at 0° C. The mixture was allowed to warm to rt. After 1 h at rt, the reaction was quenched with aqueous HCl (1.0 M, 3 mL) and extracted with EtOAc (3×10 mL). The combined organic phase was washed with brine (20 mL) then dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→3% MeOH/CH2Cl2, gradient) afforded 26 mg (38%) of 7-[(R)-2-((E)-3-hydroxy-oct-1-enyl)-6-oxo-piperidin-1-yl]-hept-5-ynoic acid methyl ester and 5.3 mg (8%) of (R)-1-(7-hydroxy-hept-2-ynyl)-6-((E)-3-hydroxy-oct-1-enyl)-piperidin-2-one.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5]2[CH:6]=[N:7][NH:8][C:9]=2[CH:10]=1.[H-].[Na+].[CH3:14]I>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5]2[CH:6]=[N:7][N:8]([CH3:14])[C:9]=2[CH:10]=1
Reactant: CI
Reactant: Nc1cc(Br)cc2[nH]ncc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1ncc2c(N)cc(Br)cc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
6-Bromo-1H-indazol-4-amine (available from Sinova, 300 mg, 1.42 mmol) was dissolved in THF (7.5 ml) and the mixture cooled to 0° C. Sodium hydride (60% in mineral oil) (62 mg) was then slowly added. The mixture was stirred for 15 min, then methyl iodide (221 mg) was added and stirring continued at 0° C. for 3 h. The reaction mixture was quenched by careful addition of methanol (2 ml), then water (10 ml), then extracted into ethyl acetate and the organic layer was concentrated in vacuo. The residue was purified by column chromatography on silica eluting with a gradient of 0-50% ethyl acetate in cyclohexane. Fractions containing desired product were combined and concentrated in vacuo to afford the title compound, 48 mg.
Reaction SMILES: [Na].[CH3:2][O:3][CH:4]([O:12]C)[C:5](=[CH:10]O)[C:6](OC)=O.C(O)C.O.[NH2:18][NH2:19]>O>[CH3:2][O:3][C:4]([C:5]1[CH:10]=[N:18][NH:19][CH:6]=1)=[O:12]
Reactant: NN
Reactant: COC(=O)C(=CO)C(OC)OC
Agent: [Na]
Solvent: CCO
Solvent: O
Product: COC(=O)c1cn[nH]c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 22.3 %

Procedure:
44.45 g of methyl 3,3-dimethoxypropionate and 45 ml of methyl formate was dissolved to 180 ml of dimethoxyethane. Under nitrogen atmosphere, 12.8 g of 60% sodium hydride was added to the solution keeping the temperature of the solution at 40 to 50° C. during addition. Then the mixture was stirred at room temperature for 18 hours. 180 ml of diethylether was added to the reaction mixture, as a result, a solid was formed. The solid was collected by filteration, followed by washing with 60 ml of diethylether. The obtained solid was dried under reduced pressure for overnight to obtain 49.41 g of methyl 2-(dimethoxymethyl)-3-hydroxy-acrylate sodium salt. 9.91 g of methyl 2-(dimethoxymethyl)-3-hydroxy-acrylate sodium salt was suspended to 100 ml of ethanol. 2.50 g of hydrazine hydrate was added to the suspension, followed by stirring at room temperature for 3 hours and at 80° C. for 1 hour. 100 ml of water was added to the reaction mixture which was cooled to room temperature. The mixture was concentrated under reduced pressure to about 100 ml. The concentrated solution was extracted by ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved to ethyl acetate, activated carbon was added to it, and stirred for overnight. The suspension was filtered. The filtrate was concentrated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to obtain 1.40 g of 4-methoxycarbonyl-1H-pyrazole.
Reaction SMILES: [C:1]([O-])([O-])=O.[K+].[K+].Br[C:8]([Br:11])([CH3:10])C.[K].[CH3:13][O:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[OH:24]>CN(C=O)C>[Br:11][CH2:8][CH2:10][CH2:1][O:24][C:16]1[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:15]=1[O:14][CH3:13]
Reactant: COc1cc([N+](=O)[O-])ccc1O
Reactant: CC(C)(Br)Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])ccc1OCCCBr

Procedure:
A suspension of K2CO3 (2.0 g, 14.5 mmol), dibromopropane (8.8 g, 43.4 mmol) and the potassium salt of 2-methoxy-4-nitrophenol (3.0 g, 14.5 mmol) in DMF (50 mL) was heated at 80° C. for 24 hr. After removal of any precipitate by filtration, the filtrate was partitioned between EtOAc/H2O (100/20 mL). The organic layer was washed with brine and dried over MgSO4. After removal of the solvent under vacuum, the residue was chromatographed on silica gel using 5%-20% gradient EtOAc/hexanes to elute the title compound as a yellow brownish solid (1.5 g, 36%) MS (ESI) 292 (M+H)+.
Reaction SMILES: C[O-].[Na+].Cl.[CH2:5]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([S:16][C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][C@H:12]1[CH2:36][C:37](=[NH:39])[NH2:38])=[O:10])[CH:6]=[CH2:7].CN(C)[CH:42]=[CH:43][CH:44]=O.C(OCC)(=O)C>CO.O>[CH2:5]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([S:16][C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][C@H:12]1[CH2:36][C:37]1[N:38]=[CH:44][CH:43]=[CH:42][N:39]=1)=[O:10])[CH:6]=[CH2:7]
Reactant: CN(C)C=CC=O
Reactant: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1Cc1ncccn1
Yield: 7.5 %

Procedure:
To a solution of 28% sodium methoxide in methanol solution (104 mg) in methanol (10 ml) were added (2R,4S)-1-allyloxycarbonyl-2-amidinomethyl-4-(triphenylmethylthio)pyrrolidine hydrochloride (1.0 g) and 3-dimethylaminoacrylaldehyde (190 mg). After stirring under reflux for 8 hours, the solution was poured into a mixture of ethyl acetate and water. The separated organic layer was washed with aqueous sodium chloride solution, dried over magnesium sulfate and evaporated. The residue was subjected to column chromatography on silica gel to give (2R,4S)-1-allyloxycarbonyl-2-(pyrimidin-2-ylmethyl)-4-(triphenylmethylthio) pyrrolidine (75 mg).
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[SH:15][CH2:16][CH:17]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:18]([N:20]1[CH2:27][CH2:26][CH2:25][C@H:21]1[C:22]([OH:24])=[O:23])=[O:19]>FC(F)(F)C(O)=O>[C:1]1([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:15][CH2:16][CH:17]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:18]([N:20]2[CH2:27][CH2:26][CH2:25][C@H:21]2[C:22]([OH:24])=[O:23])=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC(c1ccccc1)c1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)C(CS)Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@@H]1CCCN1C(=O)C(CSC(c1ccccc1)c1ccccc1)Cc1ccccc1
Reaction time: 0.5 h

Procedure:
Diphenylmethanol (0.92 g) and 1-(3-mercapto-2-benzylpropanoyl)-L-proline (1.5 g) are dissolved in trifluoroacetic acid (10 ml) and the solution is kept at room temperature for 30 minutes. The excess trifluoroacetic acid is removed in vacuo to yield 1-[3-[(diphenylmethyl)thio]-2-benzylpropanoyl]-L-proline.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.[CH2:13](Br)/[CH:14]=[C:15](/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])\[CH3:16].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH2:13]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=1)/[CH:14]=[C:15](/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])\[CH3:16]
Reactant: CC(C)=CCC/C(C)=C/CBr
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Reaction time: 1 h
Yield: 813.7 %

Procedure:
Ethyl 4-hydroxybenzoate (16.6 g), geranyl bromide (23.9 g), and potassium carbonate (27.6 g) were refluxed in acetone (200 ml) with stirring for 1 hour . The reaction mixture, with water added thereto, was extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride and then concentrated under a vacuum. To the residue dissolved in ethanol (150 ml) were added sodium hydroxide (3.90 g) and water(50 ml) and the mixture was refluxed with stirring for 1 hour. After being concentrated under a vacuum, the reaction mixture was acidified with hydrochloric acid and then extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride and then was concentrated under a vacuum. The resulting solid was recrystallized from n-hexane/ethyl acetate mixed solution, thereby yielding 223 g of the aimed compound.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].[C:17](Cl)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:7][N:6]1[C:2]([NH:1][C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:3]([NH:8][C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:4]=[N:5]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CC(=O)Nc1cnn(C)c1N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CC(=O)Nc1cnn(C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
The crude residue containing ethyl 3-[(5-amino-1-methyl-1H-pyrazol-4-yl)amino]-3-oxopropanoate was dissolved in N,N-dimethylformamide (20 ml), and trityl chloride (5.52 g) and triethylamine (4.14 ml) were added with stirring. The mixture was stirred overnight and quenched with water (10 ml). The whole mixture was extracted with ethyl acetate, and the extract was washed with water and brine, dried over magnesium sulfate and concentrated under reduced pressure to give a residual oil, which was chromatographed on silica gel eluting with dichloromethane-ethyl acetate (2:3) to give ethyl 3-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}-3-oxopropanoate (1.23 g).
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[C:14](I)=[CH:13][N:12]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[N:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:25](=[O:28])([O-])[O-].[K+].[K+]>C(O)C.C1(C)C=CC=CC=1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:1]1([NH:7][C:8]([C:10]2[C:14]([C:1]3[CH:6]=[CH:5][CH:4]=[C:3]([CH2:25][OH:28])[CH:2]=3)=[CH:13][N:12]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[N:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(Cn2cc(I)c(C(=O)Nc3ccccc3)n2)cc1
Reactant: O=C([O-])[O-]
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(Cn2cc(-c3cccc(CO)c3)c(C(=O)Nc3ccccc3)n2)cc1
Temperature: 120 °C
Yield: 263.8 %

Procedure:
A mixture of 4-iodo-1-(4-methoxy-benzyl)-1H-pyrazole-3-carboxylic acid phenylamide (50 mg; 0.11 mmol), bis(tri-tert-butylphosphine)palladium (12 mg), potassium carbonate (100 mg; 0.66 mmol) and 3-(hydroxmethyl)benzene boronic acid (21 mg; 0.14 mmol) in ethanol/toluene/water (4 ml:1 ml:1 ml) was heated at 120° C. (50 W) for 15 minutes in a CEM Discover microwave synthesiser. The reaction was evaporated and the residue partitioned between ethyl acetate and brine. The ethyl acetate layer was separated, dried (MgSO4), filtered and evaporated and the crude material purified by flash column chromatography eluting with 1:2 then 2:1 ethyl acetate/hexane. Product containing fractions were combined and evaporated to give 60 mg of 4-(3-hydroxymethyl-phenyl)-1-(4-methoxy-benzyl)-1H-pyrazole-3-carboxylic acid phenylamide.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]2[S:14][C:15]3[CH2:22][CH2:21][O:20][C:19]4[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=4[C:16]=3[N:17]=2)[CH2:8][CH2:7]1)[CH2:2][CH3:3].N1([CH:36]=[O:37])C2C=CC=CC=2N=N1.[OH-].[Na+]>C1COCC1>[N:17]1[C:16]2[C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:15]=2[S:14][C:13]=1[NH:12][CH:9]1[CH2:10][CH2:11][CH:6]([CH2:5][N:4]([CH2:1][CH2:2][CH3:3])[CH:36]=[O:37])[CH2:7][CH2:8]1
Reactant: O=Cn1nnc2ccccc21
Reactant: CCCNCC1CCC(Nc2nc3c(s2)CCOc2ccccc2-3)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCN(C=O)CC1CCC(Nc2nc3c(s2)CCOc2ccccc2-3)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 108.6 %

Procedure:
To a solution of N2-{4-[(propylamino)methyl]cyclohexyl)-4,5-dihydrobenzo[2,3]oxepino[4,5-d][1,3]thiazol-2-amine (0.254 g, 0.68 mmol) in anhydrous THF (4 ml) was added 1H-benzotriazole-1-carboxaldehyde (0.110 g, 0.75 mmol). The solution was stirred at room temperature for 1 hour and then poured into 2N NaOH (50 ml) and extracted with EtOAc (60 ml). The extract was separated and evaporated to yield 295 mg of a viscous oil. Chromatography on silica-gel eluting with 1:1 EtOAc/hexane yielded 56% (152 mg) of the product as a white solid: 1H-NMR (CDCl3) δ 0.90 (3H, m), 1.14 (4H, m), 1.58 (2H, m), 1.78 (2H, m), 2.23 (2H, m), 3.20 (8H, m), 4.32 (2H, t, J=4.9 Hz), 5.03 (1H, m), 6.99 (1H, m), 7.12 (2H, m), 8.01 (0.5H, s), 8.11 (0.5H, s), 8.22 (1H, d); m.p. 53-55° C.; 400 (ESMS, MH+).
Reaction SMILES: C=O.[C:3]([NH2:7])([CH3:6])([CH3:5])[CH3:4].[C:8]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=2)[CH:13]=1)([CH3:11])([CH3:10])[CH3:9].O1C2C=CC=CC=2CN[CH2:27]1.[ClH:36].Cl.C(O)C>C(O)(C)C.C(O)C.C(OCC)C>[ClH:36].[ClH:36].[C:8]([C:12]1[CH:13]=[C:14]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=2)[C:15]([OH:18])=[C:16]([CH2:27][NH:7][C:3]([CH3:6])([CH3:5])[CH3:4])[CH:17]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: c1ccc2c(c1)CNCO2
Reactant: Cc1ccc(-c2cc(C(C)(C)C)ccc2O)nc1
Reactant: CC(C)(C)N
Agent: C=O
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Solvent: CC(C)O
Product: Cc1ccc(-c2cc(C(C)(C)C)cc(CNC(C)(C)C)c2O)nc1
Temperature: 25 °C
Reaction time: 216 h
Yield: 83 %

Procedure:
A mixture of paraformaldehyde (661 mg, 22.0 mmol) and tert-butylamine (2.32 mL, 22.0 mmol) in isopropanol (10 mL) was gently refluxed under nitrogen for 1 hour. A solution of 4-(tert-butyl)-2-(5-methylpyridin-2-yl)phenol (1.062 g, 4.4 mmol) in isopropanol (5 mL) was added and the reaction mixture refluxed for 6 days. The cooled reaction mixture was then concentrated under reduced pressure and the residue partitioned between ethyl acetate (80 mL) and 1.0 M aqueous sodium hydroxide solution (80 mL). The organic phase was separated, washed with water (80 mL) and saturated brine (80 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give a yellow syrup. The crude 3,4-dihydro-2H-benzo[e][1,3]oxazine was dissolved in absolute ethanol (90 mL), 1.0 M aqueous hydrochloric acid solution (30 mL) added and the reaction mixture stirred at room temperature for 9 days. The reaction mixture was concentrated under reduced pressure to remove ethanol, the resulting aqueous solution diluted to 50 mL with 1.0 M aqueous hydrochloric acid solution and washed with ethyl acetate (50 mL). The aqueous phase was basified to pH 7-8 by the addition of solid sodium carbonate and the resulting milky suspension extracted with ethyl acetate (80 mL). The organic phase was separated, washed with half saturated brine (80 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give a yellow syrup. The product was dissolved in absolute ethanol (50 mL), hydrogen chloride-ethanol solution (1.25 M, 18.44 mL, 23.05 mmol) added, the mixture stood for 20 minutes then concentrated under reduced pressure to give a cream solid. Diethyl ether (50 mL) and absolute ethanol (15 mL) were added and the resulting suspension stirred vigorously overnight then filtered to give 4-(tert-butyl)-2-((tert-butylamino)methyl)-6-(5-methylpyridin-2-yl)phenol dihydrochloride (1.466 g, 83% yield) as a hygroscopic white solid.