Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:6]2[CH:7]=[C:8]([CH:13]=[O:14])[C:9](F)=[C:10]([F:11])[C:5]=2[O:4][N:3]=1.[CH3:15][C@H:16]1[O:21][C@H:20]([CH3:22])[CH2:19][NH:18][CH2:17]1.CCN(C(C)C)C(C)C>C(#N)C>[Cl:1][C:2]1[C:6]2[CH:7]=[C:8]([CH:13]=[O:14])[C:9]([N:18]3[CH2:17][C@@H:16]([CH3:15])[O:21][C@H:20]([CH3:22])[CH2:19]3)=[C:10]([F:11])[C:5]=2[O:4][N:3]=1
Reactant: O=Cc1cc2c(Cl)noc2c(F)c1F
Reactant: C[C@@H]1CNC[C@@H](C)O1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(c2c(C=O)cc3c(Cl)noc3c2F)C[C@@H](C)O1
Temperature: 25 °C

Procedure:
A solution of 3-chloro-6,7-difluorobenzo[d]isoxazole-5-carbaldehyde (Intermediate 532, 3.32 g, 10.6 mmol), (2R,6R)-2,6-dimethylmorpholine (Purchased from BASF®, 2.64 g, 22.9 mmol) and DIEA (4 ml, 22.9 mmol) in acetonitrile (20 ml) was heated at reflux for 3 hours. The mixture was cooled to room temperature before being partitioned between EtOAc and 1N HCl. The EtOAc was separated and washed with brine. The combined aqueous layers were extracted with EtOAc, which was washed with brine. The combined EtOAc was dried (MgSO4) and concentrated to give an oil that was chromatographed on silica gel (50% hexanes in CH2Cl2 followed by gradient elution to 100% CH2Cl2 followed by gradient elution to 5% EtOAc in CH2Cl2) to give 2 materials in order of elution: the first material (265 mg) is consistent with starting material and the second (3.33 g) with desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[O:13][C:12]([CH3:14])=[C:11]([CH:15]([NH:20][C:21]3[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=3)[CH2:16][CH:17]([CH3:19])[CH3:18])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:30][NH:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].Cl.C(N=C=NCCCN(C)C)C.O.OC1C2N=NNC=2C=CC=1>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[O:13][C:12]([CH3:14])=[C:11]([CH:15]([NH:20][C:21]3[CH:29]=[CH:28][C:24]([C:25]([N:31]([CH3:30])[CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:26])=[CH:23][CH:22]=3)[CH2:16][CH:17]([CH3:18])[CH3:19])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CCNC
Reactant: COc1cccc(-c2cc(C(CC(C)C)Nc3ccc(C(=O)O)cc3)c(C)o2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)CCN(C)C(=O)c1ccc(NC(CC(C)C)c2cc(-c3cccc(OC)c3)oc2C)cc1

Procedure:
A solution of 4-({1-[5-(3-methoxyphenyl)-2-methylfuran-3-yl]-3-methylbutyl}amino)benzoic acid (197 mg), ethyl 3-(methylamino)propanoate (79 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (115 mg), hydroxybenzotriazole monohydrate (92 mg) and triethylamine (84 μL) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 4 hr. Ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and water, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give ethyl 3-[{[4-({1-[5-(3-methoxyphenyl)-2-methylfuran-3-yl]-3-methylbutyl}amino)phenyl]carbonyl}(methyl)amino]propanoate. The obtained ethyl 3-[{[4-({1-[5-(3-methoxyphenyl)-2-methylfuran-3-yl]-3-methylbutyl}amino)phenyl]carbonyl}(methyl)amino]propanoate was dissolved in ethanol (2 mL) and tetrahydrofuran (2 mL), 1N lithium hydroxide (1.0 mL) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (216 mg, 91%).
Reaction SMILES: [CH3:1][CH2:2][CH2:3]Br.[CH3:5][O:6][C:7](=[O:23])[C@H:8]([CH2:17][C:18]1[N:22]=[CH:21][NH:20][CH:19]=1)[NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:13]([O:12][C:10]([NH:9][C@@H:8]([CH2:17][C:18]1[N:22]=[CH:21][N:20]([CH2:1][CH2:2][CH3:3])[CH:19]=1)[C:7]([O:6][CH3:5])=[O:23])=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OC(C)(C)C
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCn1cnc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)c1

Procedure:
n-Propyl bromide (0.17 ml, 1.85 mmol) was added to a mixture of Nα-Boc-L-histidine methyl ester (500 mg, 1.85 mmol) and potassium carbonate (200 mg, 1.85 mmol) in acetonitrile (20 ml), and the mixture was heated under reflux for 18 hours. TLC analysis showed starting material remaining, so additional n-propyl bromide (0.17 ml, 1.85 mmol) and potassium carbonate (200 mg, 1.85 mmol) were added, and the mixture was heated for a further 8 hours. The cooled, mixture was concentrated under reduced pressure. The residue was dissolved in water and the solution was extracted with ethyl acetate (3×20 ml). The combined organic extracts were washed with brine (3×20 ml), dried (Na2SO4) and evaporated under reduced pressure. The residual orange oil was purified by column chromatography on silica gel using an elution gradient of hexane:ethyl acetate (100:0 to 0:100) to afford the title compound as a colourless oil, 200 mg. 1H-NMR (CDCl3, 300 MHz) δ: 0.90 (t, 3H), 1.42 (s, 9H), 1.78 (m, 2H), 3.03 (m, 2H), 3.68 (s, 3H), 3.80 (t, 2H), 4.56 (m, 1H), 5.92 (m, 1H), 6.65 (s, 1H), 7.37 (s, 1H). LRMS: m/z (TSP+) 312.2 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:17])C=1>C(Cl)Cl.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([CH3:8])=[N+:4]([O-:17])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ncccc1Br
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1c(Br)ccc[n+]1[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 62 %

Procedure:
A mixture of 3-bromo-2-methylpyridine (0.14 mL, 1.2 mmol) and m-chloroperbenzoic acid (420 mg, 1.8 mmol) in methylene chloride (4 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with saturated aqueous sodium bicarbonate solution (20 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 4 g, ISCO, 0-10% methanol in dichloromethane) to afford the title compound as a white solid (140 mg, 61%), which was used in the next step without further purification.
Reaction SMILES: [NH:1]([C:8]1[N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14](Cl)[N:13]=[C:12]([CH3:20])[CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][Mg+].[Br-]>C1COCC1.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[NH:1]([C:8]1[N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([CH3:27])[N:13]=[C:12]([CH3:20])[CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc2c(c(Cl)n1)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Reactant: C[Mg+]
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: Cc1cc2c(c(C)n1)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Reaction time: 24 h
Yield: 41.3 %

Procedure:
To a solution of 2-anilino-5-chloro-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one (80 mg, 0.22 mmol) in THF (3mL) was added Ni(dppp)Cl2 (24 mg, 0.044 mmol) at room temperature. After stirring for a few minutes MeMgBr (3M , 0.59 mL, 1.76 mmol) was added and the mixture was allowed to stir for 24 h. The mixture was quenched with 1N HCl and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. Purification by reverse-phase preparative HPLC (10% CH3CN in water with 0.1% TFA to 95% CH3CN in water, 10 mL/min, 10 min) provided 2-anilino-5,7-dimethyl-1-phenyl-1,6-naphthyridin-4(1H)-one (31 mg, 40%): LCMS RT: 1.51 min, MH+: 342.4.
Reaction SMILES: [CH3:1][C@:2]12[CH2:18][CH2:17][C@H:16]([O:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH2:15][C:14]1=[CH:13][CH2:12][C@@H:11]1[C@@H:3]2[CH2:4][CH2:5][C@@:6]2([CH3:32])[C@H:10]1[CH2:9][CH2:8][C@@H:7]2[C@@H:24]([CH2:26][CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH3:25].CCN(C(C)C)C(C)C.CCOC(C)=O.[O:48]1[C:52](=[O:53])[CH2:51][CH2:50][C:49]1=[O:54]>C1COCC1>[CH3:25][C@@H:24]([C@@H:7]1[C@:6]2([CH3:32])[C@H:10]([C@H:11]3[C@H:3]([CH2:4][CH2:5]2)[C@:2]2([CH3:1])[C:14]([CH2:15][C@@H:16]([O:19][CH2:20][CH2:21][CH2:22][NH:23][C:52](=[O:53])[CH2:51][CH2:50][C:49]([OH:54])=[O:48])[CH2:17][CH2:18]2)=[CH:13][CH2:12]3)[CH2:9][CH2:8]1)[CH2:26][CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCN)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=C1CCC(=O)O1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCNC(=O)CCC(=O)O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Yield: 114.9 %

Procedure:
In a 2 μL round-bottomed flask, 3-((3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-((R)-6-methylheptan-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yloxy)propan-1-amine (21.15 g, 47.7 mmol, Eq: 1.00) and Huenig's base (12.3 g, 16.6 ml, 95.3 mmol, Eq: 2.00) were combined with AcOEt (845 ml) to give a colorless solution. Dihydrofuran-2,5-dione (4.77 g, 47.7 mmol, Eq: 1.00) in THF (42 ml) was added and the reaction mixture was stirred at ambient temperature over night=>white suspension. All volatiles were removed i. v., the residue dissolved in CH2Cl2, the organic layer washed with NH4Cl and brine, dried over Na2SO4, and evaporated to dryness. The crude product was dissolved in CH3CN/H2O and lyophilized to yield 29.8 g of the title compound as fluffy powder. MS (ISP): (M−H) 542.5.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH:5]1[CH2:10][CH2:9][NH:8][CH:7]=[C:6]1[C:11]([O:13][CH3:14])=[O:12].O1CCCC1.C(N(CC)CC)C>C(OCC)(=O)C>[C:1]([N:5]1[CH2:10][CH2:9][NH:8][CH:7]=[C:6]1[C:11]([O:13][CH3:14])=[O:12])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: COC(=O)C1=CNCCN1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C1=CNCCN1C(C)=O
Temperature: 25 °C
Yield: 68.8 %

Procedure:
15.10 g (192.5 mmol) of acetyl chloride was added dropwise over 25 minutes to 25.00 g (175.9 mmol) of methyl 1,4,5,6-tetrahydropyrazine-2-carboxylate, 250 ml of tetrahydrofuran and 21.30 g (210.5 mmol) of triethylamine at 0° C. The mixture was then heated to room temperature and, after 1 hour, 200 ml of ethyl acetate were added. The aqueous phase was washed a further 3 to 4 times with a total of 500 ml of ethyl acetate and the combined organic extracts were dried over magnesium sulfate. After the solvent had been stripped off, 22.30 g (69%) of the title compound were obtained as a yellow oil. Recrystallization from ethyl acetate gave methyl 1-acetyl-1,4,5,6-tetrahydropyrazine-2-carboxylate in the form of a light yellow, crystalline solid. The melting point of the title compound was: 136° to 139° C. Other data concerning the title compound was:
Reaction SMILES: [CH2:1]([NH:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[C:12]#[N:13])[CH2:2][CH2:3][CH2:4][CH3:5].[C:14]([NH:17][NH2:18])(=O)[CH3:15].C(=O)([O-])[O-].[K+].[K+]>C(O)CCC.O>[CH3:15][C:14]1[N:13]=[C:12]([C:11]2[NH:10][CH:9]=[N:8][C:7]=2[NH:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[NH:18][N:17]=1
Reactant: CC(=O)NN
Reactant: CCCCCNc1nc[nH]c1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: O
Product: CCCCCNc1nc[nH]c1-c1nc(C)n[nH]1
Temperature: 165 °C
Reaction time: 14 h
Yield: 9.6 %

Procedure:
To the mixture of 4-(pentylamino)-1H-imidazole-5-carbonitrile (0.40 g, 2 mmol), acetic acid, hydrazide (0.33 g, 4.5 mmol) in 1-butanol (10 mL) was added potassium carbonate (0.10 g, 0.72 mmol). The mixture was sealed and stirred at 165° C. for 14 hours. The reaction mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative LCMS (method A) to yield the desired product (45 mg, 10% yield). LCMS calculated for C11H19N6(M+H): 235.2. found: 235.1.
Reaction SMILES: [CH2:1]=O.[OH:3][CH2:4][CH:5]1[CH2:9][NH:8][CH2:7][CH:6]1[NH:10][CH3:11]>C(O)CCC>[CH3:11][N:10]1[CH2:1][O:3][CH2:4][CH:5]2[CH:6]1[CH2:7][NH:8][CH2:9]2
Reactant: C=O
Reactant: CNC1CNCC1CO
Solvent: CCCCO
Product: CN1COCC2CNCC21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
8.1.g (0.1 mol) of 37% strength formaldehyde solution in 20 ml of n-butanol are added dropwise to 13 g (0.101 mol) of 4-hydroxymethyl-3-methylaminopyrrolidine in 100 ml of n-butanol at room temperature. The mixture is stirred at room temperature overnight and concentrated and the residue is distilled.
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[N:3]1.[Br:16]Br.C(OCC)(=O)C.CCCCCC>C(O)C>[Br:16][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=2)[NH:2][N:3]=1
Reactant: CCOC(=O)c1ccc2[nH]ncc2c1
Reactant: BrBr
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCCCCC
Product: CCOC(=O)c1ccc2[nH]nc(Br)c2c1
Reaction time: 17 h
Yield: 97.9 %

Procedure:
ethyl 1H-indazole-5-carboxylate hydrochloride (146 g, 0.645 mol) was dissolved in ethanol (4 L, anhydrous). Bromine (113.3 g, 0.709 mol) in 200 ethanol was added at room temperature. The reaction mixture was allowed to stir for 17 hours at toom temperature. TLC (30% ethyl acetate/hexane) indicated thate starting material was left. Bromine (40 g in 100 mL of ethanol) was added at room temperature. After 1 hour, TLC indicated no starting material was left. Ethanol was evaporated (2 L removed) and the mixture was poured into ice-water (8 L). The purple solide was stirred and 750 mL of saturated Na2S2O3 and NaOH solution was added to adjust the pH to 10-11. Total volume was 10 L. The mixture was stirred for 30 minutes and the solid were filtered and washed with 1.5 L of water and dried in a vacuum oven to obtain 170 gram of product as yellow solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][N:11]2[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([C:25]#[N:26])=[CH:17][CH:16]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.[ClH:34]>ClCCl>[ClH:34].[C@H:12]12[CH2:14][C@H:9]([NH:8][CH2:13]1)[CH2:10][N:11]2[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([C:25]#[N:26])=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1ccc(C#N)c2ccccc12
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(N2C[C@@H]3C[C@H]2CN3)c2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
165RL03 (207 mg, 0.59 mmol) was dissolved in dichloromethane (2 mL). Trifluoroacetic acid (2 mL) was added and the mixture was shaken in a vial at rt for 3 hours. TLC showed no more starting material. Hydrochloric acid (1 M, 5 mL) was added and the mixture was washed with ethyl acetate (2×10 mL). The aqueous layer was made alkaline with sodium hydroxide (2 M) and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over sodium sulfate and evaporated to dryness to give an off-white solid (146 mg, 99%). The product was converted to the corresponding hydrochloride salt as described above.
Reaction SMILES: [H-].[Na+].[CH2:3]([P:14](=[O:23])([O:19][CH:20]([CH3:22])[CH3:21])[O:15][CH:16]([CH3:18])[CH3:17])[P:4](=[O:13])([O:9][CH:10]([CH3:12])[CH3:11])[O:5][CH:6]([CH3:8])[CH3:7].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].O>O1CCCC1>[CH:20]([O:19][P:14]([O:15][CH:16]([CH3:18])[CH3:17])([CH:3]([P:4]([O:9][CH:10]([CH3:11])[CH3:12])([O:5][CH:6]([CH3:8])[CH3:7])=[O:13])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:23])([CH3:22])[CH3:21]
Reactant: CC(C)OP(=O)(CP(=O)(OC(C)C)OC(C)C)OC(C)C
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CC(P(=O)(OC(C)C)OC(C)C)P(=O)(OC(C)C)OC(C)C
Reaction time: 0.17 h
Yield: 27 %

Procedure:
Under a nitrogen atmosphere, 60% sodium hydride (0.132 g) was suspended in dry tetrahydrofuran (4 ml), and tetraisopropyl methylenebisphosphonate (1.1 g) was added dropwise thereto at room temperature. After stirring for 10 minutes, ethyl bromoacetate (0.354 ml) was added dropwise thereto and the resulting mixture was stirred at the same temperature for 1 hour. Water was added thereto, followed by extraction (twice) with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (methanol:methylene chloride=2:98) to obtain ethyl 3,3-bis(diisopropoxyphosphinoyl)propionate (0.37 g, yield 27%).
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[C:13]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)=[CH:12][NH:11][N:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1>CN(C=O)C>[C:3]1([C:9]2[C:13]([N:14]3[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]3)=[CH:12][N:11]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[N:10]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: ClCc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c[nH]nc2-c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2cn(Cc3ccccn3)nc2-c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To sodium hydride (0.1 g) taken in a dry 100 ml 3-necked round bottom flask cooled to 0° C. dry DMF (2 ml) was added under nitrogen. To the above mixture compound tert-butyl 4-(3-phenyl-1H-pyrazol-4-yl)piperazine-1-carboxylate (0.5 g) in DMF (2 ml) was slowly added and allowed to stir at 0° C. for 30 minutes. 2-Chloromethyl pyridine (300 mg) in DMF (1 ml) was slowly added to the above mixture at 0°C. The reaction mixture was allowed to stir at room temperature for overnight and quenched with ice. The product was extracted with ethyl acetate (3×10 ml). The combined organic layer was washed with water, brine, dried over sodiumsulphate and concentrated under reduced pressure. The resulting crude product was purified by column chromatography using 6% ethyl acetate in hexane, to afford tert-butyl 4-(3-phenyl-1-(pyridin-2-ylmethyl)-1H-pyrazol-4-yl)piperazine-1-carboxylate as half white solid.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.C(OC([NH:20][CH2:21][CH2:22][CH2:23][N:24]1[C:28]2[CH:29]=[C:30]([C:33](O)=[O:34])[CH:31]=[CH:32][C:27]=2[N:26]=[C:25]1[NH:36][C:37]1[CH:42]=[C:41]([O:43][CH3:44])[C:40]([O:45][CH3:46])=[C:39]([O:47][CH3:48])[CH:38]=1)=O)(C)(C)C.[NH:49]1[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1.[ClH:55]>C(Cl)(Cl)Cl.O1CCCC1.CN(C)C=O.ClCCl.C(OCC)(=O)C>[ClH:55].[ClH:55].[NH2:20][CH2:21][CH2:22][CH2:23][N:24]1[C:28]2[CH:29]=[C:30]([C:33]([N:49]3[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]3)=[O:34])[CH:31]=[CH:32][C:27]=2[N:26]=[C:25]1[NH:36][C:37]1[CH:42]=[C:41]([O:43][CH3:44])[C:40]([O:45][CH3:46])=[C:39]([O:47][CH3:48])[CH:38]=1
Reactant: COc1cc(Nc2nc3ccc(C(=O)O)cc3n2CCCNC(=O)OC(C)(C)C)cc(OC)c1OC
Reactant: C1CCNCC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc(Nc2nc3ccc(C(=O)N4CCCCC4)cc3n2CCCN)cc(OC)c1OC
Temperature: 20 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
A solution of carbonyldiimidazole (CDI) (18 mg, 1.1 eq) in chloroform (0.2 ml) is added to a solution of 1-{3-[(tert-butoxycarbonyl)amino]propyl}-2-[(3,4,5-trimethoxyphenyl)amino]-1H-benzimidazole-6-carboxylic acid (50 mg, 1 eq) in tetrahydrofuran (0.45 ml) and dimethylformamide (0.05 ml). The mixture is stirred for 16 hours at a temperature of approximately 20° C., then a solution of piperidine (17 mg, 2 eq) in tetrahydrofuran (0.2 ml) is added. After stirring for 18 hours at a temperature of approximately 20° C., the mixture is diluted with dichloromethane (3 ml), and aminomethylpolystyrene resin (2 eq), TBD-methyl-polystyrene resin (2 eq) and methylisothiocyanate-polystyrene resin (4 eq) are added. After stirring for 6 hours at approximately 20° C., the mixture is filtered and the filtrate is concentrated under reduced pressure at 40° C. The residue obtained is dissolved in ethyl acetate (0.5 ml) and a solution of hydrochloric acid (1N in diethyl ether, 3 ml) is added. After stirring for 1 hour at a temperature of approximately 20° C., the precipitate obtained is filtered and dried in order to produce the expected compound (35 mg, 65%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[OH-].[Na+].Cl[CH2:15][CH2:16][OH:17].C1(C)C=CC=CC=1>CS(C)=O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:15][CH2:16][OH:17]
Reactant: Oc1ccc2ccccc2c1
Reactant: OCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: OCCOc1ccc2ccccc2c1
Yield: 70 %

Procedure:
The reaction set-up consisted of a three necked round bottom flask, equipped with a thermometer, condenser and a mechanical stirrer, and a dropping funnel. 2-Naphthol, 100 g (0.6936 moles), was dissolved in 60 mL of dimethyl sulfoxide. Sodium hydroxide, 27.7 g (0.6936 moles), was carefully added to the solution. Then 2-chloroethanol, 61.4 g (0.7629 moles), was slowly added, keeping the reaction temperature at 80.C. The reaction was followed by GC. After →→80% conversion was achieved, the reaction was worked-up by adding toluene and extracting the unreacted naphthol with 5% aqueous NaOH. The product was then recrystallized in ethanol or distilled under vacuum (70-80% yield).
Reaction SMILES: CCOCC.[CH2:6]([Mg]Cl)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([OH:30])=[C:20]([CH:29]=1)[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22].[Cl-].[NH4+]>C1C=CC=CC=1>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([OH:30])=[C:20]([C:21]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[OH:22])[CH:29]=1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1O
Reactant: Cl[Mg]Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: c1ccccc1
Product: Oc1ccc(Cl)cc1C(O)(Cc1ccccc1)c1ccccc1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
322 ml of an ether solution titrating 1.12 M/liter of benzyl magnesium chloride were added over one hour to a solution of 34 g of 5-chloro-2-hydroxy-benzophenone in 150 ml of benzene and the mixture was allowed to stand for one hour and was then stirred at 20° C. for 16 hours. The mixture was poured into one liter of aqueous saturated ammonium chloride solution and the mixture was washed with water and was extracted 3 times with 400 ml of ether. The ether phase was dried over magnesium sulfate and was evaporated to dryness under reduced pressure. The residue was taken up in 100 ml of cyclohexane and the mixture stood for 16 hours at 20° C. and was iced and vacuum filtered to obtain 42.9 g of 5-chloro-2-hydroxy-α-benzyl-α-phenyl-benzene methanol melting at 128° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=2)[C:9](O)=[O:10])=[CH:4][CH:3]=1.CC[N:23]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=2)[C:9]([NH2:23])=[O:10])=[CH:4][CH:3]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: CSc1ccc(C=C(C(=O)O)c2ccc(F)cc2)cc1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSc1ccc(C=C(C(N)=O)c2ccc(F)cc2)cc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 66.9 %

Procedure:
To a mixture 2-(4-fluorophenyl)-3-(4-methylthiophenyl)acrylic acid (prepared according to procedure given in Example 1) (3 g, 10.4 mmol), EDCI (4 g, 20.8 mmol), HOBt (1.4 g, 10.4 mmol) in DMF (35 mL) and triethylamine (3 mL, 20.8 mmol) was added slowly and stirred for 30 min. Reaction mixture was cooled to 5° C. and anhydrous ammonia gas purged for 10 min and stirred at 30° C. for 30 min. Reaction mixture was poured into water (250 mL) and extracted with ethyl acetate (2×200 mL). Combined organic layer was successively washed with water (3×200 mL) and brine solution (1×150 mL), dried over anhydrous sodium sulfate (2 g) and concentrated to afford the crude compound. The crude compound was triturated with hexane:ethyl acetate (9:1) (40 mL) for 3 times to afford a title compound as colorless solid (2 g, 67% yield).