Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)(=O)[CH2:2][CH3:3].[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[NH:12][NH2:13]>C(O)C>[N:8]1[CH:9]=[CH:10][C:5]([C:1](=[N:13][NH:12][C:11]([O:15][CH2:16][CH3:17])=[O:14])[CH2:2][CH3:3])=[CH:6][CH:7]=1
Reactant: CCC(=O)c1ccncc1
Reactant: CCOC(=O)NN
Solvent: CCO
Product: CCOC(=O)NN=C(CC)c1ccncc1
Temperature: 25 °C
Yield: 49 %

Procedure:
A solution of 4.05 gm (0.03 mole) of 4-propionylpyridine, 3.12 gm (0.03 mole) of ethyl carbazate and 100 ml of absolute ethanol is refluxed 6 hr. The hot solution is filtered. The filtrate is diluted with water to the cloud point. The mixture is cooled to room temperature and then chilled in the refrigerator to give crystals which are collected, washed with Skellysolve B and dried to yield 3.25 gm (49%) of the title compound having a melting point of 147.1° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=2)=[CH:6][N:5]=[CH:4][N:3]=1.CS(C)=O.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=[C:32]1[C:40]([C:42]1[CH:47]=[CH:46][C:45]([OH:48])=[CH:44][CH:43]=1)=[O:41]>O>[NH:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=[C:32]1[C:40]([C:42]1[CH:47]=[CH:46][C:45]([O:48][C:2]2[C:7]([C:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=3)=[CH:6][N:5]=[CH:4][N:3]=2)=[CH:44][CH:43]=1)=[O:41]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cncnc2Cl)CC1
Reactant: O=C(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC=C(c2cncnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)CC1
Temperature: 100 °C

Procedure:
To a vial was added tert-butyl 4-(4-chloropyrimidin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate (320 mg, 1.082 mmol), DMSO (5.4 mL), cesium carbonate (370 mg, 1.136 mmol), and (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (258 mg, 1.082 mmol) before sealing and heating to 100° C. for 45 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate before drying over magnesium sulfate, filtering, and concentrating under reduced pressure. The crude material was taken after purifying by column chromatography (10% methanol/dichloromethane), affording tert-butyl 4-(4-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrimidin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate. MS (ESI, pos. ion) m/z: 498.3 (M+1).
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[CH:26]=[CH:25][C:14]2[NH:15][C@@H:16]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:17][O:18][C:13]=2[CH:12]=1.[O:27]=[C:28]1[CH2:33][O:32][C:31]2[CH:34]=[CH:35][C:36]([C:38](O)=[O:39])=[CH:37][C:30]=2[NH:29]1.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>C(OCCCC)(=O)C.CCOC(C)=O>[Br:10][C:11]1[CH:26]=[CH:25][C:14]2[N:15]([C:38]([C:36]3[CH:35]=[CH:34][C:31]4[O:32][CH2:33][C:28](=[O:27])[NH:29][C:30]=4[CH:37]=3)=[O:39])[C@@H:16]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:17][O:18][C:13]=2[CH:12]=1
Reactant: CCOC(=O)C[C@H]1COc2cc(Br)ccc2N1
Reactant: O=C1COc2ccc(C(=O)O)cc2N1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCOC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@H]1COc2cc(Br)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Temperature: 140 °C
Reaction time: 2 h
Yield: 57.9 %

Procedure:
DIPEA (46.4 g, 360 mmol) was added to ethyl [(3S)-7-bromo-3,4-dihydro-2H-1,4-benzoxazin-3-yl]acetate (Intermediate 27a, 36 g, 120 mmol), 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid (28 g, 144 mmol) and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50% solution in EtOAc) (152.6 g, 240 mmol) in butyl acetate (100 mL) at rt. The resulting suspension was stirred at 140° C. for 2 hours. The reaction mixture was diluted with EtOAc (700 mL) and washed with saturated NaHCO3 (500 mL), 1 M HCl (500 mL) and brine (500 mL). The organic layer was dried over anhydrous Na2SO4, filtered and evaporated to afford crude product. The residue was purified by a silica chromatography, eluent gradient from 5% to 20% of EtOAc in PE. The pure fraction was evaporated to dryness to afford title compound (33 g, 58%) as an off-white solid.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:18])[N:4](C)[C:5]2[C:10]([C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:19][O:20]C1C=C2C(=CC=1)NC(=O)C2=O>>[OH:1][C:2]1[C:3](=[O:18])[NH:4][C:5]2[C:10]([C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][C:8]([O:20][CH3:19])=[CH:7][CH:6]=2
Reactant: CCOC(=O)c1c(O)c(=O)n(C)c2ccccc12
Reactant: COc1ccc2c(c1)C(=O)C(=O)N2
Product: CCOC(=O)c1c(O)c(=O)[nH]c2ccc(OC)cc12

Procedure:
Intermediate 27 was prepared as a white powder following the procedure described for Intermediate 16 by replacing indoline-2,3-dione with 5-methoxyindoline-2,3-dione. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.20 (1 H, s), 10.22 (1 H, br. s.), 7.27 (1H, d, J=8.8 Hz), 7.04 (1H, dd, J=9.1, 2.5 Hz), 6.82 (1 H, d, J=2.5 Hz), 4.41 (2 H, q, J=7.1 Hz), 3.32 (3 H, s), 1.35 (3 H, t, J=7.1 Hz). LC-MS (ESI) m/z 264.0 (M+H), RT=1.64 min (Method B).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7].[C:8](OC(=O)C)(=[O:10])[CH3:9]>N1C=CC=CC=1>[C:8]([O:1][C@H:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7])(=[O:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1NCC[C@@H]1O
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1CCNC1=O
Reaction time: 4 h
Yield: 86.3 %

Procedure:
To a solution of 1.439 g of (S)-(-)-3-hydroxy-2-pyrrolidinone [P. W. K. Woo, Tetrahedron Letters, 2617 (1971); mp. 103.5°-104.5° C., [α]D26 =-118.8°±2.3° (c=0.688, CHCl3)] in 14 ml of pyridine is added 2.8 ml of acetic anhydride, and the mixture is allowed to stand at room temperature for 4 hours and concentrated under reduced pressure at a temperature below 40° C. The residue is crystallized from ether and recrystallized from methylene chloride-n-hexane to give 1.735 g of (S)-(-)-3-acetoxy-2-pyrrolidinone in 86.3% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([Br:7])[S:4][C:3]=1[C:8]([OH:10])=O.[Cl-].[NH4+].C([N:15](CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(=O)([O-])O.[Na+]>CN(C=O)C>[NH2:1][C:2]1[CH:6]=[C:5]([Br:7])[S:4][C:3]=1[C:8]([NH2:15])=[O:10]
Reactant: Nc1cc(Br)sc1C(=O)O
Reactant: CCN(CC)CC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: NC(=O)c1sc(Br)cc1N
Reaction time: 0.17 h
Yield: 77.4 %

Procedure:
A mixture of 3-amino-5-bromothiophene-2-carboxylic acid (0.154 g, 0.690 mmol), ammonium chloride (0.369 g, 6.90 mmol), triethylamine (0.964 mL, 6.90 mmol) and DMF (4.0 mL) was stirred for 10 min. Then, 1-hydroxybenzotriazole (0.284 g, 2.10 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.403 g, 2.10 mmol) were added and stirring was continued for 4 days. The mixture was then poured into sat. aqueous sodium hydrogen carbonate (100 mL). Extraction with ethyl acetate (60 mL, 20 mL), washing with brine, drying over magnesium sulfate, filtration and concentration at reduced pressure gave an oil. This oil was purified by column chromatography (Combiflash, silica gel, hexanes to 90:10 hexanes/ethyl acetate) to afford the title compound (0.118 g, 78%) as a brown oil:
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9]CC)=O.[NH2:12][C:13]([NH2:15])=[O:14].Cl>CCO>[NH:12]1[C:2]2[CH2:6][CH2:5][CH2:4][C:3]=2[C:7](=[O:9])[NH:15][C:13]1=[O:14]
Reactant: NC(N)=O
Reactant: CCOC(=O)C1CCCC1=O
Agent: Cl
Solvent: CCO
Product: O=c1[nH]c2c(c(=O)[nH]1)CCC2
Temperature: 25 °C
Yield: 73 %

Procedure:
A solution of ethyl 2-oxocyclopentanecarboxylate (15.6 g, 0.10 mol), urea (9.0 g 0.15 mol) and hydrochloric acid (37%, aqueous, 5 mL) in EtOH (100 mL) was heated to 80° C. for 24 h. The mixture was cooled to rt and the precipitate was collected by filtration and dried to afford 6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione (11.1 g, 73%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([C:12]#[N:13])[CH:3]=1.[OH-].[Li+].Cl>C(COC)OC.O.[Cl-].[Na+].O>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[C:4]([C:12]#[N:13])[CH:3]=1
Reactant: COC(=O)c1ccc(Br)cc1C#N
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: COCCOC
Solvent: O
Product: N#Cc1cc(Br)ccc1C(=O)O
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
Methyl 4-bromo-2-cyanobenzoate (8.53 g) described in Preparation Example 75 was dissolved in dimethoxyethane (140 mL), a solution of lithium hydroxide 1 hydrate (2.24 g) in water (54 mL) was added dropwise under ice-cooling, and the mixture was stirred at the same temperature for 30 min. To the reaction mixture was added dropwise 1N hydrochloric acid (60 mL) under ice-cooling, saturated brine was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated to give the title compound (7.97 g).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][OH:9])[CH2:4][CH2:3]1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH:8]=[O:9])[CH2:4][CH2:3]1
Reactant: C[C@H]1CC[C@H](CO)CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C[C@H]1CC[C@H](C=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of trans-(4-methylcyclohexyl)methanol (160 g, 1.25 mol) in DCM (1500 mL) was added pyridinium chlorochromate (405 g, 1.88 mol) at 0° C., and the mixture was stirred at room temperature for 2 h. It was filtered and the filtrate was concentrated in vacuo to give trans-4-methylcyclohexanecarbaldehyde.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2O.P(Br)(Br)([Br:16])=O.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Br:16][C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][CH:7]=1
Reactant: O=P(Br)(Br)Br
Reactant: COc1ccc2nccc(O)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1ccc2nccc(Br)c2c1
Yield: 50 %

Procedure:
This was prepared by heating 6-methoxy-quinolin-4-ol (1 g) and phosphorus oxybromide (5 g) in chloroform (40 ml) under reflux for 18 hours. The mixture was cooled, basified with sodium bicarbonate, extracted with 5% methanol-chloroform, and dried (sodium sulfate). The product was chromatographed on silica gel (2-5% methanol-dichloromethane) to afford a solid (0.68 g).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([CH3:9])([CH3:8])[C:5](=[O:7])[CH3:6].[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=O)[CH:11]=1>O>[CH3:3][C:4]([CH3:9])([CH3:8])[C:5](=[O:7])[CH:6]=[CH:16][C:12]1[CH:11]=[N:10][CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)C(C)(C)C
Reactant: O=Cc1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)C(=O)C=Cc1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.5 %

Procedure:
100 ml of 10% strength sodium hydroxide solution were added to a solution of 35 g (0.35 mol) of 3,3-dimethylbutan-2-one and 38 g (0.355 mol) of 3-pyridinealdehyde in 2,000 ml of water and the solution was stirred overnight at room temperature. The crystalline precipitate was filtered off, dried and recrystallized from n-hexane. 34.1 g (51.5% of theory) of 4,4-dimethyl-1-pyridin-3-yl-1-penten-3-one of melting point 68°-70° C. were obtained. ##STR117##
Reaction SMILES: [C:1]([OH:14])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:15]([CH:17]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:18]O)[CH3:16]>C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:1]([O:14][CH2:18][CH:17]([CH2:15][CH3:16])[CH2:20][CH2:21][CH2:22][CH3:23])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)O
Reactant: CCCCC(CC)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCCCCCCCCCC(=O)OCC(CC)CCCC

Procedure:
2-ethylhexyl laurate was prepared by esterification reaction between lauric acid and 2-ethylhexanol in the presence of p-toluenesulfonic acid as a catalyst, and subsequent steps for recovery of unreacted 2-ethylhexanol, neutralization, washing with hot water, and dehydration.
Reaction SMILES: B1C2CCCC1CCC2.[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH:14]=[CH2:15])[CH3:11].Cl[C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][N:29]3[CH:32]=[CH:33][N:34]=[C:28]3[CH:27]=2)[CH:23]=[CH:22][N:21]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>O.O1CCOCC1>[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH2:14][CH2:15][C:22]1[CH:23]=[C:24]([C:26]2[CH:31]=[CH:30][N:29]3[CH:32]=[CH:33][N:34]=[C:28]3[CH:27]=2)[CH:25]=[CH:20][N:21]=1)[CH3:11]
Reactant: Clc1cc(-c2ccn3ccnc3c2)ccn1
Reactant: C=CC(OCC)OCC
Agent: B1C2CCCC1CCC2
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(CCc1cc(-c2ccn3ccnc3c2)ccn1)OCC
Yield: 100 %

Procedure:
In a round bottomed flask, add 9-BBN (0.5 M in THF, 42.2 mL, 2 equiv.) under nitrogen. Add acrolein diethyl acetal (3.4 mL, 2.1 equiv.) via syringe and stir at room temperature overnight. In a separate flask on the second day, combine 7-(2-chloro-pyridin-4-yl)-imidazo[1,2-a]pyridine (2.42 g, 11 mmol), potassium phosphate (4.47 g, 2 equiv.), S-Phos (0.54 g, 12.5 mol %), dioxane (90 mL), and water (45 mL). De-gas with nitrogen then add palladium (II) acetate (0.118 g, 5 mol %) under nitrogen. To this solution add the material from the first flask via canula. Heat the reaction at 80° C. for 5.5 hours. Concentrate to dryness. Slurry in DCM then filter to remove insoluble material. Wash with DCM. Concentrate filtrate and purify by silica plug (1:1 Hexanes:Ethyl Acetate→Ethyl Acetate→5% Methanol:DCM→10% Methanol:DCM) to give a residue (4.15 g, >100%) which is used as is for the next step. MS (ES), m/z 326 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:12][CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][N:15]2[CH3:19])[C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH2:11])=[CH:6][CH:5]=2.I.CS[C:23]([C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)=[NH:24]>C(O)C.C([O-])(O)=O.[Na+]>[CH3:1][C:2]1[N:3]([CH2:12][CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][N:15]2[CH3:19])[C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH:11][C:23]([C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)=[NH:24])=[CH:6][CH:5]=2
Reactant: Cc1cc2cc(N)ccc2n1CCC1CCCN1C
Reactant: CSC(=N)c1cccs1
Agent: I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1cc2cc(NC(=N)c3cccs3)ccc2n1CCC1CCCN1C
Reaction time: 4 h
Yield: 98.8 %

Procedure:
A solution of compound 31 (0.32 g, 1.243 mmol) in dry ethanol (10 mL) was treated with thiophene-2-carboximidothioic acid methyl ester hydroiodide (0.7 g, 2.486 mmol) at room temperature and stirred for 4 h. The reaction was diluted with sat. NaHCO3 solution (25 mL) and product was extracted into CH2Cl2 (2 25 mL). The combined CH2Cl2 layer washed with brine (15 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 5:95) to obtain compound 32 (0.45 g, 99%) as a foam. 1H NMR (DMSO-d6) δ 1.48-1.68 (m, 4H), 1.87-1.98 (m, 2H), 2.01-2.18 (m, 2H), 2.22 (s, 3H), 2.39 (s, 3H), 2.92-2.98 (m, 1H), 4.07 (t, 2H, J=7.8 Hz), 6.09 (s, 1H), 6.19 (brs, 2H), 6.62 (dd, 1H, J=1.5, 8.5 Hz), 6.87 (s, 1H), 7.08 (dd, 1H, J=3.6, 4.9 Hz), 7.26 (d, 1H, J=8.4 Hz), 7.57 (d, 1H, J=5.4 Hz), 7.70 (d, 1H, J=3.6 Hz); ESI-MS (m/z, %) 367 (MH+, 62), 184 (100), 126 (37); ESI-HRMS calculated for C21H27N4S (MH+), calculated: 367.1950, observed: 367.1965; HPLC purity: 96.2% by area.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]#[C:22][CH2:23][OH:24])[CH:17]=3)[N:12]([CH2:25][C:26]([O:28]C(C)(C)C)=[O:27])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]#[C:22][CH2:23][OH:24])[CH:17]=3)[N:12]([CH2:25][C:26]([OH:28])=[O:27])[CH:11]=2)=[O:9])=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)ccc21
Reaction time: 3 h
Yield: 80.9 %

Procedure:
To a suspension of tert-butyl 2-[3-{[(4-chlorobenzyl)amino]carbonyl}-6-(3-hydroxy-1-propynyl)-4-oxo-1(4H)quinolinyl]acetate (0.07 g) from Example No. 28 in dichloromethane (1 mL) is added trifluoroacetic acid (1 mL). After 3 hours, the resulting solution is concentrated under reduced pressure. The residue is dissolved in a small amount of dichloromethane:methanol:DMF and slowly added to vigorously stirring 1:1 diethyl ether:pentane. The resulting precipitate is collected filtration to afford 0.05 g of the title compound as a solid.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[OH:10][C:11]1[CH:12]=[C:13]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[O:10][C:11]1[CH:12]=[C:13]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:14]=[CH:15][CH:16]=1)#[N:5]
Reactant: N#Cc1ccccc1F
Reactant: CCOC(=O)Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cccc(Oc2ccccc2C#N)c1
Temperature: 160 °C

Procedure:
4.23 g (35 mmol) of 2-fluorobenzonitrile, 6.3 g (35 mmol) of ethyl 3-hydroxyphenylacetate and 4.84 g of potassium carbonate (anhydrous) are dissolved in 40 ml of dimethylformamide and heated with stirring to a temperature of 160° C. Ethyl 3-(2-cyanophenoxy)-phenylacetate is formed takes place [sic]. The mixture is stirred for three hours while maintaining the temperature. The cooled reaction solution is treated with 150 ml of water and extracted with methyl t-butyl ether. The organic phase is separated off, washed with water and NaCl solution and dried. After distilling off the solvent, the product is obtained as an oil.
Reaction SMILES: [C:1]([O:14][CH2:15][C@@H:16]([O:45][C:46](=[O:58])[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH2:17][S:18][CH2:19][C@H:20]([NH2:44])[C:21]([NH:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][P:36]([O:41]CC)([O:38]CC)=[O:37])=[CH:28][CH:27]=1)=[O:22])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C[Si](Br)(C)C>C(Cl)Cl>[NH2:44][C@@H:20]([CH2:19][S:18][CH2:17][C@H:16]([O:45][C:46](=[O:58])[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH2:15][O:14][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:21]([NH:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][P:36](=[O:37])([OH:41])[OH:38])=[CH:28][CH:27]=1)=[O:22]
Reactant: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](N)C(=O)NCCc1ccc(OCCCP(=O)(OCC)OCC)cc1)OC(=O)CCCCCCCCCCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](N)C(=O)NCCc1ccc(OCCCP(=O)(O)O)cc1)OC(=O)CCCCCCCCCCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-3-((R)-2-amino-3-(4-(3-(diethoxyphosphoryl)propoxy)phenethylamino)-3-oxopropylthio)propane-1,2-diyl didodecanoate (1 eq) in DCM (0.1 M) was added trimethylsilyl bromide (10 eq). The reaction mixture was stirred at room temperature overnight and then concentrated. The crude mixture was purified by reverse phase high performance liquid chromatography (HPLC) with C4 column eluting with a gradient of 50-100% MeCN/10 mM NH4OAc (95:5) in 10 mM NH4OAc (pH 9) to give the product as a white solid. 1H NMR (DMSO-d6): δ 7.13 (d, 2H), 6.85 (d, 2H), 5.10-5.19 (m, 2H), 4.28 (dd, 1H), 4.12 (dd, 1H), 3.97 (t, 1H), 3.81-3.90 (m, 1H), 2.93 (dd, 1H), 2.70-2.86 (m, 3H), 2.64-2.70 (m, 2H), 2.31-2.35 (m, 2H), 2.24-2.31 (m, 2H), 2.14-2.21 (m, 2H), 1.82-1.93 (m, 4H), 1.57-1.70 (m, 4H), 1.41-1.57 (m, 4H), 1.07-1.38 (m, 32H), 0.85 (t, 6H). LRMS [M+H]=801.5.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([C:13]2[S:14][CH:15]=[C:16]([CH2:18][O:19][C:20]3[CH:41]=[CH:40][C:23]([CH2:24][N:25]4[CH:29]=[C:28]([C:30](OCC)=[O:31])[C:27]([C:35]5[S:36][CH:37]=[CH:38][CH:39]=5)=[N:26]4)=[CH:22][CH:21]=3)[N:17]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[C:7]1([C:13]2[S:14][CH:15]=[C:16]([CH2:18][O:19][C:20]3[CH:41]=[CH:40][C:23]([CH2:24][N:25]4[CH:29]=[C:28]([CH2:30][OH:31])[C:27]([C:35]5[S:36][CH:37]=[CH:38][CH:39]=5)=[N:26]4)=[CH:22][CH:21]=3)[N:17]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1cn(Cc2ccc(OCc3csc(-c4ccccc4)n3)cc2)nc1-c1cccs1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cn(Cc2ccc(OCc3csc(-c4ccccc4)n3)cc2)nc1-c1cccs1
Reaction time: 0.5 h
Yield: 97 %

Procedure:
Lithium aluminium hydride (540 mg) was added gradually to a solution of ethyl 1-[4-(2-phenyl-4-thiazolylmethoxy)benzyl]-3-(2-thienyl)-1H-pyrazole-4-carboxylate (7.10 g) in tetrahydrofuran (50 ml) at 0° C., which was stirred for 30 minutes. Sodium sulfate decahydrate (4.33 g) was added to the reaction mixture, and the precipitate was removed by filtration. The filtrate was concentrated, and the residue was subjected to silica gel column chromatography to obtain [1-[4-(2-phenyl-4-thiazolylmethoxy)benzyl]-3-(2-thienyl)-1H-pyrazol-4-yl]methanol (6.31 g, yield: 96%) as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 147˜148° C.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=2)=[CH:8][CH:7]=1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[NH4+]>C(OCC)C.O>[F:21][C:19]([F:20])([F:22])[C:16]1[CH:17]=[CH:18][C:13]([O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][OH:3])=[CH:7][CH:8]=2)=[N:14][CH:15]=1
Reactant: CCOC(=O)Cc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: OCCc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The (4-(5-(trifluoromethyl)-2-pyridinyloxy)phenyl)acetic acid ethyl ester (15.6 g, 48 mmol) was then added to a slurry of lithium aluminum hydride (2.3 g, 60 mmol) in ethyl ether (500 mL). The mixture was stirred overnight at room temperature. Then a saturated solution of ammonium chloride in water was added, and the title product, an oil, was separated from remaining solids by filtration. Yield 11 g.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4([CH3:31])OCC[O:27]4)[CH2:23][CH2:22][C:21]([C:32]([NH:34][C:35]4[CH:40]=[CH:39][C:38]([CH2:41][N:42]([CH3:49])[CH:43]5[CH2:48][CH2:47][O:46][CH2:45][CH2:44]5)=[CH:37][CH:36]=4)=[O:33])=[CH:20][C:19]=3[CH:50]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].O.O.O.O.O.O.O.[Cl-].[Ce+3].[Cl-].[Cl-].[I-].[Na+].C(#N)C>O>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26](=[O:27])[CH3:31])[CH2:23][CH2:22][C:21]([C:32]([NH:34][C:35]4[CH:36]=[CH:37][C:38]([CH2:41][N:42]([CH3:49])[CH:43]5[CH2:48][CH2:47][O:46][CH2:45][CH2:44]5)=[CH:39][CH:40]=4)=[O:33])=[CH:20][C:19]=3[CH:50]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3CC2(C)OCCO2)cc1
Agent: [Ce+3]
Agent: [Cl-]
Agent: [I-]
Solvent: O
Solvent: CC#N
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3CC(C)=O)cc1
Temperature: 60 °C
Reaction time: 120 h
Yield: 55.6 %

Procedure:
A mixture of 7-[4-(2-butoxyethoxy)phenyl]-1-[(2-methyl-1,3-dioxolan-2-yl)methyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (100 mg), cerium chloride heptahydrate (300 mg), sodium iodide (19 mg) and acetonitrile (5 ml) was stirred at 60° C. for 5 days. Water was added to the reaction system, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified with column chromatography (ethanol:ethyl acetate=1:3) to give 7-[4-(2-butoxyethoxy)phenyl]-1-(2-oxopropyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 108) (52 mg) as yellow crystals.