Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]#[N:12].[H-].[K+].C([Li])CCC.C([O:24][B:25](OCCCC)[O:26]CCCC)CCC>C1COCC1>[C:11]([C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([B:25]([OH:26])[OH:24])[CH:3]=2)[NH:7][CH:6]=1)#[N:12]
Reactant: CCCCOB(OCCCC)OCCCC
Reactant: N#Cc1c[nH]c2ccc(Br)cc12
Agent: [H-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#Cc1c[nH]c2ccc(B(O)O)cc12
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A solution of 5-bromo-3-cyanoindole (4.00 g, 18.1 mMol) in THF (20 mL) was added to a suspension of potassium hydride (2.28 g, 35% mineral oil dispersion, 19.9 mMol) in anhydrous THF (50 mL) at 0° C. After stirring for 15 min, the solution was cooled to −78° C., whereupon some precipitation occurred. A solution of n-butyllithium (2.5 M in hexanes, 16 mL) was slowly added via syringe. The resulting mixture was stirred at −78° C. for 15 minutes and then tributylborate (9.16 g, 39.8 mMol) was added. The mixture was removed from the cooling bath, stirred for 15 minutes, carefully quenched with water, and concentrated in vacuo. The residue was vigorously mixed with 1 N hydrochloric acid and extracted three times with ethyl acetate. The ethyl acetate layers were extracted three times with 1 N sodium hydroxide. The combined aqueous extracts were made acidic with concentrated hydrochloric acid to give 3-cyano-5-indolylboronic acid as a light tan precipitate which was collected by filtration and dried under vacuum (1.82 g, 55%). 1H-NMR (400 MHz, DMSO) δ 12.19 (1H, br s), 6.05 (1H, d, J=5.2 Hz), 8.24 (1H, d, J=2.8 Hz), 8.17 (1H, d, 6.4 Hz), 7.69 (1H, d, J=8.2 Hz), 7.49 (1H, d, J=8.2 Hz).
Reaction SMILES: [C:1]([O:20]C)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].O1CCN=C1>>[C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OC
Agent: C1=NCCO1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)O
Yield: 6.8 %

Procedure:
A blanker oil composition was prepared by melting 56 grams of oxidized hydrocarbon wax ("Idasoil D906") and 24 grams of sodium petroleum sulfonate ("Petrosul H-60 Sod Sulfonate") at approximately 150° F. until a homogeneous solution was obtained. To this mixture was added 200 grams of methyl oleate (Keil chemical), one gram of Di-2-butyl cresol ("Lubrizol 817") and 5 grams of oxazoline-type surfactant ("Alkaterge ® T-IV") and 1 gram of an organic acid salt corrosion inhibitor ("Hostacor E"). The mixture was stirred to provide a homogeneous solution and 680 grams of mineral seal oil ("Grade 45 oil" Sterling Oil and Chemical Company) was added. The resultant mixture was stirred until a uniform solution obtained and at this point 13 grams of oleic acid was added and the stirring continued until a homogeneous solution obtained.
Reaction SMILES: C([NH:5][C:6]1[CH:11]=[C:10]([C:12]2[C:13]([C:26]3[CH:27]=[C:28]([NH:32][C:33]([NH:35][C:36]4[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=4)=[O:34])[CH:29]=[CH:30][CH:31]=3)=[N:14][N:15](CC3C=CC(OC)=CC=3)[CH:16]=2)[CH:9]=[CH:8][N:7]=1)(C)(C)C.O.C([O-])(O)=O.[Na+]>FC(F)(F)C(O)=O>[NH2:5][C:6]1[CH:11]=[C:10]([C:12]2[C:13]([C:26]3[CH:27]=[C:28]([NH:32][C:33]([NH:35][C:36]4[CH:41]=[CH:40][C:39]([C:42]([F:44])([F:45])[F:43])=[CH:38][CH:37]=4)=[O:34])[CH:29]=[CH:30][CH:31]=3)=[N:14][NH:15][CH:16]=2)[CH:9]=[CH:8][N:7]=1
Reactant: COc1ccc(Cn2cc(-c3ccnc(NC(C)(C)C)c3)c(-c3cccc(NC(=O)Nc4ccc(C(F)(F)F)cc4)c3)n2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Nc1cc(-c2c[nH]nc2-c2cccc(NC(=O)Nc3ccc(C(F)(F)F)cc3)c2)ccn1
Temperature: 70 °C
Yield: 71.3 %

Procedure:
100 mg (0.16 mmol) of 1-(3-{4-[2-(tert-butylamino)pyridin-4-yl]-1-(4-methoxybenzyl)-1H-pyrazol-3-yl}phenyl)-3-[4-(trifluoromethyl)phenyl]urea were dissolved in 5 ml of trifluoroacetic acid and the mixture heated at 70° C. under stirring. After 16 hours the solution was poured into icy water, neutralized with aqueous NaHCO3 and extracted with dichloromethane. The organic layer was then dried over Na2SO4 and evaporated to dryness. The product was purified by chromatography on a silica gel column eluted with dichloromethane-methanol (gradient from 1% to 5%) obtaining 50 mg (71% yield) of the title compound.
Reaction SMILES: O[CH:2]([CH:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12])[CH2:3][CH2:4][CH2:5][CH3:6].IN1C(=O)CCC1=O.C1(C)C=CC=CC=1>O>[CH2:2]([C:7]1[C:8](=[O:12])[CH2:9][CH2:10][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC(O)C1CCCC1=O
Agent: O=C1CCC(=O)N1I
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCC1=CCCC1=O
Yield: 85.6 %

Procedure:
In a 50 ml four-neck flask fitted with a thermometer, a reflux condenser and a stirrer were placed 2-(1-hydroxypentyl)cyclopentanone (20 g) synthesized in Reference Example 1, N-iodosuccinimide (0.1 g) and toluene (10 ml), and water was removed under refluxing, followed by 4 hours of the reaction at 150° C. The reaction mixture was washed with water and the layers were separated from each other. Further, the resulting organic layer was washed with saturated brine and separated. The organic layer was evaporated on a rotary evaporator under reduced pressure to recover toluene, whereby a crude product was obtained. The product was distilled using a Claisen distillation apparatus to obtain 15.3 g of 2-pentyl-2-cyclopentenone (boiling point: 104° C./930 Pa; GC purity: 98.4%).
Reaction SMILES: [F:1][C:2]1([F:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([N:11]2[C:15]([CH2:16][OH:17])=[CH:14][N:13]=[CH:12]2)[C:3]1([CH3:19])[CH3:18].[H-].[Na+].I[CH2:24][CH3:25]>CN(C=O)C.C([O-])(O)=O.[Na+].C(OCC)(=O)C>[F:20][C:2]1([F:1])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([N:11]2[C:15]([CH2:16][O:17][CH2:24][CH3:25])=[CH:14][N:13]=[CH:12]2)[C:3]1([CH3:18])[CH3:19]
Reactant: CCI
Reactant: CC1(C)C(n2cncc2CO)c2ccccc2C1(F)F
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOCc1cncn1C1c2ccccc2C(F)(F)C1(C)C
Reaction time: 2 h

Procedure:
To a solution of [3-(3,3-difluoro-2,2-dimethyl-indan-1-yl)-3H-imidazol-4-yl]-methanol, (160 mg, 0.575 mmol) in DMF (5 mL) is added a 60% dispersion of NaH in oil (46 mg, 1.15 mmol). The reaction is permitted to stir for 30 minutes at room temperature, at which time iodoethane (0.05 mL, 0.63 mmol) is added. The reaction is permitted to stir for 2 hours at which time it is diluted with saturated aqueous NaHCO3 and ethyl acetate. The layers are separated and the organic layer is dried with Na2SO4, filtered and concentrated. The resulting residue is purified by silica gel flash chromatography (ethyl acetate-dichloromethane, 0:1 to 1:6) to furnish 1-(3,3-difluoro-2,2-dimethyl-indan-1-yl)-5-ethoxymethyl-1H-imidazole; HRMS: (ESI) m/z 307.1634 [(M+H)+: Calcd for C17H21N2OF2: 307.1622]; 1H NMR (400 MHz, CDCl3) δ ppm 0.94 (d, J=2.5 Hz, 3 H), 1.28 (t, J=7.1 Hz, 3 H), 1.33 (d, J=3.3 Hz, 3 H), 3.51-3.68 (m, 2 H), 4.54-4.70 (m, 2 H), 5.58 (br. s., 1 H), 7.19 (s, 1 H), 7.23-7.26 (m, 1 H), 7.34 (s, 1 H), 7.55-7.63 (m, 2 H), 7.69-7.76 (m, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[C:4]([CH3:10])[CH:3]=1.[C-:11]#[N:12].[Na+].O.C([O-])(O)=O.[Na+]>CN(C=O)C.CCCCCC.CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:11]#[N:12])=[C:4]([CH3:10])[CH:3]=1
Reactant: [C-]#N
Reactant: Cc1cc(Br)ccc1CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1cc(Br)ccc1CC#N
Temperature: 2.5 °C
Reaction time: 8 h
Yield: 92.7 %

Procedure:
1-Bromo-4-(bromomethyl)-3-methylbenzene (13.2 g, 50.1 mmol) is dissolved in DMF (65 mL). The reaction mixture is cooled to 0-5° C. and NaCN (3.66 g, 74.6 mmol) is added follow by water (8 mL). The reaction is stirred overnight at room temperature and water (170 mL) is added followed by NaHCO3 sat. (130 mL) and hexane/Et2O (2:1) (150 mL). The organic phase is separated and the aqueous phase extracted with hexane/Et2O (2:1) (3×150 mL). The combined organic phases are washed with water (170 mL), dried over MgSO4, filtered and concentrated under reduced pressure to provide the expected product 2-(4-bromo-2-methylphenyl)acetonitrile (9.76 g, 93%) as an orange oil. 1H NMR (300 MHz, CHLOROFORM-D): δ 7.40-7.32 (2H, m), 7.23 (2H, d, J=8.2 Hz), 3.61 (2H, s), 2.32 (3H, s).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])(=[O:4])=[O:3].[CH2:19](I)[CH2:20][CH3:21]>>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([N:13]2[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][CH3:21])[CH2:17][CH2:18]2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])(=[O:3])=[O:4]
Reactant: CCCI
Reactant: COc1ccc(N2CCNCC2)cc1S(C)(=O)=O
Product: CCCN1CCN(c2ccc(OC)c(S(C)(=O)=O)c2)CC1

Procedure:
Beginning with 1-(3-Methanesulfonyl-4-methoxy-phenyl)-piperazine and n-Pr-I, the title compound was recovered by the procedure described in Example 2;: MS m/z (rel. intensity, 70 eV)) 312 (M+, 38), 284 (17), 283 (bp), 70 (49), 56 (17).
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:49]([C:51]1[N:52]=[C:53]([CH:56]2[CH2:61][CH2:60][N:59]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[CH2:58][CH2:57]2)[S:54][CH:55]=1)#[CH:50]>O1CCCC1.CC#N.CC#N.Cl[Pd]Cl>[C:2]1([CH2:1][C:50]#[C:49][C:51]2[N:52]=[C:53]([CH:56]3[CH2:61][CH2:60][N:59]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[CH2:58][CH2:57]3)[S:54][CH:55]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: C#Cc1csc(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: Cl[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C#CCc3ccccc3)cs2)CC1
Temperature: 65 °C

Procedure:
Under argon, benzyl chloride (134 mg), bis(acetonitrile)dichloropalladium(II) (5.5 mg), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (30 mg) and caesium carbonate (363 mg) are added to a degassed solution of tert-butyl 4-(4-ethynyl-1,3-thiazol-2-yl)piperidine-1-carboxylate (X-1, 310 mg) in tetrahydrofuran (4 ml). The mixture is then warmed to 65° C. After subsequent cooling, the catalyst is removed by filtration over Celite and the filtrate is concentrated under reduced pressure. After chromatographic purification, this gives tert-butyl 4-[4-(3-phenylprop-1-yn-1-yl)-1,3-thiazol-2-yl]piperidine-1-carboxylate (329 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:10])[CH:7](Br)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[P:11]([O:18]CC)([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14]>>[C:1]([O:5][C:6](=[O:10])[CH:7]([P:11]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])=[O:18])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(Br)C(=O)OC(C)(C)C
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(OCC)C(C)C(=O)OC(C)(C)C
Temperature: 110 °C
Reaction time: 8 h
Yield: 108.1 %

Procedure:
2-Bromo-propanoic acid tert-butyl ester (17.4 g, 83 mmol) and triethyl phosphite (14.5 g, 87 mmol) were mixed, and the mixture was stirred at 110° C. overnight. The reaction mixture was dried under reduced pressure to give the title compound (23.9 g).
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:16])[CH:4]=[C:5]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[O:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br>>[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:1][C:2]1[C:3](=[O:16])[CH:4]=[C:5]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[O:6][CH:7]=1
Reactant: BrCCCCCCCBr
Reactant: O=c1cc(COC2CCCCO2)occ1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=c1cc(COC2CCCCO2)occ1OCCCCCCCBr
Temperature: 80 °C
Yield: 78 %

Procedure:
The compound was prepared according to example 11 procedure using 5-hydroxy-2-(tetrahydro-pyran-2-yloxymethyl)-4H-pyran-4-one (1.00 g, 4.42 mmol), Cs2CO3 (1.58 g, 4.86 mmol) and 1,7-dibromoheptane (2.5 mL, 14.6 mmol). The sealed tube was heated at 80° C. for 2 h 30. A white solid 5-(7-bromo-heptyloxy)-2-(tetrahydro-pyran-2-yloxymethyl)-4H-pyran-4-one 4 was obtained (1.40 g, 78% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]#[N:19])=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.[N-:22]=[N+:23]=[N-:24].[Na+].[Cl-].[NH4+].Cl>CN(C)C=O>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[NH:24][N:23]=[N:22][N:19]=4)=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[CH:4][CH:3]=1
Reactant: N#CCOc1ccc2c(ccn2Cc2ccc(Cl)cc2)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Clc1ccc(Cn2ccc3cc(OCc4nnn[nH]4)ccc32)cc1
Temperature: 140 °C

Procedure:
A mixture of (1-(4-Chlorobenzyl)indol-5-yl)oxyacetonitrile (2.0 g), sodium azide (0.55 g) and ammonium chloride (0.43 g) in N,N-dimethylformamide (15 ml) were heated at 140° C. for 5 hrs. The cooled mixture was poured into 5%-hydrochloride solution. The solution was extracted with ethyl acetate and the separated organic layer was washed with water, dried over magnesium sulfate, and concentrated in vacuo. The crude product was recrystallized from ethanol to yield the titled product, m.p. 162°-163° C.
Reaction SMILES: [C:1]([C:3]1([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:18][CH:17]=2)[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][CH2:4]1)#[N:2].FC(F)(F)C(O)=O>ClCCl>[N:26]1([CH2:25][CH2:24][CH2:23][O:22][C:19]2[CH:20]=[CH:21][C:16]([C:3]3([C:1]#[N:2])[CH2:4][CH2:5][NH:6][CH2:7][CH2:8]3)=[CH:17][CH:18]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccc(OCCCN3CCCC3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CC1(c2ccc(OCCCN3CCCC3)cc2)CCNCC1
Temperature: 25 °C
Yield: 115.8 %

Procedure:
tert-Butyl 4-cyano-4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]piperidine-1-carboxylate (500 mg, 1.24 mmol) was stirred for 1 hour in trifluoroacetic acid (1.91 ml, 24.8 mmol) and dichloromethane (30 ml). More trifluoroacetic acid (3 ml) was added and the reaction stirred at room temperature for another hour. The reaction mixture was quenched with saturated aqueous sodium carbonate solution (15 ml) and the layers separated. The organic layer was dried over sodium sulphate and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (95:5:0.5 to 90:10:1 by volume) to provide the title compound (450 mg, 18% over 2 steps). 1H NMR (400 MHz, CD3OD) δ 1.81-1.85 (m, 4H), 1.91-2.09 (m, 6H), 2.59-2.62 (m, 4H), 2.69 (t, 2H), 2.99 (t, 2H), 3.12-3.15 (m, 2H), 4.04 (t, 2H), 6.96 (d, 2H), 7.42 (d, 2H). HRMS ESI+ m/z 314.2227 [MH]+.
Reaction SMILES: C([O:7][CH2:8][CH2:9][C@H:10]1[C@H:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:13][C:12]2([CH2:25][CH2:24][CH2:23][CH2:22]2)[O:11]1)(=O)C(C)(C)C.C(OCC[C@H]1[C@H](CC2C=CC=CC=2)OC(CC)(CC)O1)(=O)C(C)(C)C>>[CH2:15]([C@@H:14]1[O:13][C:12]2([CH2:25][CH2:24][CH2:23][CH2:22]2)[O:11][C@H:10]1[CH2:9][CH2:8][OH:7])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)C(=O)OCC[C@@H]1OC2(CCCC2)O[C@H]1Cc1ccccc1
Agent: CCC1(CC)O[C@@H](CCOC(=O)C(C)(C)C)[C@H](Cc2ccccc2)O1
Product: OCC[C@@H]1OC2(CCCC2)O[C@H]1Cc1ccccc1
Yield: 80 %

Procedure:
The substantially same method as described in Example 247 was conducted, except that 2-((2S,3S)-3-benzyl-1,4-dioxaspiro[4.4]nonan-2-yl)ethyl pivalate (Preparation example 251) was used instead of (2-((4S,5S)-5-benzyl-2,2-diethyl-1,3-dioxolan-4-yl)ethyl pivalate (Preparation example 246), to obtain the title compound (0.7 g, 80˜95%)
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.Cl[CH2:14][CH2:15][N:16]1[CH:20]=[CH:19][C:18]([C:21]([O:23]C)=[O:22])=[C:17]1[CH2:25][C:26]([O:28]C)=[O:27].[OH-].[Na+].Cl>O1CCCC1.O>[CH:25]1([C:26]([OH:28])=[O:27])[CH2:14][CH2:15][N:16]2[CH:20]=[CH:19][C:18]([C:21]([OH:23])=[O:22])=[C:17]12
Reactant: COC(=O)Cc1c(C(=O)OC)ccn1CCCl
Agent: Cl
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)c1ccn2c1C(C(=O)O)CC2
Temperature: 50 °C
Reaction time: 4 h
Yield: 95.2 %

Procedure:
n-Butyllithium (2.6M in hexane, 295.5 mL, 0.77 mol) was added dropwise at 0°-3° C., with stirring, to a solution of di(isopropyl)amine (109.3 mL, 78.9 g, 0.78 mol) in tetrahydrofuran (freshly distilled, 200 mL). The resulting solution was transferred to an addition funnel and added dropwise at room temperature to a stirred solution of methyl N-(2-chloroethyl)-3-methoxycarbonyl-2-pyrroleacetate (150.0 g, 0.58 mol) in tetrahydrofuran (dry, 750 mL). The addition took 4 hours, and the temperature was maintained in the range of 23°-27° C. The resulting solution was stirred for 16 hours, then diluted with water (500 mL) over 10 minutes with slight heat evolution. The solvents were stripped by atmospheric distillation to a pot temperature of 75° C. The pot solution was cooled to 50° C. and sodium hydroxide (53.0 g, 1.33 mol) added; then methanol was removed by atmospheric distillation to a pot temperature of 95° C.; with a total of 1370 mL of solvents collected. The pot solution was cooled to -3°-0° C. and acidified with hydrochloric acid (12M, 180 mL, 216 mmol), resulting in a temperature rise to 18° C. The resulting mixture was cooled to -3°-0° C., aged for 30 minutes at that temperature, and filtered, and the precipitate washed with ice-cold water (300 mL) and dried, to give 107.8 g of crude 2,3-dihydro-1H-pyrrolo[1,2-a]pyrrole-1,7-dicarboxylic acid. Assay of the crude material indicated that it contained 96.6% 2,3-dihydro-1H-pyrrolo-[1,2-a]pyrrole-1,7-dicarboxylic acid.
Reaction SMILES: C(O[C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:9]=1)(C)(C)C.C([Li])(C)(C)C.[O:25]=[C:26]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[O:38][C:39]([F:42])([F:41])[F:40])C(OCC)=O.[NH4+].[Cl-]>CCOCC.CCCCC.C1COCC1>[Cl:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][C:10]=1[C:15]([F:16])([F:17])[F:18])[NH:7][C:6](=[O:19])[C:26]2([OH:25])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[O:38][C:39]([F:40])([F:41])[F:42]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CCOC(=O)C(=O)c1ccccc1OC(F)(F)F
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C1Nc2cc(C(F)(F)F)c(Cl)cc2C1(O)c1ccccc1OC(F)(F)F
Temperature: -40 °C
Reaction time: 1 h
Yield: 64.1 %

Procedure:
To a solution of 4.00 g of tert-butyl[4-chloro-3-(trifluoromethyl)phenyl]carbamate in Et2O (30 ml) under cooling at −78° C. was added dropwise a solution of 1.6 mol/L tert-butyl lithium in n-pentane (21 ml), and the reaction mixture was stirred for 1 hour. Thereafter, the solution was warmed to −40° C. and was stirred under the same temperature condition for 2.5 hours. The solution was cooled again to −78° C., a solution of 4.25 g of ethyl oxo[2-(trifluoromethoxy)phenyl]acetate in THF (15 ml) was added dropwise to the reaction mixture and the reaction mixture was stirred under the same temperature condition for two hours. Thereafter, the solution was warmed to room temperature and stirred for 15 hours. To the reaction solution was added a saturated aqueous solution of NH4Cl, the resulting mixture was extracted with EtOAc, the organic layer was washed with saturated brine, dried over MgSO4 and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (silicagel 60; mobile phase: EtOAc/n-hexane=1/4; v/v) to obtain 3.57 g of the title compound (colorless powder).
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[C:12]([C:43](O)=[O:44])=[C:13]([N:28]([CH2:34][C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])[C:29](OCC)=[O:30])[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][O:26][CH3:27])=[O:24])=[CH:18][CH:17]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:46][O:47][C:48]1[CH:53]=[CH:52][C:51]([NH2:54])=[CH:50][CH:49]=1>>[CH2:1]([N:8]([CH2:10][C:11]1[C:12]2[C:43](=[O:44])[N:54]([C:51]3[CH:52]=[CH:53][C:48]([O:47][CH3:46])=[CH:49][CH:50]=3)[C:29](=[O:30])[N:28]([CH2:34][C:35]3[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=3[F:42])[C:13]=2[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][O:26][CH3:27])=[O:24])=[CH:18][CH:17]=1)[CH3:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(N)cc1
Reactant: CCOC(=O)N(Cc1c(F)cccc1F)c1sc(-c2ccc(NC(=O)NOC)cc2)c(CN(C)Cc2ccccc2)c1C(=O)O
Product: CONC(=O)Nc1ccc(-c2sc3c(c2CN(C)Cc2ccccc2)c(=O)n(-c2ccc(OC)cc2)c(=O)n3Cc2c(F)cccc2F)cc1
Yield: 62 %

Procedure:
The similar reaction as described in Example 5 by using 4-(N-benzyl-N-methylaminomethyl)-2-(N-(2,6-difluorobenzyl)-N-ethoxycarbonylamino)-5-(4-(3-methoxyureido)phenyl)thiophene-3-carboxylic acid (5.0 g, 7.83 mmol) and p-anisidine (1.93 g, 15.65 mmol) gave N-(4-(5-((benzyl(methyl)amino)methyl)-1-(2,6-difluorobenzyl)-3-(4-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea (3.39 g, 62%) as white solids. The similar reaction as described in Reference Example 18 by using the compound (80 mg, 0.11 mmol) gave the title compound (50 mg, 74%) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[CH:9][C:4]=1[CH:5]=[CH:6][CH:7]=[O:8].C(C1C(=O)C(Cl)=C(Cl)[C:21](=[O:22])C=1C#N)#N.CO>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[CH:9][C:4]=1[CH:5]=[CH:6][C:7]([O:22][CH3:21])=[O:8]
Reactant: COc1cc(OC)c(OC)cc1C=CC=O
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)C=Cc1cc(OC)c(OC)cc1OC
Yield: 84 %

Procedure:
A homogeneous mixture containing 2,4,5-trimethoxycinnamaldehyde (7.5 mmol), DDQ (11.3 mmol), MeOH (15 mL) and toluene (10 mL) is taken in a round bottom flask and catalytic amount of AMBERLITE® IR 120 (0.1 g) is added to it. The mixture is refluxed for 6 hrs under Dean Stark apparatus. After completion of the reaction (observed by TLC and by GC analysis), the reaction mixture is filtered and washed with MeOH (5 ml×2). Concentrate the filtrate under reduced pressure and the crude product thus obtained is loaded on a neutral alumina column and eluted with diethyl ether. Methyl 2,4,5-trimethoxycinnamate (from formula I where X1═OCH3, X2═H, X3═OCH3, X4═OCH3, X5═H, R═CH3) is isolated in 84% yield. 1H-NMR (CDCl3, 300 MHz) δ7.91 (1H, d, J=16.10 Hz), 7.01 (1H, s), 6.50 (1H, s), 6.37 (1H, d, J=16.10 Hz), 3.93 (3H, s), 3.88 (3H, s), 3.87 (3H, s), 3.80 (3H, s); 13C-NMR (CDCl3, 75.4 MHz) δ168.2, 153.9, 151.9, 143.4, 139.7, 116.6, 115.4, 112.6, 96.9, 56.5, 56.4, 56.1, 51.5.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:22][C:21]3[N:20]([OH:23])[C:19]4[C:14](=[CH:15][C:16]([Cl:24])=[CH:17][CH:18]=4)[C:13](=[O:25])[C:12]=3[C:11](=O)[CH2:10]2)=[CH:5][CH:4]=1.[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([NH2:36])[CH2:32][CH2:31]1>C(O)C>[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([N:36]=[C:11]2[C:12]3[C:13](=[O:25])[C:14]4[C:19](=[CH:18][CH:17]=[C:16]([Cl:24])[CH:15]=4)[N:20]([OH:23])[C:21]=3[CH2:22][CH:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:28])([F:1])[F:27])=[CH:4][CH:5]=3)[CH2:10]2)[CH2:32][CH2:31]1
Reactant: O=C1CC(c2ccc(C(F)(F)F)cc2)Cc2c1c(=O)c1cc(Cl)ccc1n2O
Reactant: CN1CCN(N)CC1
Solvent: CCO
Product: CN1CCN(N=C2CC(c3ccc(C(F)(F)F)cc3)Cc3c2c(=O)c2cc(Cl)ccc2n3O)CC1

Procedure:
40.75 g (0.1 mole) of 3-(4-trifluoromethylphenyl)-7-chloro-10-hydroxy-3,4-dihydroacridine-1,9(2H,10H)-dione are suspended in 500 ml of ethanol, 11.5 g (0.1 mole) of N-methyl-N'-aminopiperazine are added and the reaction mixture is heated to reflux for 30 minutes. A clear orange-red solution forms during this. After cooling down, the ethanol is distilled out in a rotary evaporator and the solid residue is recrystallized from toluene/cyclohexane (1:1). 43 g=85% of theory of the title compound is thus obtained in the form of orange-yellow crystals of melting point 213° C.