Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C@H:3]([F:10])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].FC(F)(F)S(O[C:17]1[C:22]([F:23])=[CH:21][C:20]([CH:24]2[CH2:29][CH2:28][Si:27]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][O:41][CH3:42])(C3C=CC=CC=3)[CH2:26][CH2:25]2)=[CH:19][C:18]=1[F:43])(=O)=O>>[CH3:42][O:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][Si@H:27]1[CH2:28][CH2:29][C@H:24]([C:20]2[CH:19]=[C:18]([F:43])[C:17]([CH2:2][C@H:3]([F:10])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[C:22]([F:23])[CH:21]=2)[CH2:25][CH2:26]1
Reactant: COCCCCC[Si]1(c2ccccc2)CCC(c2cc(F)c(OS(=O)(=O)C(F)(F)F)c(F)c2)CC1
Reactant: CCCCCC[C@@H](F)CBr
Product: CCCCCC[C@@H](F)Cc1c(F)cc([C@H]2CC[Si@H](CCCCCOC)CC2)cc1F

Procedure:
The general procedure of Example 18 was repeated using (R)-1-bromo-2-fluorooctane and (2,6-difluoro-4-(4-(5-methoxypentyl)-4-phenyl-4-silacyclohexyl)phenyl) trifluoromethanesulfonate, thereby obtaining the intended compound.
Reaction SMILES: [NH2:1][C:2](=[S:13])[C:3]1[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[O:10])[S:6][C:7]=1[CH3:8].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([C:24](=O)[CH2:25]Br)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]>>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([C:24]2[N:1]=[C:2]([C:3]3[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[O:10])[S:6][C:7]=3[CH3:8])[S:13][CH:25]=2)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: COC(=O)c1cc(C(N)=S)c(C)s1
Reactant: COc1ccc(C(=O)CBr)cc1OC
Product: COC(=O)c1cc(-c2nc(-c3ccc(OC)c(OC)c3)cs2)c(C)s1
Yield: 53 %

Procedure:
Methyl 4-[4-(3,4-dimethoxyphenyl)(1,3-thiazol-2-yl)]-5-metltylthiophene-2-carboxylate: A solution of 257 mg (0.48 mmol, based on a mixture containing 60% nitrile) of methyl 4-(aminothioxomethyl)-5-methylthiophene-2-carboxylate was reacted with 124 mg (0.48 nmuol) of 2-bromo-(3′, 4′-dimethoxy)-acetophenone (Example 31, step (a)) was reacted in a manner similar to Example 8, step (a) to give methyl 4-[4-(3,4-dimethoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiophene-2-carboxylate (95 mg, 53%) as a solid. Mass spectrum (MALDI-TOF, CHCA matrix, m/z): Calcd. for C18H17NO4S2 376.1 (M+H), found 376.3.
Reaction SMILES: [OH:1][C@H:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][C@@H:12]3[CH3:24])[C:5]=2[C@H:4]([CH3:25])[CH2:3]1.[ClH:26]>C(Cl)Cl>[ClH:26].[ClH:26].[CH3:25][C@H:4]1[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][C@@H:12]3[CH3:24])=[N:9][CH:8]=[N:7][C:6]=2[C@H:2]([OH:1])[CH2:3]1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)OC(C)(C)C)C[C@@H]3C)c21
Agent: Cl
Solvent: ClCCl
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCNC[C@@H]3C)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
T a solution of the (S)-tert-butyl 4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (0.106 g, 0.304 mmol) in DCM (20 mL) was added HCl (4M in dioxane, 4 mL). The mixture was stirred at room temperature overnight. The solvent was removed to afford (5R,7R)-5-methyl-4-((S)-2-methylpiperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (0.098 g, 99%). MS (APCI+) [M+H]+249.
Reaction SMILES: C[O:2][C:3](=O)/[CH:4]=[CH:5]/[CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[H-].C([Al+]CC(C)C)C(C)C.CCCCCC>CCOCC>[CH:6]1(/[CH:5]=[CH:4]/[CH2:3][OH:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)/C=C/C1CCCCC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Solvent: CCOCC
Product: OC/C=C/C1CCCCC1
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
29.25 g (0.174 mol) of (2E)-3-cyclohexylpropenoic acid methyl ester was dissolved in 200 ml of ether (dried over dry nap). Thereto was added 412 ml (0.383 mol) of diisobutylaluminum hydride (n-hexane solution, 0.93N) in an argon stream at -60° C. over a 15-minute period. The mixture was stirred at the same temperature for 30 minutes. n-Hexane and diethyl ether were added. The resulting mixture was washed with a saturated aqueous ammonium chloride solution, hydrochloric acid (0.2N) and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated. The concentrate was purified by silica gel column chromatography (n-hexane/ethyl acetate=19/1 to 9/1) and distillation (57.0°-58.5° C./0.40-0.42 mmHg) to obtain 20.1 g (0.143 mol) of (2E)-3-cyclohexyl-2-propen-1-ol.
Reaction SMILES: [C@@H:1]1([O:11][CH2:12][CH2:13][NH:14][C:15](=[O:58])[CH2:16][N:17]([CH2:35][C:36]([NH:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44](OC2C(F)=C(F)C(F)=C(F)C=2F)=[O:45])=[O:37])[CH2:18][C:19](=[O:34])[NH:20][CH2:21][CH2:22][O:23][C@@H:24]2[O:32][C@@H:31]([CH3:33])[C@@H:29]([OH:30])[C@@H:27]([OH:28])[C@@H:25]2[OH:26])[O:9][C@@H:8]([CH3:10])[C@@H:6]([OH:7])[C@@H:4]([OH:5])[C@@H:2]1[OH:3].Cl.[NH2:60][CH2:61][C@@H:62]([C:81]([OH:83])=[O:82])[NH:63][C:64]([O:66][CH2:67][CH:68]1[C:80]2[CH:79]=[CH:78][CH:77]=[CH:76][C:75]=2[C:74]2[C:69]1=[CH:70][CH:71]=[CH:72][CH:73]=2)=[O:65].CCN(C(C)C)C(C)C>CN(C=O)C>[O:58]=[C:15]([NH:14][CH2:13][CH2:12][O:11][C@@H:1]1[O:9][C@@H:8]([CH3:10])[C@@H:6]([OH:7])[C@@H:4]([OH:5])[C@@H:2]1[OH:3])[CH2:16][N:17]([CH2:35][C:36]([NH:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44]([NH:60][CH2:61][C@@H:62]([C:81]([OH:83])=[O:82])[NH:63][C:64]([O:66][CH2:67][CH:68]1[C:69]2[CH:70]=[CH:71][CH:72]=[CH:73][C:74]=2[C:75]2[C:80]1=[CH:79][CH:78]=[CH:77][CH:76]=2)=[O:65])=[O:45])=[O:37])[CH2:18][C:19]([NH:20][CH2:21][CH2:22][O:23][C@@H:24]1[O:32][C@@H:31]([CH3:33])[C@@H:29]([OH:30])[C@@H:27]([OH:28])[C@@H:25]1[OH:26])=[O:34]
Reactant: C[C@@H]1O[C@@H](OCCNC(=O)CN(CC(=O)NCCCCCC(=O)Oc2c(F)c(F)c(F)c(F)c2F)CC(=O)NCCO[C@@H]2O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]2O)[C@@H](O)[C@H](O)[C@@H]1O
Reactant: NC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H]1O[C@@H](OCCNC(=O)CN(CC(=O)NCCCCCC(=O)NC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)CC(=O)NCCO[C@@H]2O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]2O)[C@@H](O)[C@H](O)[C@@H]1O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of pentafluorophenyl 6-[({bis[2-({2-[(α-L-fucopyranosyl)oxy]ethyl}amino)-2-oxoethyl]amino}acetyl)amino]hexanoate (270 mg, 0.318 mmol) in DMF at 0° C. was added 3-amino-N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-alanine hydrochloride (303 mg, 0.306 mmol) and, 5 min later, DIPEA (111 μL, 0.636 mmol). After stirring at 0° C. for 2 hr, the reaction mixture was concentrated and the residue was purified by flash chromatography on silica gel (22 g), eluting first with 100 mL of EtOAc and then 0-20% of Solvent B in Solvent A (Solvent A: v/v EtOAc/MeOH/AcCN/H2O: 6/1/1/1; Solvent B v/v EtOAc/MeOH/AcCN/H2O: 2/1/1/1) to afford the title compound. LC-MS Method A: m/e=991.66 [M+1]; Rt=1.84 min.
Reaction SMILES: P(Br)(Br)[Br:2].[CH2:5]([N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[N:17])[CH:14]=2)[CH:9]=[C:8]1[CH2:18]O)[CH3:6]>ClCCl>[C:16]([C:13]1[CH:14]=[C:15]2[C:10]([CH:9]=[C:8]([CH2:18][Br:2])[N:7]2[CH2:5][CH3:6])=[CH:11][CH:12]=1)#[N:17]
Reactant: BrP(Br)Br
Reactant: CCn1c(CO)cc2ccc(C#N)cc21
Solvent: ClCCl
Product: CCn1c(CBr)cc2ccc(C#N)cc21
Temperature: 0 °C
Reaction time: 4 h

Procedure:
In a 500 ml flask, 18.2 g of 1-ethyl-2-(hydroxymethyl)indole-6-carbonitrile was dissolved in 200 ml of dichloromethane and then cooled to 0° C. 3.45 ml of PBr3 was slowly added thereto, and the mixture was stirred for 4 hours at room temperature. dichloromethane was then added and the reaction mixture was washed with aqueous Na2CO3 solution, diluted with water and then extracted three times with dichloromethane. The organic extracts were combined, dried over MgSO4 and then evaporated to obtain 6-cyano-1-ethyl-2-bromomethyl indole. The resulting product was dissolved in 200 ml of toluene and 30.9 g of triphenylphosphine was added thereto. The mixture was stirred for 10 hours at refluxing temperature and then cooled to room temperature. To this reaction solution was added diethyl ether, and the resulting precipitate was then filtered, washed several times with diethyl ether and dried to obtain 29 g of the title compound as a pale brown solid.
Reaction SMILES: [O:1]=[C:2]1[C:11](=[O:12])[NH:10][C:9]2[C:4](=[CH:5][C:6]([N:13]3[CH:17]=[CH:16][N:15]=[CH:14]3)=[CH:7][CH:8]=2)[N:3]1[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].[OH-].[Na+].[N+:26]([O-])([OH:28])=[O:27]>>[O:1]=[C:2]1[C:11](=[O:12])[NH:10][C:9]2[C:4](=[CH:5][C:6]([N:13]3[CH:17]=[CH:16][N:15]=[CH:14]3)=[C:7]([N+:26]([O-:28])=[O:27])[CH:8]=2)[N:3]1[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)Cn1c(=O)c(=O)[nH]c2ccc(-n3ccnc3)cc21
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)Cn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c(-n3ccnc3)cc21
Temperature: 25 °C
Yield: 26 %

Procedure:
At the temperature of 0C or less, 3.63 g of ethyl 2-[2,3-dioxo-7-(1H-imidazol-1-yl)-1,2,3,4-tetrahydroquinoxalin-1-yl]acetate was dissolved in 15 ml of fuming nitric acid under stirring. The resulting solution was heated to room temperature, stirred for one hour, and poured into ice water, followed by adjustment to about pH 2.0 with an aqueous solution of sodium hydroxide. The resulting insoluble matter was removed by filtration. To the filtrate, an aqueous solution of sodium hydroxide was added to adjust the pH of the resulting liquid to about pH 6.5. The resulting insoluble matter was collected by filtration, washed with water and dried under reduced pressure to give 1.07 g (26%, purity: about 95% (HPLC)) of ethyl 2-[2,3-dioxo-7-(1H-imidazol-1-yl)-6-nitro-1,2,3,4-tetrahydroquinoxalin-1-yl]acetate.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:23])[N:4]([C:19]([CH3:22])([CH3:21])[CH3:20])[N:5]=[CH:6][C:7]=1[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][CH:11]=1.S(OCC)(O[CH2:28]C)(=O)=O>>[Cl:1][C:2]1[C:3](=[O:23])[N:4]([C:19]([CH3:20])([CH3:22])[CH3:21])[N:5]=[CH:6][C:7]=1[NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([O:18][CH3:28])=[O:17])=[CH:14][CH:15]=1
Reactant: CC(C)(C)n1ncc(NCc2ccc(C(=O)O)cc2)c(Cl)c1=O
Reactant: CCOS(=O)(=O)OCC
Product: COC(=O)c1ccc(CNc2cnn(C(C)(C)C)c(=O)c2Cl)cc1

Procedure:
The compounds as identified in Table 12 were prepared in the synthetic manner and after-treatment similar to those in Example 5 except that the carboxylic acids with Y1, Y2, Y3, R1, R2 and R3 as identified in Table 12 were used instead of the starting 4-chloro-5-(4-carboxybenzylamino)-2-t-butyl-3(2H)pyridazinone used in Example 5. For the preparation of Compound No. 52, diethyl sulfate was used as an esterifying agent. In the NMR data, only the characteristic absorptions are given in Table 12.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:9]=1[Cl:10])[C:5]#[N:6].[O:17](C(OC(C)(C)C)=O)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=O.C(N(CC)CC)C>ClCCl>[NH2:1][C:2]1[C:9]([Cl:10])=[C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:17])[CH2:13][CH2:12]2)[CH:7]=[C:4]([C:5]#[N:6])[CH:3]=1
Reactant: N#Cc1cc(N)c(Cl)c(N2CCNCC2)c1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2cc(C#N)cc(N)c2Cl)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.5 %

Procedure:
(I11C): To the stirred solution of 3-amino-4-chloro-5-(piperazin-1-yl)benzonitrile (1.0 g, 4.22 mmol) in dichloromethane (10 mL) was added BOC2O (0.981 mL, 4.22 mmol) at 0° C., drop wise over a period of 10 minutes followed by triethylamine (0.883 mL, 6.34 mmol). The reaction mixture was allowed to warm to room temperature, stirred it for 1 hour. The reaction mixture was diluted with methylene chloride (100 mL), washed with brine (30 mL), dried over Na2SO4 and concentrated at 45° C. to get tert-butyl 4-(3-amino-2-chloro-5-cyanophenyl)piperazine-1-carboxylate (1.4 g) as a brown solid. The crude material was washed with diethyl ether four times and dried under vacuum to get tert-butyl 4-(3-amino-2-chloro-5-cyanophenyl)piperazine-1-carboxylate (1.4 g) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:12].N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>C(Cl)Cl.CCOC(C)=O>[C:21]([Si:18]([O:12][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([F:10])([F:11])[F:9])[C:2]=1[Cl:1])([CH3:20])[CH3:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1cccc(C(F)(F)F)c1Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C(F)(F)F)c1Cl
Reaction time: 0.08 h
Yield: 99.4 %

Procedure:
To a solution of 2-chloro-3-trifluoromethyl-phenol (509 mg, 2.59 mmol) in CH2Cl2 (20 mL) was added imidazole (264 mg, 3.88 mmol). The mixture was stirred for 5 minutes, to which was added portionwise tert-butyldimethylsilyl chloride (467 g, 3.1 mmol). The mixture was stirred for 2 hours at room temperature and was diluted with EtOAc. The crude mixture was washed with 1N HCl, water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography to give tert-butyl-(2-chloro-3-trifluoromethyl-phenoxy)-dimethyl-silane (800 mg, 99%).
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]([CH:15]([NH:17][C:18]1[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:25])[CH3:16])([O:13][CH3:14])=[O:12]>C1(C)C=CC=CC=1.CN(C)C=O>[CH3:24][C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:25])[C:18]=1[N:17]([CH:15]([C:11]([O:13][CH3:14])=[O:12])[CH3:16])[C:8](=[O:9])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C(C)Nc1c(C)cccc1C
Reactant: O=C(Cl)Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)C(C)N(C(=O)Cc1ccccc1)c1c(C)cccc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
17 g (0.11 mol) of phenylacetylchloride were added dropwise in 30 minutes and at room temperature, to a solution of N-(1-carbomethoxy-ethyl)-2,6-dimethyl-aniline(21.2 g at a purity of 95%, 0.1 mol) in toluene (150 ml) and dimethylformamide (1 ml.). The reaction mixture was stirred 1 hour at room temperature and 3 hours at reflux temperature, then it was cooled down to room temperature and washed with an aqueous solution of NaHCO3 at 5% and successively with water. The organic phase was separated and anhydrified with anhydrous Na2SO4. The solvent was evaporated and the rough product obtained was recrystallized from ligroin (75°-120° C.), so obtaining 26 g. of the desired product (white solid, m.p. 78°-80° C.).
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:39]=[CH:38][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[C@@H:21]2[CH2:30][CH2:29][C:28]3[CH:27]=[C:26]([O:31]C(=O)C(C)(C)C)[CH:25]=[CH:24][C:23]=3[CH2:22]2)=[CH:7][CH:6]=1)(O)=O.[CH2:40]([NH:42][CH2:43][CH3:44])[CH3:41]>>[CH2:40]([N:42]([CH2:43][CH3:44])[CH2:1][CH2:4][C:5]1[CH:39]=[CH:38][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[C@@H:21]2[CH2:30][CH2:29][C:24]3[CH:25]=[C:26]([OH:31])[CH:27]=[CH:28][C:23]=3[CH2:22]2)=[CH:7][CH:6]=1)[CH3:41]
Reactant: CCNCC
Reactant: COc1ccc([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCc2ccc(CC(=O)O)cc2)c1
Product: CCN(CC)CCc1ccc(CCCNc2cc(OC)ccc2[C@@H]2CCc3cc(O)ccc3C2)cc1
Yield: 11.5 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(4-carboxymethylbenzyl)ethylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and diethylamine (12 mg) according to an analogous synthetic method to Example 715 and purified by LC-MS, the title compound (2.0 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.C(O[CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])C>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:5][CH:4]=1
Reactant: COc1ccc(N)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1ccc(OC)cc1)C(=O)OCC
Temperature: 130 °C
Yield: 98.7 %

Procedure:
A mixture of p-anisidine (2.20 g, 17.9 mmol) and diethyl ethoxymethylenemalonate 3.6 mL, 17.9 mmol) is heated at 130° C. for 2 h. While warm, the mixture is evacuated, then cooled to give 5.18 g of diethyl (4-methoxyphenylaminomethylene)malonate as an oil.
Reaction SMILES: [F:1][C:2]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[F:23])[C:17](Cl)=[O:18].C(N(CC)CC)C>ClCCl>[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[F:23])[C:17]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[C:8]([C:9]([F:10])([F:11])[F:12])[C:2]=1[F:1])=[O:18]
Reactant: O=C(Cl)c1ccc(F)c(Br)c1
Reactant: Nc1cccc(C(F)(F)F)c1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(C(F)(F)F)c1F)c1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Fluoro-3-(trifluromethyl)aniline (0.515 g, 0.37 mL, 2.88 mmol) was added to a solution of 3-bromo-4-fluorobenzoyl chloride (0.650 g, 2.74 mmol) in dichloromethane (5 ml), and the mixture stirred at room temperature for 30 min. Triethylamine (0.360 g, 0.50 ml, 3.56 mmol) was added and the solution stirred at room temperature for 1 h. The reaction mixture was partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The aqueous phase was separated and extracted with dichloromethane. The combined organic phases were washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a light yellow solid. Trituration with dichloromethane and filtering afforded 3-bromo-4-fluoro-N-(2-fluoro-3-(trifluoromethyl)phenyl)benzamide as a white solid. MS (M−H+) 377.9; Calculated for C14H7BrF5NO: 379.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(Cl)(=O)C([Cl:28])=O>>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([Cl:28])=[O:21])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1
Product: CCCCCCCCOc1ccc(-c2ccc(C(=O)Cl)cc2)cc1

Procedure:
4-[4-Octyloxyphenyl]benzoic acid (OPBA) was converted into its acid chloride, OPBC, by heating it at reflux with oxalyl chloride after which excess oxalyl chloride was allowed to distil out and the residue taken up in ethanol free chloroform.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[H-].[Na+].[CH2:19](I)[CH3:20]>O>[CH2:19]([NH:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:20]
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCNc1ccc(Cl)cc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
To a solution of 6.95 g of 2-amino-5-chlorobenzophenone was added portionwise 1.37 g of 63 % sodium hydride. After the mixture was stirred at room temperature for 30 minutes, 5.62 g of ethyl iodide was added dropwise thereto, and the reaction mixture was further stirred at room temperature for 2 hours. Then, the mixture was poured into 400 ml of water and extracted twice with 100 ml of methylene chloride. The extracts were combined, washed with diluted hydrochloric acid, followed by water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was chromatographed on silica gel using chloroform as an eluent to give 7.1 g of 2-ethylamino-5-chlorobenzophenone as red oil, which was recrystalized from ethanol-cyclohexane to give yellow prisms having a melting point of 57° - 58° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][NH:7][C:6](=O)[C:5]=2[CH:4]=[C:3]1[CH3:16].P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:6]1[C:5]2[CH:4]=[C:3]([CH3:16])[N:2]([CH3:1])[C:10]=2[C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][N:7]=1
Reactant: COC(=O)c1c[nH]c(=O)c2cc(C)n(C)c12
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cnc(Cl)c2cc(C)n(C)c12

Procedure:
A solution of methyl 1,2-dimethyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-7-carboxylate (1.311 g) in phosphorus oxychloride (7 ml) was heated under reflux for four hours, then evaporated under reduced pressure. The residual liquid was added to a mixture of ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous layer was extracted with a further portion of ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium bicarbonate and then water. After filtering the water and ethyl acetate mixture, the organic phase washed with brine, dried (MgSO4) and evaporated. Purification by chromatography on silica gel (ethyl acetate/toluene) afforded the title compound as a pale cream solid 1.027 g.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].[CH:29]([C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38]([OH:40])=[O:39])=[CH:33][CH:32]=1)=O>>[C:38]([CH2:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:29][CH2:2][CH2:1][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=2[C@@H:12]2[CH2:21][CH2:20][C:19]3[CH:18]=[C:17]([O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[CH:16]=[CH:15][C:14]=3[CH2:13]2)=[CH:32][CH:33]=1)([OH:40])=[O:39]
Reactant: CCNc1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=Cc1ccc(CC(=O)O)cc1
Product: COc1ccc([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCc2ccc(CC(=O)O)cc2)c1
Yield: 92.2 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (296 mg) and (4-formylphenyl)acetic acid (630 mg) according to an analogous synthetic method to Example 212, the title compound (379 mg) was obtained.
Reaction SMILES: [O:1]=[O+][O-].C=[C:5]1[CH2:8][CH:7]([C:9]([O:11][CH2:12][CH2:13][CH3:14])=[O:10])[CH2:6]1.CSC>CO>[O:1]=[C:5]1[CH2:8][CH:7]([C:9]([O:11][CH2:12][CH2:13][CH3:14])=[O:10])[CH2:6]1
Reactant: O=[O+][O-]
Reactant: C=C1CC(C(=O)OCCC)C1
Solvent: CSC
Solvent: CO
Product: CCCOC(=O)C1CC(=O)C1
Temperature: 25 °C
Yield: 88 %

Procedure:
An ozone gas was blown into a solution (200 mL) of propyl 3-methylidenecyclobutanecarboxylate (15 g) in methanol at −78° C. for 2 hr. Dimethyl sulfide (21 g) was added to the reaction mixture at the same temperature, and the mixture was warmed to room temperature over 1 hr. The obtained mixture was concentrated and purified by silica gel column chromatography to give the title compound as a colorless oil (13 g, 88%).
Reaction SMILES: [C:1]1([C:7]2[NH:11][CH:10]=[C:9]([CH:12]=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.Cl[S:32]([C:35]1[CH:36]=[C:37]([CH:42]=[CH:43][CH:44]=1)[C:38]([O:40][CH3:41])=[O:39])(=[O:34])=[O:33]>>[CH:12]([C:9]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:11]([S:32]([C:35]2[CH:36]=[C:37]([CH:42]=[CH:43][CH:44]=2)[C:38]([O:40][CH3:41])=[O:39])(=[O:34])=[O:33])[CH:10]=1)=[O:13]
Reactant: O=Cc1c[nH]c(-c2ccccc2)c1
Reactant: COC(=O)c1cccc(S(=O)(=O)Cl)c1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1cccc(S(=O)(=O)n2cc(C=O)cc2-c2ccccc2)c1
Yield: 68.8 %

Procedure:
Using 5-phenyl-1H-pyrrole-3-carbaldehyde (1.32 g), sodium hydride (60% in oil, 444 mg), 15-crown-5 (2.04 g) and methyl 3-(chlorosulfonyl)benzoate (2.17 g), a procedure as in Reference Example 219 was performed to give the title compound as a pale-yellow oil (yield 1.96 g, 69%).