Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[CH:13]1(Br)[CH2:17][CH2:16][CH2:15][CH2:14]1.N12CCCN=C1CCCCC2>CN(C)C=O>[CH:13]1([O:1][N:2]2[C:3](=[O:12])[C:4]3[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:7])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: BrC1CCCC1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1c2ccccc2C(=O)N1OC1CCCC1
Temperature: 55 °C
Reaction time: 1.5 h
Yield: 80.2 %

Procedure:
A mixture of N-hydroxypthalimide (10.00 g, 61.3 mmol), cyclopentylbromide (8.21 mL, 76.63 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (13.75 mL, 76.6 mmol) were combined under an Argon atmosphere in dimethylformamide (50 mL). The mixture was heated to 55° C. and stirred vigorously for 1.5 hours. After cooling to ambient temperature, the solvent was removed in vacuo and the residue was partitioned between ethyl acetate and 1N hydrochloric acid. After separating the phases, the aqueous layer was extracted again with ethyl acetate. The combined organic layers were washed with 5% w/v potassium carbonate, saturated aqueous brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue was triturated with hexane, filtered, and dried under high vacuum to provide 2-(cyclopentyloxy)-1H-isoindole-1,3(2H)-dione (11.37 g, 80%). H1-NMR (chloroform-D3): 1.61 (m, 2H), 1.77 (m, 2H), 1.97 (m, 4H), 4.91 (m, 1H), 7.73 (m, 2H), 7.82 (m, 2H). MS(ESI): 254 (M+Na).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22].N1C=CC=CC=1.[C:31]1([CH3:41])[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>C(Cl)Cl>[S:37]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])([C:34]1[CH:35]=[CH:36][C:31]([CH3:41])=[CH:32][CH:33]=1)(=[O:39])=[O:38]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)CCCCCCCCCCCCCCCCCCCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)CCCCCCCCCCCCCCCCCCCS(=O)(=O)c1ccc(C)cc1
Reaction time: 14 h
Yield: 94 %

Procedure:
In 90 ml of methylene chloride was dissolved methyl 20-hydroxyeicosanoate (8.0 g, 23.4 mmoles). To the obtained solution were added pyridine (7.93 g, 93.4 mmoles) and then, under ice-cooling, p-toluenesulfonyl chloride (8.90 g, 46.7 mmoles) gradually over a period of 1 hour. The mixture was stirred for 14 hours in a refrigerator. After the completion of the reaction, the reaction mixture was subjected to the same after-treatment steps as in Reference Example 1, to give methyl 20-tosyleicosanoate (10.57 g, 91%) having the following properties.
Reaction SMILES: [C@@H:1]12[N:8]([CH3:9])[C@@H:5]([CH2:6][CH2:7]1)[CH:4]([NH:10][C:11]([C:13]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][N:14]=1)=[O:12])[CH2:3][CH2:2]2.[H-].[Na+].I[CH:25]([CH3:27])[CH3:26]>CN(C)C=O>[C@@H:1]12[N:8]([CH3:9])[C@@H:5]([CH2:6][CH2:7]1)[CH:4]([NH:10][C:11]([C:13]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH:25]([CH3:27])[CH3:26])[N:14]=1)=[O:12])[CH2:3][CH2:2]2
Reactant: CC(C)I
Reactant: CN1[C@H]2CCC(NC(=O)c3n[nH]c4ccccc34)[C@@H]1CC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1nc(C(=O)NC2CC[C@H]3CC[C@@H]2N3C)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.2 %

Procedure:
To a solution of N-(tropan-4-yl)-1H-indazole-3-carboxamide (2.98 g, 10 mmol) in 75 mL of dimethylformamide under a nitrogen atmosphere was added, in portions, sodium hydride (60% dispersion in mineral oil, 420 mg, 10 mmol). The resulting solution was allowed to stir for about 1 hour at room temperature before adding 2-iodopropane (1.2 mL, 12 mmol). This resulting solution was allowed to stir at room temperature for about 18 hours. The dimethylformamide was evaporated under reduced pressure and the residue was dissolved in about 100 mL of 1N hydrochloric acid. The acidic solution was washed with ethyl acetate and then cooled before making it basic with saturated aqueous sodium carbonate. The basic mixture was extracted 3 times with methylene chloride. The extracts were washed with brine, dried over sodium sulfate, filtered, then evaporated under reduced pressure to give a viscous oil. The oil was purified by preparative HPLC (gradient methylene chloride:methanol 0-25%, 1% ammonium hydroxide) to give 2.52 g of an oil. Yield: 77%. MS(FD) M+ 326.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:13])[CH:8]=2)[N:3]=1.[Br:14][C:15]1[CH:16]=[CH:17][C:18]2[CH2:24][NH:23][CH2:22][CH2:21][CH2:20][C:19]=2[CH:25]=1.C(O)CCC>C(OCC)(=O)C>[Br:14][C:15]1[CH:16]=[CH:17][C:18]2[CH2:24][N:23]([C:2]3[CH:11]=[C:10]([Cl:12])[C:9]4[C:4](=[CH:5][CH:6]=[C:7]([Cl:13])[CH:8]=4)[N:3]=3)[CH2:22][CH2:21][CH2:20][C:19]=2[CH:25]=1
Reactant: Clc1ccc2nc(Cl)cc(Cl)c2c1
Reactant: Brc1ccc2c(c1)CCCNC2
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: Clc1ccc2nc(N3CCCc4cc(Br)ccc4C3)cc(Cl)c2c1
Temperature: 160 °C
Reaction time: 1 h
Yield: 40.8 %

Procedure:
The mixture of 2,4,6-trichloroquinoline (300 mg, 1.29 mmol), 7-bromo-2,3,4,5-tetrahydro-1H-2-benzazepine (291 mg, 1.29 mmol) and n-butanol (3 mL) was heated with stirring in a 10 mL microwave process vial for 1 hour at 160° C. under microwave irradiation. The mixture was cooled to room temperature and diluted with ethyl acetate (10 mL), and then washed with water (10 mL). The organic layer was dried over sodium sulfate and evaporated to give a residue which was purified by column chromatography on silica gel to give 222 mg of product as a white solid (yield was 41%). MS obsd. (ESI+) [(M+H)+] 421.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]([CH3:12])[C:8]([NH:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.[F:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[F:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([CH3:12])[C:8]([NH:10][CH3:11])=[O:9])=[CH:13][CH:14]=1
Reactant: CNC(=O)C(C)Oc1ccc(O)cc1
Reactant: Fc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CNC(=O)C(C)Oc1ccc(OCc2ccccc2F)cc1

Procedure:
In analogy to the procedure described in Example 3b), the alkylation of (RS)-2-(4-hydroxy-phenoxy)-N-methyl-propionamide with 2-fluoro-benzylbromide in 2-butanone using potassium carbonate as the base yielded the (RS)-2-[4-(2-fluoro-benzyloxy)-phenoxy]-N-methyl-propionamide as white crystals; MS: m/e=304 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([NH2:12])(=[O:11])=[O:10].[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>C(#N)C>[N:13]1([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[S:9]([NH2:12])(=[O:11])=[O:10])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C1CCNC1
Reactant: NS(=O)(=O)c1ccccc1CCl
Solvent: CC#N
Product: NS(=O)(=O)c1ccccc1CN1CCCC1
Reaction time: 1 h
Yield: 92.8 %

Procedure:
A solution of 2-(chloromethyl)benzenesulfonamide (2.00 g, 10 mmol) in acetonitrile (20 ml) was contacted with pyrrolidine (1.6 ml, 20 mmol). After 1.0 hr at ambient temperature, the volatiles were removed under vacuum and the residue was treated with water (40 ml) and chilled. The resulting solid was pulverized, filtered, and dried to give 2.23 g of white solid, m.p. 110°-112°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH3:13])=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:10][N:9]=2)=[CH:4][CH:3]=1.C1C(=O)N([Br:26])C(=O)C1>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:26][CH2:13][C:12]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[N:9][O:10][C:11]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1onc(-c2ccc(F)cc2)c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1onc(-c2ccc(F)cc2)c1CBr
Yield: 109.5 %

Procedure:
Ethyl 3-(4-fluorophenyl)-4-methylisoxazole-5-carboxylate (8.6 g, 34.5 mmol), NBS (6.8 g, 38.0 mmol), and benzoyl peroxide (0.84 g, 3.45 mmol) were added to 200 mL of carbon tetrachloride and the mixture was refluxed for 16 h. The reaction mixture was filtered and the filtrate was removed in vacuo to give 12.4 g of the title compound. 1H NMR (CDCl3, 200 MHz): δ=9.21 (s, 1H), 7.75-7.85 (m, 2H), 7.22-7.32 (m, 2H), 4.66 (s, 2H), 4.54 (q, 2H, J=7.0 Hz), 1.41 (t, 3H, J=7.0 Hz).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=2)[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=3)[C:10]3[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(C(F)(F)F)cc23)cc1OC
Product: COc1ccc(CNc2nc(-n3cccn3)nc3sc(C(F)(F)F)cc23)cc1OC

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with yields 2-chloro-6-trifluoromethyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-trifluoromethyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([C:3]1[CH:30]=[CH:29][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[C:10]([O:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[N:9]=2)=[CH:5][CH:4]=1)#[N:2].[C:31]([O:35][C:36](=[O:46])[NH:37][CH2:38][CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)([CH3:34])([CH3:33])[CH3:32]>>[C:31]([O:35][C:36](=[O:46])[NH:37][CH2:38][CH2:39][CH:40]1[CH2:41][CH2:42][N:43]([C:12]([C:11]2[C:10]([O:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:26])([F:27])[F:28])=[CH:20][CH:19]=3)=[N:9][C:8]([O:7][C:6]3[CH:29]=[CH:30][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)=[CH:16][CH:15]=2)=[O:13])[CH2:44][CH2:45]1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)NCCC1CCNCC1
Reactant: N#Cc1ccc(Oc2ccc(C(=O)O)c(Oc3ccc(OC(F)(F)F)cc3)n2)cc1
Product: CC(C)(C)OC(=O)NCCC1CCN(C(=O)c2ccc(Oc3ccc(C#N)cc3)nc2Oc2ccc(OC(F)(F)F)cc2)CC1
Yield: 66.5 %

Procedure:
6-(4-Cyano phenoxy)-2-(4-trifluoromethoxy phenoxy)nicotinic acid (0.15 g, 0.36 mmol) and (2-piperidin-4-yl-ethyl)-carbamic acid tert-butyl ester (0.082 g, 0.36 mmol) were coupled using the procedure of Example 5(c) to afford 0.15 g of the required product. Percentage purity (LCMS): 43.23%.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH2:9][CH2:10][CH2:11][CH3:12])[CH:6]=[CH:5][C:3]=1[NH2:4].O[CH2:14][CH:15]([CH2:17]O)O>>[CH2:9]([C:7]1[CH:6]=[C:5]2[C:3](=[C:2]([Br:1])[CH:8]=1)[N:4]=[CH:17][CH:15]=[CH:14]2)[CH2:10][CH2:11][CH3:12]
Reactant: OCC(O)CO
Reactant: CCCCc1ccc(N)c(Br)c1
Product: CCCCc1cc(Br)c2ncccc2c1

Procedure:
2-bromo-4-(n-butyl)aniline and glycerol can be combined to form 6-(n-butyl)-8-bromoquinoline,
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([CH:18]2OCC[O:19]2)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1>C(O)=O>[Cl:1][C:2]1[CH:17]=[C:16]([CH:18]=[O:19])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1
Reactant: NC(=O)c1ccc(Oc2ccc(C3OCCO3)cc2Cl)cn1
Solvent: O=CO
Product: NC(=O)c1ccc(Oc2ccc(C=O)cc2Cl)cn1
Yield: 85.5 %

Procedure:
Using a method similar to Example 403, Part B, a reaction of 5-(2-chloro-4-[1,3]dioxolan-2-ylphenoxy)pyridine-2-carboxamide (0.263 g, 0.820 mmol) in 88% formic acid gives the title compound (0.194 g, 85.5%): TOF MS ES− 277.0 (M+H)+, HRMS calcd for C13H10N2O3Cl 277.0380 (M+H)+, found 277.0378, time 0.38 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=10.3 min. 100% purity.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:6]([CH3:8])([CH3:7])[O:5][B:4](C2CC3(CC(C(OC)=O)C3)C=2)[O:3]1.[C:21]([NH:24][C:25]1([C:39]([O:41][CH3:42])=[O:40])[CH2:30][CH2:29][C:28](OS(C(F)(F)F)(=O)=O)=[CH:27][CH2:26]1)(=[O:23])[CH3:22]>>[C:21]([NH:24][C:25]1([C:39]([O:41][CH3:42])=[O:40])[CH2:30][CH2:29][C:28]([B:4]2[O:5][C:6]([CH3:8])([CH3:7])[C:2]([CH3:20])([CH3:1])[O:3]2)=[CH:27][CH2:26]1)(=[O:23])[CH3:22]
Reactant: COC(=O)C1(NC(C)=O)CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: COC(=O)C1CC2(C=C(B3OC(C)(C)C(C)(C)O3)C2)C1
Product: COC(=O)C1(NC(C)=O)CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Yield: 48.4 %

Procedure:
The title compound was prepared following the method described in step 2 for the preparation of methyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[3.3]hept-5-ene-2-carboxylate, using methyl 1-acetamido-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-enecarboxylate as the reactant. (48.4% yield). MS: m/e 325.25 (M+H)+, 2.126 min (method 8). 1H NMR (400 MHz, CHLOROFORM-d) δ 6.42 (br. s., 1H), 5.90 (s, 1H), 3.83-3.59 (m, 3H), 2.65 (d, J=18.8 Hz, 1H), 2.35 (d, J=18.1 Hz, 1H), 2.25 (d, J=11.0 Hz, 2H), 2.13-2.03 (m, 1H), 1.98-1.90 (m, 3H), 1.88-1.75 (m, 1H), 1.36-1.18 (m, 12H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[NH:26][C:25]([CH2:27][NH:28]C(=O)OC(C)(C)C)=[CH:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[ClH:36].C(O)C>O1CCCC1>[ClH:1].[ClH:36].[NH2:28][CH2:27][C:25]1[NH:26][C:19]2[C:18]([NH:17][C:4]3[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]4[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=4)=[C:2]([Cl:1])[CH:3]=3)=[N:23][CH:22]=[N:21][C:20]=2[CH:24]=1
Reactant: CC(C)(C)OC(=O)NCc1cc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2[nH]1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: NCc1cc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2[nH]1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl [4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-6-yl]methylcarbamate (500 mg) in tetrahydrofuran (12 mL) was added 2N hydrochloric acid (6.0 mL) at room temperature. The mixture was stirred at 60° C. for 2 hrs, ethanol was added to the reaction system and the mixture was concentrated under reduced pressure. The resultant crystals were collected by filtration and washed with diisopropyl ether to give the title compound (481.4 mg) as pale-yellow powder crystals.
Reaction SMILES: C([O:5][C:6](=[O:20])[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C@@H:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:9]1=[O:19])(C)(C)C.[CH3:21][O:22][C:23]1[CH:48]=[CH:47][C:26]([CH2:27][CH:28]([CH2:32][C:33](=[O:46])[N:34]2[CH2:39][CH2:38][N:37]([C:40]3[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=3)[CH2:36][CH2:35]2)[C:29](O)=[O:30])=[CH:25][CH:24]=1.Cl.C(N=C=NCCCN(C)C)C>C(#N)C>[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:27][C@@H:28]([CH2:32][C:33](=[O:46])[N:34]2[CH2:35][CH2:36][N:37]([C:40]3[CH:41]=[CH:42][N:43]=[CH:44][CH:45]=3)[CH2:38][CH2:39]2)[C:29]([N:11]2[CH2:12][CH2:13][N:8]([CH2:7][C:6]([OH:5])=[O:20])[C:9](=[O:19])[CH:10]2[CH2:14][C:15]([O:17][CH3:18])=[O:16])=[O:30])=[CH:47][CH:48]=1
Reactant: COC(=O)C[C@@H]1NCCN(CC(=O)OC(C)(C)C)C1=O
Reactant: COc1ccc(CC(CC(=O)N2CCN(c3ccncc3)CC2)C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Product: COC(=O)CC1C(=O)N(CC(=O)O)CCN1C(=O)[C@H](CC(=O)N1CCN(c2ccncc2)CC1)Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 58.5 %

Procedure:
To a suspension of (S)-(3-methoxycarbonylmethyl-2-oxopiperazin-1-yl)acetic acid tert-butyl ester (0.29 g) and 2-(4-methoxybenzyl)-4-oxo-4-(4-pyridin-4-ylpiperazin-1-yl)butanoic acid (0.385 g) produced in Reference Example 9 in acetonitrile (30 ml) was added 1-ethyl-3-(3-di-methylaminopropyl)carbodiimide hydrochloride (0.4 g) and the suspension was stirred for 24 hours at room temperature. The reaction mixture was concentrated under reduced pressure and purified by means of a silica gel column chromatography (acetonitrile:methanol=7:3). To the produced ester derivative was added trifluoroacetic acid (6 ml) and the solution was stirred for 2 hours at room temperature. The reaction mixture was concentrated under reduced pressure and the concentrate was purified by means of CHP-20 column chromatography (H2O→20% acetonitrile aqueous solution). The objected fraction was concentrated and subjected to lyophilization to give the titled compound (0.35 g) as a white amorphous powdery product.
Reaction SMILES: [CH3:1][P:2](Cl)([CH3:4])=[O:3].[CH2:6]([OH:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>ClCCl>[CH3:1][P:2]([CH3:4])(=[O:3])[O:13][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OCc1ccccc1
Reactant: CP(C)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CP(C)(=O)OCc1ccccc1

Procedure:
To a cooled (0°) solution of dimethylphosphinyl chloride (3.4 g., 0.03 moles) in dichloromethane (50 ml.) is added dropwise (over a period of 20 minutes), with stirring, a solution of benzyl alcohol (3.2 g., 0.03 moles) and triethylamine (3.4 g., 0.03 moles) in dichloromethane (30 ml.). After stirring at 0° for one hour, and at ambient temperature overnight, the mixture is filtered and the filtrate is concentrated in vacuo. The residue (5 g., 90%) becomes semi-solid at room temperature. It is recrystallized from pentane (450 ml.) with a recovery of dimethylphosphinic acid, phenylmethyl ester, yield 3.6 g. (65%) m.p. 41°-45°. A second recrystallization of 0.5 g. from pentane (75 ml.) gives a recovery of 0.26 g. of product, m.p. 46°-47°.
Reaction SMILES: [C:1]([Si:5]([CH3:17])([CH3:16])[O:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH:9]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:8][CH2:7][O:6][Si:5]([C:1]([CH3:3])([CH3:2])[CH3:4])([CH3:17])[CH3:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)[Si](C)(C)OCCCc1ccccc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)[Si](C)(C)OCCC(Br)c1ccccc1

Procedure:
A suspension of tert-butyldimethyl(3-phenylpropoxy)silane (2.22 g, 8.86 mmol), N-bromosuccinimide (1.58 g, 8.86 mmol) and benzoyl peroxide (66.4 mg, 266 μmol) in carbon tetrachloride (17.8 mL) was heated to reflux for 3 hours. The reaction was filtered, the precipitate washed with carbon tetrachloride and the solvent was evaporated. Water was added and the reaction was extracted twice with diethyl ether. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The title compound was obtained as a light yellow oil (1.63 g, 55%) after column chromatography on silica gel using heptane/ethyl acetate 19:1 (v/v) as eluent. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.42-7.26 (m, 5H), 5.42 (dd, 1H), 3.76 (m, 1H), 3.68 (m, 1H), 2.48 (m, 1H), 2.28 (m, 1H), 0.90 (s, 9H), 0.06 (s, 3H), 0.03 (s, 3H).
Reaction SMILES: C([O:5][C:6](=[O:32])[CH2:7][O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11]([NH:28][C:29]([NH2:31])=[O:30])=[C:12]([CH2:26][CH3:27])[N:13]2[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Br:25])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:26]([C:12]1[N:13]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Br:25])[C:14]2[C:10]([C:11]=1[NH:28][C:29]([NH2:31])=[O:30])=[C:9]([O:8][CH2:7][C:6]([OH:32])=[O:5])[CH:17]=[CH:16][CH:15]=2)[CH3:27]
Reactant: CCc1c(NC(N)=O)c2c(OCC(=O)OC(C)(C)C)cccc2n1Cc1ccccc1Br
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1c(NC(N)=O)c2c(OCC(=O)O)cccc2n1Cc1ccccc1Br
Reaction time: 4 h

Procedure:
[[2-Ethyl-1-(2-bromo-phenylmethyl)-3-ureido-1H-indol-4-yl]oxy]acetic acid tert-butyl ester (0.7 g) was dissolved in 5 mL of dichloromethane and 1 mL of trifluoroacetic acid was added. After stirring for 4 hours the reaction mixture was concentrated to dryness, the residue dissolved in ethyl acetate and extracted with 1 N sodium hydroxide. This solution was acidified and extracted with ethyl acetate, the solvent removed by flash evaporation, and the residue slurried in 1 N hydrochloric acid. The resulting greenish solid was isolated by filtration and vacuum dried. This material was flash chromatographed on silica eluting with 19:1 ethyl acetate/methanol containing 2.5% acetic acid to provide [[2-ethyl-1-(2-bromo-phenylmethyl)-3-ureido-1H-indol-4-yl]oxy]acetic acid.
Reaction SMILES: [CH2:1]([C:4]1[N:9]=[C:8]([SH:10])[N:7]=[C:6]([OH:11])[C:5]=1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]#[N:26])=[CH:15][CH:14]=1)[CH2:2][CH3:3].[OH-].[K+].[CH3:29]I>CO>[CH2:1]([C:4]1[N:9]=[C:8]([S:10][CH3:29])[N:7]=[C:6]([OH:11])[C:5]=1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]#[N:26])=[CH:15][CH:14]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc(S)nc(O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCc1nc(SC)nc(O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
26 g of 6-n-propyl-2-mercapto-4-hydroxy-5[(2'-cyano-4-biphenylyl)methyl]pyrimidine, prepared in Example 100, are stirred for 15 minutes in a solution of 5 g of potassium hydroxide in 100 ml of methanol. 6 ml of methyl iodide are added to the mixture, which is then stirred for 4 hours at room temperature. The crystals formed are drained, washed with water and then with ether and dried to give 23 g of 6-n-propyl-2-methylthio-4-hydroxy-5-[(2'-cyano-4-biphenylyl)methyl]pyrimidine in the form of crystals of melting point 218° C.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[CH3:27][N:28]([CH3:38])[CH2:29][CH2:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1.[OH-].[Na+]>CN(C=O)C.CO>[CH3:38][N:28]([CH3:27])[CH2:29][CH2:30][C:31]1[CH:37]=[CH:36][C:34]([NH:35]/[C:16](=[C:6]2\[C:5](=[O:26])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:33][CH:32]=1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: CN(C)CCc1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CN(C)CCc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 82 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-(2-dimethylamino-ethyl)-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4](F)[CH:3]=1.[C:11]([NH2:14])(=[NH:13])[CH3:12]>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH:6]=[N:13][C:11]([CH3:12])=[N:14]2)=[CH:8][CH:9]=1
Reactant: CC(=N)N
Reactant: O=Cc1ccc(Br)cc1F
Solvent: CC(=O)N(C)C
Product: Cc1ncc2ccc(Br)cc2n1
Temperature: 140 °C
Yield: 4 %

Procedure:
The 4-Bromo-2-fluoro-benzaldehyde (1 g, 4.9 mmol), acetamidine and DMA were mixed and heated to 140° C. for 5 hours. The mixture was cooled to room temperature and dried under vacuum. The mixture was purified by flash column afforded 47 mg product in 4% yield. MS (ESI) m/e 223 (M+1)+.