Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[N:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH:28]([CH3:32])[C:29]([NH2:31])=[O:30])[C:17]([C:33]([F:36])([F:35])[F:34])=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C=O.[C:39](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:39][N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[N:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH:28]([CH3:32])[C:29]([NH2:31])=[O:30])[C:17]([C:33]([F:34])([F:36])[F:35])=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C(N)=O)c1ccccc1CCc1nc(Nc2ccc(C3CCNCC3)nc2)ncc1C(F)(F)F
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CC(C(N)=O)c1ccccc1CCc1nc(Nc2ccc(C3CCN(C)CC3)nc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 30 %

Procedure:
To a mixture of 2-(2-(2-(2-((6-(piperidin-4-yl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)propanamide 62 (0.064 g, 0.13 mmol) in anhydrous MeOH (2.0 mL) was added 37% aqueous formaldehyde (0.04 mL, 0.5 mmol) and sodium triacetoxyborohydride (0.138 g, 0.649 mmol). The mixture was stirred for 3 hours at room temperature under a nitrogen atmosphere and then quenched by the addition of sat. aq. NaHCO3 (30 mL). The aqueous phase was extracted with EtOAc (2×20 mL), the combined organics were dried using a phase separation cartridge and then concentrated under reduced pressure. The organic residues were purified by prep-LCMS to give the title compound 63 (0.020 g, 30%) as the formic acid salt (2 equivs. determined by 1H NMR). LCMS-A: rt 4.786 min; m/z 513.3 [M+H]+.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([Br:8])[CH:2]=1.S(C1C=CC(C)=CC=1)(O[C@@H:13]([CH3:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>C1(=O)CCCCC1>[CH3:19][C@@H:13]([O:7][C:6]1[CH:5]=[CH:4][C:3]([Br:8])=[CH:2][CH:1]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: Oc1ccc(Br)cc1
Reactant: CCCCC[C@H](C)OS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C1CCCCC1
Product: CCCCC[C@@H](C)Oc1ccc(Br)cc1
Yield: 89.3 %

Procedure:
A reaction vessel was charged with 10 g of p-bromophenol, 19 g of (S)-1-methylhexyl tosylate, 10 g of potassium carbonate and 150 ml of cyclohexanone, and the mixture was stirred under reflux for 15 hours (the starting materials were confirmed to have disappeared by GLC). The reaction liquid was filtered and the filter cake was washed with benzen. The washings and the filtrate were combined, washed with water and then dried over Glauber's salt. The solvents were distilled off and the residue was purified by way of column chromatography on silica gel (eluent:hexane) to obtain 14 g (89.4%) of (R)-4-(1-methylhexyl)oxybromobenzene.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[CH:31][CH:32]=[C:33]([OH:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[CH:31][CH:32]=[C:33]([OH:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(O)cccc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2c(O)cccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-4-hydroxy-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: ClC1C=C2C(C)(C)C(/C=C/C(/C3C=CC=C(CCCCC([NH:59][CH2:60][CH2:61][N:62]4[C:66](=[O:67])[CH:65]=[CH:64][C:63]4=[O:68])=O)C=3)=C/C=C3/N(CCCS([O-])(=O)=O)C4C(C/3(C)C)=CC(S([O-])(=O)=O)=CC=4)=NC2=[N+](CCCS([O-])(=O)=O)C=1.[Na+:69].[Na+].[Cl:71][C:72]1[CH:73]=[C:74]2[C:88]([CH3:90])([CH3:89])/[C:87](=[CH:91]\[CH:92]=[C:93](/[C:127]3[CH:132]=[CH:131][CH:130]=[C:129]([CH2:133][CH2:134][CH2:135][CH2:136][C:137](ON4C(=O)CCC4=O)=[O:138])[CH:128]=3)\[CH:94]=[CH:95]\[C:96]3[C:104]([CH3:106])([CH3:105])[C:103]4[C:102]5[CH:107]=[C:108]([S:115]([O-:118])(=[O:117])=[O:116])[CH:109]=[C:110]([S:111]([O-:114])(=[O:113])=[O:112])[C:101]=5[CH:100]=[CH:99][C:98]=4[N+:97]=3[CH2:119][CH2:120][CH2:121][CH2:122][S:123]([O-:126])(=[O:125])=[O:124])/[N:86]=[C:75]2[N:76]([CH2:78][CH2:79][CH2:80][CH2:81][S:82]([O-:85])(=[O:84])=[O:83])[CH:77]=1.[Na+].[Na+].[Na+]>>[Cl:71][C:72]1[CH:73]=[C:74]2[C:88]([CH3:89])([CH3:90])/[C:87](=[CH:91]\[CH:92]=[C:93](/[C:127]3[CH:132]=[CH:131][CH:130]=[C:129]([CH2:133][CH2:134][CH2:135][CH2:136][C:137]([NH:59][CH2:60][CH2:61][N:62]4[C:66](=[O:67])[CH:65]=[CH:64][C:63]4=[O:68])=[O:138])[CH:128]=3)\[CH:94]=[CH:95]\[C:96]3[C:104]([CH3:105])([CH3:106])[C:103]4[C:102]5[CH:101]=[C:110]([S:111]([O-:114])(=[O:113])=[O:112])[CH:109]=[C:108]([S:115]([O-:118])(=[O:116])=[O:117])[C:107]=5[CH:100]=[CH:99][C:98]=4[N+:97]=3[CH2:119][CH2:120][CH2:121][CH2:122][S:123]([O-:126])(=[O:124])=[O:125])/[N:86]=[C:75]2[N:76]([CH2:78][CH2:79][CH2:80][CH2:81][S:82]([O-:85])(=[O:83])=[O:84])[CH:77]=1.[Na+:69].[Na+:69].[Na+:69]
Reactant: CC1(C)C(/C=C/C(=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)c2cccc(CCCCC(=O)NCCN3C(=O)C=CC3=O)c2)=Nc2c1cc(Cl)c[n+]2CCCS(=O)(=O)[O-]
Reactant: CC1(C)C2=CC(Cl)=CN(CCCCS(=O)(=O)[O-])C2=N/C1=C/C=C(/C=C/C1=[N+](CCCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c2C1(C)C)c1cccc(CCCCC(=O)ON2C(=O)CCC2=O)c1
Agent: [Na+]
Product: CC1(C)C2=CC(Cl)=CN(CCCCS(=O)(=O)[O-])C2=N/C1=C/C=C(/C=C/C1=[N+](CCCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c2C1(C)C)c1cccc(CCCCC(=O)NCCN2C(=O)C=CC2=O)c1

Procedure:
Compound 35 is prepared analogously to compound 34 (Example 45), except that compound 29 is used as a starting material.
Reaction SMILES: [Cl-].[C:2]1([CH2:12][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:34]([C:38]1[CH:45]=[CH:44][C:41]([CH:42]=O)=[CH:40][CH:39]=1)([CH3:37])([CH3:36])[CH3:35]>C1COCC1>[C:34]([C:38]1[CH:39]=[CH:40][C:41]([CH:42]=[CH:12][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4][CH:3]=2)=[CH:44][CH:45]=1)([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: c1ccc([P+](Cc2cccc3ccccc23)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C=Cc2cccc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An oven-dried 500 ml three-neck round bottom flask was equipped with a magnetic stir bar, addition funnel and nitrogen inlet connector. The flask was charged with (1-napthylmethyl)triphenylphosphonium chloride (12.07 g, 27.5 mmol) and 200 ml of anhydrous THF. Sodium hydride (1.1 g, 25 mmol) was added in one portion. The mixture became bright orange and was left to stir overnight at room temperature. A solution of 4-tert-butyl-benzaldehyde (7.1 g, 25 mmol) in anhydrous THF (30 ml) was added to the addition funnel with a cannula. The aldehyde solution was added to the reaction mixture dropwise over 45 minutes. Reaction was left to stir at room temperature for 24 hours (orange color went away). Silica gel was added to the reaction mixture and volatiles were removed under reduced pressure. The crude product was purified by column chromatography on silica gel using 5-10% dichloromethane in hexanes. The product was isolated as a mixture of cis- and trans-isomers (6.3 g, 89%) and used without separation. The structure was confirmed by 1H NMR.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]2[S:12][C:13]3[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:4][CH:3]=1.[C:21]([N:29]=[C:30]=[S:31])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1.C(Cl)Cl>[C:21]([NH:29][C:30]([NH:20][C:18]1[CH:17]=[CH:16][C:14]2[N:15]=[C:11]([NH:10][CH2:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)[S:12][C:13]=2[CH:19]=1)=[S:31])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1ccc2nc(NCCc3ccc(Br)cc3)sc2c1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(NC(=S)Nc1ccc2nc(NCCc3ccc(Br)cc3)sc2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
N2-[2-(4-Bromo-phenyl)-ethyl]-benzothiazole-2,6-diamine (Example 33(a), 71 mg, 0.205 mmol) was dissolved in tetrahydrofuran (3 mL). Benzoyl isothiocyanate (20 μl, 1.1 eq) was added and the mixture stirred at room temperature for 24 hours. The solvent was evaporated to give a yellow solid. The solid was dissolved in CH2Cl2 (5 mL) and absorbed onto silica gel. The absorbed compound was loaded onto a silica column and eluted with a mixture of ethyl acetate/hexanes (1:1) to give a yellow solid (99 mg, 95%). 1H NMR (CDCl3) δ: 12.61 (s, 1H), 9.10 (s, 1H), 8.19 (s, 1H), 7.90 (d, 2H, J=8.5 Hz), 7.67–7.43 (m, 8H), 7.12 (d, 2H, J=8.5 Hz), 3.69 (t, 2H, J=6.9 Hz), 2.97 (d, 2H, J=6.9 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:25])=[C:7]([C:15]([C:17]2[CH:18]=[N:19][N:20]([CH2:23][CH3:24])[C:21]=2[OH:22])=[O:16])[CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12])=[O:4].C(N(CC)CC)C.[CH3:33][CH2:34][S:35][C:36](Cl)=[O:37]>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:25])=[C:7]([C:15]([C:17]2[CH:18]=[N:19][N:20]([CH2:23][CH3:24])[C:21]=2[O:22][C:36]([S:35][CH2:34][CH3:33])=[O:37])=[O:16])[CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12])=[O:4]
Reactant: CCSC(=O)Cl
Reactant: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(C(=O)OC)c2C)c1O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCSC(=O)Oc1c(C(=O)c2ccc(S(C)(=O)=O)c(C(=O)OC)c2C)cnn1CC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66.2 %

Procedure:
5-Hydroxy-1-ethylpyrazol-4-yl 3-(methoxycarbonyl)-2-methyl-4-(methylsulfonyl)phenyl ketone (510 mg, 1.39 mmol) was dissolved in dry tetrahydrofuran (20 mL), and triethylamine (281 mg, 2.78 mmol) was added thereto. A solution (4 mL) of 96% S-ethyl chlorothiolformate (217 mg) dissolved in dry tetrahydrofuran was added thereto little by little under cooling with ice water. The reaction mixture was stirred for 90 minutes while the reaction temperature was allowed to warm to room temperature. The reaction mixture was poured into ice water, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=6:4) to obtain the desired product as an oil (417 mg, 0.92 mmol) (yield: 66%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH-:19].C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>CN(C)C=O>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH:19][C:7](=[O:9])[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:13])[F:12])=[CH:11][CH:10]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Reactant: COc1ccccc1C[NH-]
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccccc1CNC(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.8 %

Procedure:
5.7 g of 4-(trifluoromethyl)benzoic acid and 4.0 g of 2-methoxybenzylamide were dissolved in 100 ml N,N-dimethylformamide, and 4.8 ml diethyl cyanophosphonate and 4.2 ml triethylamine were added under ice-cooling. The reaction mixture was stirred at room temperature for 16 hours, then poured into ice-water and extracted with ethyl acetate. The organic layer was successively washed with 1N hydrochloric acid and brine, dried over anhydrous magnesium sulfate and the solvent was evapoarated. The residue was subjected to silica gel column chromatography, and from fractions eluted with hexane-ethyl acetate (2:1), 8.7 g of N1-(2-methoxybenzyl)-4-(trifluoromethyl)benzamide was obtained.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C(N(CC)CC)C.FC(F)(F)S(O[Si:22]([CH3:25])([CH3:24])[CH3:23])(=O)=O>C1(C)C=CC=CC=1>[CH3:23][Si:22]([N:2]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[Si:22]([CH3:25])([CH3:24])[CH3:23])([CH3:25])[CH3:24]
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)CN([Si](C)(C)C)[Si](C)(C)C
Temperature: 25 °C
Reaction time: 19 h

Procedure:
About 6.02 g of ethyl glycinate hydrochloride, 14.39 g of triethylamine, and 10 ml of toluene were mixed in a round-bottom reaction flask cooled with an ice bath. To this mixture was added, in a dropwise fashion, a solution of 21.1 g of trimethylsilyl trifluoromethanesulfonate in 50 ml of toluene. The resulting mixture was stirred at room temperature for 19 hours to give a biphasic mixture. The top layer was transferred to another flask, and the bottom layer was extracted with 40 ml of toluene. The combined toluene solution was evaporated under vacuum. The residue was extracted with 100 ml of hexane, and the hexane layer was evaporated under vacuum, yielding ethyl [bis(trimethylsilyl)amino]acetate, also known as ethyl N,N-bis(trimethylsilyl)glycinate (BTMSEG), as a colorless liquid (9.23 g, 87% yield). The 1H NMR data (C6D6, 25° C., referenced to tetramethylsilane) of the product are listed as follows: δ 3.89 (quartet, 2 H, OCH2 protons), 3.51 (singlet, 2 H, NCH2 protons), 0.90 (triplet, 3 H, CH3 protons), 0.14 (singlet, 18H, Si—CH3 protons). From the 1H NMR data, the structure of the product was determined to be as follows:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:17]([CH3:21])=[C:18]([CH3:20])[N:19]=2)[CH:5]=[CH:6][C:7]=1[C:8](=[O:16])[CH:9]=[CH:10][C:11]1[CH:15]=[CH:14][S:13][CH:12]=1.S(=O)(=O)(O)O.[OH-].[Na+]>>[CH3:20][C:18]1[N:19]=[C:3]2[C:2]3[NH:1][CH:10]([C:11]4[CH:15]=[CH:14][S:13][CH:12]=4)[CH2:9][C:8](=[O:16])[C:7]=3[CH:6]=[CH:5][N:4]2[C:17]=1[CH3:21]
Reactant: Cc1nc2c(N)c(C(=O)C=Cc3ccsc3)ccn2c1C
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc2c3c(ccn2c1C)C(=O)CC(c1ccsc1)N3
Yield: 69.2 %

Procedure:
2.6 g of 8-amino-2,3-dimethyl-7-[3-(3-thienyl)-1-oxo-2-propenyl]imidazo[1,2-a]pyridine are treated at room temperature with 20 ml of aqueous 70% strength sulfuric acid, poured onto ice water (100 ml) after 90 minutes, neutralized with aqueous 6 N sodium hydroxide solution and extracted three times with 50 ml of methylene chloride each time. The combined organic phases are washed with water, dried over sodium sulfate, the solvent is stripped off in vacuo and the remaining yellow oil is stirred with 15 ml of diethyl ether. The yellowish solid obtained here is filtered off and dried in vacuo. 1.8 g of the title compound of m.p. 176-77° C. (diethyl ether) are obtained.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=1)([F:7])[F:6])C.[BH4-].[Na+]>CO>[Cl:14][C:10]1[CH:9]=[C:8]([C:5]([F:6])([F:7])[CH2:4][OH:3])[CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)C(F)(F)c1cccc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCC(F)(F)c1cccc(Cl)c1
Reaction time: 8 h
Yield: 85.3 %

Procedure:
1.00 g (4.26 mmol) (3-chloro-phenyl)-difluoro-acetic acid ethyl ester (prepared according to the procedure described in WO 2006/122788) were dissolved in 100 ml of methanol and treated in an ice bath with 120 mg (0.75 mmol) of sodium borohydride. After stirring overnight the mixture was evaporated and the residue was purified by silica gel chromatography (DCM/methanol 98:2) to give 700 mg of the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[O:15][CH3:16])[N:5]=[C:4]([NH2:17])[N:3]=1.Cl.[F:19][C:20]([F:29])([F:28])[C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1>C(O)C.O1CCOCC1>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([O:15][CH3:16])=[C:8]([C:6]2[N:5]=[C:4]([NH2:17])[N:3]=[C:2]([NH:25][C:24]3[CH:26]=[CH:27][C:21]([C:20]([F:19])([F:28])[F:29])=[CH:22][CH:23]=3)[CH:7]=2)[CH:13]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: COc1ccc(Cl)cc1-c1cc(Cl)nc(N)n1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: COc1ccc(Cl)cc1-c1cc(Nc2ccc(C(F)(F)F)cc2)nc(N)n1

Procedure:
To a stirred suspension of 4-chloro-6-(5-chloro-2-methoxy-phenyl)-pyrimidin-2-yl-amine (0.050 g, 0.185 mmol) in ethanol (7.5 ml) was added a solution of hydrogen chloride in dioxane (4.0 M, 0.03 ml) followed by 4-(trifluoromethyl)aniline (0.06 g, 0.37 mmol). The mixture was stirred under reflux for 45 minutes. After evaporation of volatiles under reduced pressure, the residue was treated with 1.0 M hydrochloric acid (10 ml) and stirred for 30 min. Filtration provided the hydrochloride salt of the title compound which was dissolved in methanol (10 ml). A solution of sodium carbonate in water (1.0 M, 1 ml) was added. After stirring for 1 hour, volatiles were evaporated under reduced pressure. The crude product was treated with water (10 ml) and stirred for 15 minutes. Filtration provided the title compound (0.053 g, 74% yield) as a white powder. 1H NMR (DMSO-d6) δ 3.90 (s, 3H, CH3), 6.44 (s, 2H, NH2), 6.81 (s, 1H, Ar), 7.19 (d, 1H, J=8.8 Hz, Ar), 7.46 (dd, 1H, J=8.8 Hz, J=2.6 Hz, Ar), 7.61 (d, 2H, J=8.5 Hz, Ar), 7.94 (d, 1H, J=2.6 Hz, Ar), 7.26 (d, 2H, J=8.5 Hz, Ar), 9.63 (s, 1H, NH).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11]2[O:17][CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][C:12]=2[CH:25]=1.C(OCC)(=O)C.[ClH:32]>C(OCC)(=O)C>[ClH:32].[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11]2[O:17][CH2:16][CH2:15][NH:14][CH2:13][C:12]=2[CH:25]=1
Reactant: Cc1ccccc1-c1ccc2c(c1)CN(C(=O)OC(C)(C)C)CCO2
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1ccccc1-c1ccc2c(c1)CNCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
A mixture of tert-butyl 7-(2-methylphenyl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.589 mmol), ethyl acetate (1 ml) and 4N hydrogen chloride-ethyl acetate solution (4 ml) was stirred for 1 hr at room temperature, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and ether to give the desired product (133 mg, 82.1%) as a solid.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([CH3:33])([CH3:32])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CS(C)=O.[CH2:40]([CH2:42][NH2:43])[OH:41]>C(OCC)(=O)C>[F:11][C:9]([F:12])([F:10])[C:7]1[CH:6]=[C:5]([C:13]([CH3:32])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([NH:43][CH2:42][CH2:40][OH:41])=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[CH3:17])=[O:15])[CH:4]=[C:3]([C:2]([F:1])([F:34])[F:35])[CH:8]=1
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(Cl)cc1-c1ccccc1Cl
Reactant: NCCO
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(NCCO)cc1-c1ccccc1Cl
Temperature: 140 °C
Reaction time: 24 h
Yield: 92.8 %

Procedure:
A mixture of 28.6 g (56 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide, 50 ml dimethyl sulfoxide and 50 ml (830 mmol) ethanolamine was stirred at 140° C. for 24 h. The reaction mixture was cooled to room temperature, diluted with 200 ml ethyl acetate and washed with 200 ml 1 N sodium carbonate solution and 100 ml water. The aqueous layers were extracted with two 200-ml portions of ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was crystallized from a mixture of 150 ml diisopropyl ether and 150 ml heptane to give 29.1 g (93%) of the title compound as white crystals. M.p. 117-118° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:9][C:8]([C:10](=O)[CH2:11][C:12](=O)[C:13]([F:16])([F:15])[F:14])=[N:7][C:6]=2[CH:19]=1.Cl.[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][NH2:32])=[CH:27][CH:26]=1)(=[O:24])=[O:23]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:9][C:8]([C:10]3[N:31]([C:28]4[CH:27]=[CH:26][C:25]([S:22]([CH3:21])(=[O:24])=[O:23])=[CH:30][CH:29]=4)[N:32]=[C:12]([C:13]([F:16])([F:15])[F:14])[CH:11]=3)=[N:7][C:6]=2[CH:19]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1nc2cc(F)ccc2[nH]1
Reactant: CS(=O)(=O)c1ccc(NN)cc1
Agent: Cl
Product: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2nc3cc(F)ccc3[nH]2)cc1
Yield: 25 %

Procedure:
The procedure of Example 9 was repeated using 1-(6-fluorobenzimidazol-2-yl)-4,4,4-trifluorobutane-1,3-dione and 4-methylsulfonylphenylhydrazine hydrochloride as the starting materials to obtain 6-fluoro-2-[1-(4-methylsulfonylphenyl)-3-trifluoromethyl-1H-pyrazol-5-yl]benzimidazole (yield, 25%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1.CN(C=O)C>[CH2:19]([N:11]([C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(O)CCN(Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of N-benzyloxycarbonyl-β-alanine (11.16 g, 50.00 mmol) in anhydrous THF (160 mL) and DMF (40 mL) at 0° C. was slowly added NaH (60% in oil, 6.000 g, 150.0 mmol). After stirring at 0° C. for 15 min, benzyl bromide (9.10 mL, 75.00 mmol) was added. The reaction mixture was stirred at rt for 22 h. It was quenched with water (90 mL), followed by 1 N HCl (110 mL), and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by Combiflash (40-60% EtOAc/hexane) to afford 3-{benzyl[(benzyloxy)cabonyl]amino}propanoic acid as a viscous pale yellow oil (14.2 g, 91% in yield). MS (ESI): 312.0 (M−H).
Reaction SMILES: [Na:1].[CH2:2]1[O:4][CH2:3]1.[C:5]([OH:10])(=[O:9])[C:6]([CH3:8])=[CH2:7].[CH2:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])(=[O:22])[CH:20]=[CH2:21].S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].S([O-])([O-])(=O)=O.[NH4+].[NH4+]>O>[CH:11]([CH2:7][C:6](=[CH2:8])[C:5]([OH:10])=[O:9])=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])(=[O:22])[CH:20]=[CH2:21].[Na:1].[CH2:3]1[O:4][CH2:2]1.[C:5]([OH:10])(=[O:9])[C:6]([CH3:8])=[CH2:7]
Reactant: C=Cc1ccccc1
Agent: C=C(C)C(=O)O
Agent: C=CC(=O)OCCCC
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Solvent: O
Solvent: C1CO1
Product: C=C(CC=Cc1ccccc1)C(=O)O
Temperature: 75 °C
Reaction time: 5 h

Procedure:
In a reactor equipped with a stirring rod and a thermometer were placed 683 parts of water, 11 parts of a sodium salt of sulfuric acid ester of ethylene oxide adduct of methacrylic acid ELEMINOL RS-30 (trade name, available from Sanyo Chemical Industries, Ltd., Japan), 68 parts of styrene, 93 parts of methacrylic acid, 115 parts of butyl acrylate, and 1 part of ammonium persulfate, and the mixture was stirred at 400 rpm for 15 minutes to yield a white emulsion. The emulsion was heated to an inner temperature of 75° C., followed by reaction for 5 hours. The reaction mixture was further treated with 30 parts of a 1% aqueous solution of ammonium sulfate, was aged at 75° C. for 5 hours and thereby yielded an aqueous dispersion [Fine Particle Dispersion 5] of a vinyl resin (a copolymer of styrene-methacrylic acid-butyl acrylate-sodium salt of sulfuric acid ester of ethylene oxide adduct of methacrylic acid). Fine Particle Dispersion 5 had a volume-average particle diameter of 90 nm when measured with a laser diffraction-scattering size distribution analyzer LA-920. Part of Fine Particle Dispersion 5 was dried to isolate the resin component. The resin component had a Tg of 56° C. and a weight-average molecular weight of 15×104.