Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH3:23])[NH:5][C:6](=[O:22])[C@H:7]([CH3:21])[NH:8][C:9](=[O:20])[C@H:10]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[S:19])[CH3:18])[NH2:11].[N:25]([C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=1)=[N+:26]=[N-:27].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH3:23])[NH:5][C:6](=[O:22])[C@H:7]([CH3:21])[NH:8][C:9](=[O:20])[C@H:10]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[S:19])[CH3:18])[NH:11][C:32](=[O:33])[C:31]1[CH:30]=[CH:29][C:28]([N:25]=[N+:26]=[N-:27])=[CH:36][CH:35]=1
Reactant: COC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCCNC(C)=S
Reactant: [N-]=[N+]=Nc1ccc(C(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCCCNC(C)=S)NC(=O)c1ccc(N=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 82.1 %

Procedure:
To a solution of Nε-thioacetyl-lysinyl-alaninyl-alanine methyl ester (50 mg, 0.14 mmol) in 0.8 mL of THF was added a solution of 4-azidobenzoic acid (35 mg, 0.21 mmol) in 0.8 mL of THF. PyBOP (109 mg, 0.21 mmol) and DIPEA (59 mg, 0.42 mmol) were introduced into the reaction mixture. The reaction was stirred at room temperature for 6 h, and then solvent was removed under reduced pressure. Silica gel column chromatography (ethyl acetate: hexanes 10:1) afforded Nα-4-azidobenzoyl-Nε-thioacetyl-lysinyl-alaninyl-alanine methyl ester (58 mg, 0.115 mmol, 82%) as a pale yellow solid. 1H NMR (CD2Cl2, 500 MHz) δ (ppm): 1.39 (s, 3H), 1.40 (s, 3H), 1.47 (m, 2H), 1.67 (m, 2H), 1.88 (m, 2H), 2.87 (s, 3H), 3.57 (m, 2H), 3.68 (s, 3H), 4.41 (m, 1H), 4.46 (m, 1H), 4.64 (m, 1H), 7.05 (d, J=8.6 Hz, 2H), 7.20 (d, J=7.2 Hz, 1H), 7.36 (d, J=6.8 Hz, 1H), 7.44 (d, J=7.0 Hz, 1H), 7.86 (d, J=8.6 Hz, 2H), 8.32 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:38]=[CH:37][C:5]([CH:6]=[CH:7][C:8]([NH:10][CH2:11][C:12]([N:14]([C:16]2[C:17]([Cl:36])=[C:18]([C:32]([Cl:35])=[CH:33][CH:34]=2)[CH2:19][O:20][C:21]2[CH:22]=[CH:23][CH:24]=[C:25]3[C:30]=2[N:29]=[C:28]([CH3:31])[CH:27]=[CH:26]3)[CH3:15])=[O:13])=[O:9])=[CH:4][C:3]=1[CH3:39].C(N(CC)CC)C.[C:47](Cl)(=[O:51])[CH:48]([CH3:50])[CH3:49]>ClCCl>[Cl:36][C:17]1[C:16]([N:14]([CH3:15])[C:12](=[O:13])[CH2:11][NH:10][C:8](=[O:9])[CH:7]=[CH:6][C:5]2[CH:37]=[CH:38][C:2]([NH:1][C:47](=[O:51])[CH:48]([CH3:50])[CH3:49])=[C:3]([CH3:39])[CH:4]=2)=[CH:34][CH:33]=[C:32]([Cl:35])[C:18]=1[CH2:19][O:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:30]=1[N:29]=[C:28]([CH3:31])[CH:27]=[CH:26]2
Reactant: CC(C)C(=O)Cl
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(N)c(C)c4)c3Cl)c2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(NC(=O)C(C)C)c(C)c4)c3Cl)c2n1
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
To a solution of 8-[3-[N-(4-amino-3-methylcinnamoylglycyl)-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylquinoline (200 mg) and triethylamine (35.9 mg) in dichloromethane was dropwise added isobutyryl chloride (41.6 mg) at 0° C. under nitrogen atmosphere, and the mixture was stirred for 30 minutes at the same temperature. The mixture was concentrated, and the residue was dissolved in methanol (3 ml). To the solution was added saturated sodium bicarbonate solution (1 ml), and the mixture was stirred for 2 hours at ambient temperature and concentrated. To the residue were added ethyl acetate and water, and the organic layer was washed with water, saturated sodium bicarbonate solution and brine, dried and concentrated. The residue was purified by preparative thin-layer chromatography (dichloromethane:methanol=15:1, V/V) to give 8-[2,6-dichloro-3-[N-methyl-N-(4-isobutyramido-3-methylcinnamoylglycyl)amino]benzyloxy]-2-methylquinoline (195 mg) as an amorphous powder.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=3[CH2:30]Cl)[CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:38]([NH:40][CH2:41][CH3:42])[CH3:39]>C(#N)C>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=3[CH2:30][N:40]([CH2:41][CH3:42])[CH2:38][CH3:39])[CH:8]=2)[N:3]=1
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3cc(F)ccc3CCl)ccc2n1
Reactant: CCNCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCN(CC)Cc1ccc(F)cc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
200 mg of [2-amino-6-(2-chloromethyl-5-fluorophenyl)quinazolin-4-yl]-(1,3-dihydroisoindol-2-yl)methanone are dissolved in 5 ml of acetonitrile. 301 mg of caesium carbonate and 73 μl of diethylamine are added, and the mixture is stirred at 80° C. for 16 h. After cooling to 25° C., the mixture is filtered, and the filtrate is evaporated to dryness. The residue is taken up in 5 ml of ethyl acetate, the solution is washed with 5 ml of 2N sodium hydroxide solution, and the combined organic phases are dried over sodium sulfate. After filtration, the filtrate is evaporated to dryness and purified by chromatography (reversed phase HPLC).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](O)=O.[BH4-].[Na+].[N:10]1[CH2:11][CH2:12][N:13]2[C:17]3[CH:18]=[C:19]([NH2:22])[CH:20]=[CH:21][C:16]=3[S:15][C:14]=12>>[F:1][C:2]([F:7])([F:6])[CH2:3][NH:22][C:19]1[CH:20]=[CH:21][C:16]2[S:15][C:14]3=[N:10][CH2:11][CH2:12][N:13]3[C:17]=2[CH:18]=1
Reactant: Nc1ccc2c(c1)N1CCN=C1S2
Reactant: O=C(O)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Product: FC(F)(F)CNc1ccc2c(c1)N1CCN=C1S2
Temperature: 0 °C

Procedure:
To a stirred mixture of 60 parts of trifluoroacetic acid and 4 parts of sodium borohydride are added portionwise, during a 5 hours-period, 4 parts of 2,3-dihydroimidazo[2,1-b]benzothiazol-6-amine at 30°-40° C. The reaction mixture is poured onto 300 parts of ice-water. The precipitated product is filtered off, washed with water and taken up in trichloromethane. The mixture is washed with ammonium hydroxide. The organic phase is dried, filtered and evaporated. The residue is crystallized from acetonitrile, yielding 3.3 parts of 2,3-dihydro-N-(2,2,2-trifluoroethyl)imidazo[2,1-b]benzothiazol-6-amine; mp. 211.7° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:20]=[CH:19][C:18](I)=[C:17]([O:22][CH3:23])[CH:16]=2)[N:10]=1.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[CH:32])[C:26]=1[F:33]>>[Cl:24][C:25]1[C:26]([F:33])=[C:27]([C:31]#[C:32][C:18]2[CH:19]=[CH:20][C:15]([N:11]3[C:12](=[O:14])[NH:13][C:9]([C:3]4[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])=[N:10]3)=[CH:16][C:17]=2[O:22][CH3:23])[CH:28]=[CH:29][CH:30]=1
Reactant: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1I
Reactant: C#Cc1cccc(Cl)c1F
Product: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1C#Cc1cccc(Cl)c1F

Procedure:
The title compound was prepared according to the procedure described in Example-3 using 3-(2-chloro-6-fluorophenyl)-1-(4-iodo-3-methoxyphenyl)-1H-1,2,4-triazol-5(4H)-one (Intermediate-32, 0.050 g, 0.11 mmol), 1-chloro-3-ethynyl-2-fluorobenzene
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[CH2:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2.[CH3:16][Si:17](Cl)([CH3:19])[CH3:18]>CCCCCC>[CH3:16][Si:17]([CH3:19])([CH3:18])[CH:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:15]([Si:17]([CH3:19])([CH3:18])[CH3:16])=[C:7]1[CH3:6]
Reactant: CC1=Cc2ccccc2C1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CC1=C([Si](C)(C)C)c2ccccc2C1[Si](C)(C)C
Reaction time: 10 h
Yield: 85 %

Procedure:
500 ml of hexane and 70 ml of butyllithium (as a 2.5 molar solution in hexane) were introduced into a 1000 ml flask. 0.175 mol of 2-methylindene was added dropwise to this at ambient temperature; the mixture was stirred for a further 10 hours. 0.18 mol of trimethylsilyl chloride was then added dropwise at room temperature; the mixture was stirred for a further 10 hours. LiCl was filtered off and 70 ml of butyllithium (as a 2.5 molar solution in hexane) were added to the clear filtrate. After further stirring for 10 hours, 0.18 mol of trimethylsilyl chloride was again added and the mixture was stirred for a further 10 hours. LiCl was filtered off and the solvent was removed in vacuo. Compound 54 remained as a colorless oil. Yield: 85% of the theoretical yield.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([C:10]2([OH:31])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]#[N:20])[CH:17]=3)[N:12]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:11]2=[O:30])=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:2].Cl[C:33]([O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:34]>N1C=CC=CC=1.ClCCl>[C:33](=[O:34])([O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[O:31][C:10]1([C:9]2[C:4]([O:3][CH2:1][CH3:2])=[N:5][CH:6]=[CH:7][CH:8]=2)[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]#[N:20])[CH:17]=2)[N:12]([S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:23])=[O:22])[C:11]1=[O:30]
Reactant: CCOc1ncccc1C1(O)C(=O)N(S(=O)(=O)c2ccccc2)c2ccc(C#N)cc21
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOc1ncccc1C1(OC(=O)Oc2ccccc2)C(=O)N(S(=O)(=O)c2ccccc2)c2ccc(C#N)cc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2.65 g (6.09 mmol) of optically active 3-(2-ethoxypyridin-3-yl)-3-hydroxy-2-oxo-1-(phenylsulfonyl)indoline-5-carbonitrile from example 4B.1 were dissolved in 4.9 ml of pyridine and 6.0 ml of dichloromethane while cooling at 0° C. in ice, the solution becoming brown in color. At this temperature, 1.24 g (7.91 mmol) of phenyl chloroformate were slowly added dropwise. The reaction mixture was stirred in an ice bath for 2 hours. After conversion was complete, the reaction mixture was further diluted with dichloromethane and poured into ice-water. The phases were separated, and the organic phase was washed again with saturated sodium chloride solution (1×) and water (1×). The solvent was evaporated in vacuo, and excess pyridine was removed by codistillation with toluene. 50 ml of diisopropyl ether were added to precipitate the product, and, after the solid had been filtered off with suction and washed with diisopropyl ether, a total of 2.16 g (3.89 mmol, 64%) of the optically active 5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl phenyl carbonate was isolated. Further purification of the mother liquor by normal-phase chromatography with dichloromethane as mobile phase resulted in 800 mg of the optically active 5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-ylphenyl carbonate.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[C:9]([OH:17])=[C:10]([CH2:14][CH:15]=O)[CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1.C(O)(=O)[CH2:21][C:22]([OH:24])=[O:23]>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[C:9]([OH:17])=[C:10]([CH2:14][CH:15]=[CH:21][C:22]([OH:24])=[O:23])[CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=CCc1cccc(C(=O)c2ccc(Cl)cc2)c1O
Product: O=C(O)C=CCc1cccc(C(=O)c2ccc(Cl)cc2)c1O

Procedure:
Another modification of the process comprises reacting 3-bromo-1-propene with methyl 2-hydroxybenzoate to obtain methyl 2'-(3-oxy-1-propene)-benzoate, hydrolyzing the latter to form the free acid, reacting the latter with a chlorinating agent such as thionyl chloride to form the corresponding acid chloride, condensing the latter with cadmium chlorophenyl to form 3-(2'-p-chlorobenzoyl-phenyl)oxy-1-propene, heating the latter to form 3-(3'-p-chlorobenzoyl-2'-hydroxy-phenyl)-1-propene, reacting the latter with an oxidizing atent to form 2-(3'-p-chlorobenzoyl-2'-hydroxy-phenyl)-1-oxo-ethane, condensing the latter with malonic acid, decarboxylating the resulting dicarboxylic acid to form 4-(3'-p-chlorobenzoyl-2'-hydroxy-phenyl)-2-butenoic acid and hydrogenating the latter in the presence of palladium to obtain 4-(3'-p-chlorobenzoyl-2-'-hydroxyphenyl)-butyric acid and finally with an oxidizing agent to form 4-(3'-p-chlorobenzoyl-2',5'-dihydroxy-phenyl)-butyric acid.
Reaction SMILES: F[C:2]1[CH:7]=[C:6](F)[CH:5]=[C:4](F)[N:3]=1.[OH:10][C:11]1[N:15]([CH3:16])[N:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1.[C:21](=[O:24])([O-])[O-].[K+].[K+]>S1(CCCC1)(=O)=O>[CH3:16][N:15]1[C:11]([O:10][C:2]2[CH:7]=[C:6]([O:10][C:11]3[N:15]([CH3:16])[N:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=3)[CH:5]=[C:4]([O:24][C:21]3[N:15]([CH3:11])[N:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=3)[N:3]=2)=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[N:14]1
Reactant: O=C([O-])[O-]
Reactant: Fc1cc(F)nc(F)c1
Reactant: Cn1nc(C(F)(F)F)cc1O
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: Cn1nc(C(F)(F)F)cc1Oc1cc(Oc2cc(C(F)(F)F)nn2C)nc(Oc2cc(C(F)(F)F)nn2C)c1
Temperature: 80 °C

Procedure:
A stirred mixture of 2,4,6-trifluoropyridine (4.8 g, 36 mmol), 5-hydroxy-1-methyl-3-trifluoromethylpyrazole (19.8 g, 119 mmol) and potassium carbonate (18.1 g, 131 mmol) in anhydrous sulfolane (25 ml) is heated to 80° C. over a period of 3 days.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:6][C:5](=O)[C:4](=O)[CH2:3]1.COP([CH2:16][C:17]([C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[C:26]([F:29])([F:28])[F:27])=O)(=O)OC.O.[NH2:31][NH2:32]>>[Cl:25][C:23]1[CH:22]=[CH:21][C:20]([C:26]([F:29])([F:28])[F:27])=[C:19]([C:17]2[N:32]=[N:31][C:4]3[CH2:3][C:2]([CH3:9])([CH3:1])[CH2:6][C:5]=3[CH:16]=2)[CH:24]=1
Reactant: NN
Reactant: COP(=O)(CC(=O)c1cc(Cl)ccc1C(F)(F)F)OC
Reactant: CC1(C)CC(=O)C(=O)C1
Solvent: O
Product: CC1(C)Cc2cc(-c3cc(Cl)ccc3C(F)(F)F)nnc2C1

Procedure:
yellow solid. MS (EI): 326.2 (M+). Prepared from 4,4-dimethyl-cyclopentane-1,2-dione, [2-(5-Chloro-2-trifluoromethyl-phenyl)-2-oxo-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:27][CH2:28]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([CH2:14][C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH:24]([CH3:26])[CH3:25])[CH:18]=3)=[O:16])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:35]1([C:41]2([C:47]([NH2:49])=[O:48])[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:27][CH2:28][N:44]3[CH2:43][CH2:42][C:41]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)([C:47]([NH2:49])=[O:48])[CH2:46][CH2:45]3)[CH2:13][CH2:12][N:11]([CH2:14][C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH:24]([CH3:25])[CH3:26])[CH:18]=3)=[O:16])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Reactant: CC(C)Oc1cccc(C(=O)CN2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)c1
Agent: Cl
Product: CC(C)Oc1cccc(C(=O)CN2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)c1

Procedure:
Prepare by the method of example 27.3.1 using 2-[3-(3,4-dichloro-phenyl)-1-(3-isopropoxy-phenacyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (0.24 g, 0.5 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (0.24 g, 0.98 mmol). Chromatograph on silica gel to give the title compound: Rf =0.45 (silica gel, 6% methanol/dichloromethane).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)(=[O:4])=[O:3].C(N(CC)CC)C.Br[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23]>CO.C(O)C>[CH3:1][S:2]([NH:5][C:6]1[CH:12]=[CH:11][C:9]([NH:10][CH2:21][C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: O=C(CBr)c1ccccc1
Reactant: CS(=O)(=O)Nc1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc(NCC(=O)c2ccccc2)cc1
Temperature: 5 °C
Yield: 62.4 %

Procedure:
4-Methanesulfonamidoaniline (150 g, 0.8 mol) and triethylamine (81.4 g, 0.8 mol) were combined with 2.4 liters of 1:1 methanol/ethanol in a five liter round bottom flask, and stirred mechanically until all solids dissolved. 2-Bromoacetophenone (240 g, 1.2 mol) was added as a solid in several portions over a twenty minute period. The reaction was stirred at 25° C. for 14 h, during which an off-white precipitate formed. The mixture was chilled to 5° C., then the product was collected by filtration, washed with cold ethanol and dried under vacuum to yield 152 g (62%) of 2-(4-methanesulfonamidoanilino)acetophenone as an off-white solid, m.p. 165°-167° C. NMR and mass spectral data were consistent with the assigned structure.
Reaction SMILES: C([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH2:23][CH:24]([O:30][C:31](=[O:33])[CH3:32])[CH2:25][O:26][C:27](=[O:29])[CH3:28])(OCC1C=CC=CC=1)=O.C(O)(=O)C>CO.[Pd]>[C:31]([O:30][CH:24]([CH2:25][O:26][C:27](=[O:29])[CH3:28])[CH2:23][O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][CH2:14][CH2:13][CH2:12][NH2:11])(=[O:33])[CH3:32]
Reactant: CC(=O)OCC(COc1ccccc1CCCCNC(=O)OCc1ccccc1)OC(C)=O
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CC(=O)OCC(COc1ccccc1CCCCN)OC(C)=O
Reaction time: 3 h
Yield: 88 %

Procedure:
Cbz-protected amine 34 (0.6 g, 1.3 mmol) was dissolved in methanol (25 mL) containing 1% acetic acid then Pd/C (0.22 g, 5% wet.) was added. The reaction mixture was stirred for 3 h under hydrogen (1 atm), then the solution was filtered through a pad of silica gel and the solvent was evaporated to give amine 35 (0.37 g, 86%) as a clear oil.
Reaction SMILES: Br[CH2:2][CH2:3][S:4]([C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1)(=[O:6])=[O:5].[CH3:15][C:16]1[N:20]=[CH:19][NH:18][N:17]=1>>[CH3:15][C:16]1[N:20]=[CH:19][N:18]([CH2:2][CH2:3][S:4]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[N:17]=1
Reactant: Cc1nc[nH]n1
Reactant: N#Cc1ccc(S(=O)(=O)CCBr)cc1
Product: Cc1ncn(CCS(=O)(=O)c2ccc(C#N)cc2)n1

Procedure:
To a stirred suspension of 10 g of thiosemicarbazide in 100 mL of pyridine was slowly added 7.8 ml of acetyl chloride at 0° C. The temperature was maintained throughout the addition (0° C.-4° C.). The reaction mixture was allowed to warm to room temperature and stirred for 16 h. Evaporation gave 1-acetyl thiosemicarbazide. The crude 1-acetyl thiosemicarbazide was dissolved in 70 mL of MeOH and 12 g of sodium methoxide, and was refluxed for 10 h. The solvent was removed and the residue was dissolved in H2O, then acidified to pH 2 by the addition of 1N HCl. The resulting solid was filtered and washed with H2O to give 3-methyl-1,2,4-triazole-5-thiol. 1 g of 3-methyl-1,2,4-triazole-5-thiol was added to a solution of 61 mg of sodium nitrite in 3 ml of nitric acid and 6 mL of H2O at 0° C. The reaction mixture was stirred for 1 h at 0° C., and basified with saturated sodium carbonate and concentrated. The residue was dissolved with MeOH and filtered. The filtrate was evaporated to give 3-methyl-1,2,4-triazole. 230 mg of 4-(2-bromoethylsulfonyl)benzonitrile was used in Procedure P with 3-methyl-1,2,4-triazole to yield 4-(2-(3-methyl-1H-1,2,4-triazole-1-yl)ethylsulfonyl)benzonitrile. 310 mg of 4-(2-(3-methyl-1H-1,2,4-triazole-1-yl)ethylsulfonyl)benzonitrile was reacted via Procedure T to give 4-(2-(3-methyl-1H-1,2,4-triazole-1-yl)ethylsulfonyl)benzoic acid.
Reaction SMILES: C1([O:7][C:8](=O)[NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:29][CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[C:24]([C:27]#[N:28])[CH:25]=4)[N:20]=[CH:19][CH:18]=3)=[CH:12][C:11]=2[Cl:37])C=CC=CC=1.[CH3:39][N:40](C)C=O.O1CCCC1>O>[CH2:30]([O:29][C:23]1[CH:22]=[C:21]2[C:26]([C:17]([O:16][C:13]3[CH:14]=[CH:15][C:10]([NH:9][C:8]([NH:40][CH3:39])=[O:7])=[C:11]([Cl:37])[CH:12]=3)=[CH:18][CH:19]=[N:20]2)=[CH:25][C:24]=1[C:27]#[N:28])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: N#Cc1cc2c(Oc3ccc(NC(=O)Oc4ccccc4)c(Cl)c3)ccnc2cc1OCc1ccccc1
Reactant: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)Nc1ccc(Oc2ccnc3cc(OCc4ccccc4)c(C#N)cc23)cc1Cl
Reaction time: 0.17 h

Procedure:
[4-(7-Benzyloxy-6-cyanoquinolin-4-yloxy)-2-chloro phenyl]carbamic acid phenyl ester (1.17 g) was added to dimethylformamide (6 ml), and then amethylamine-containing 2N tetrahydrofuran solution (0.4 ml) was added and the mixture was stirred for 10 minutes. Water (15 ml) was added, and the precipitated crystals were filtered out and washed with diethyl ether to obtain the title compound (968 mg)
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[OH:11])[CH2:6][CH2:5]1)(=O)C.[OH-].[K+]>C(O)C.O>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)([CH:7]2[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]2)[OH:11])=[CH:19][CH:20]=1
Reactant: CC(=O)N1CCC(C(O)(c2ccccc2)c2ccc(F)cc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: OC(c1ccccc1)(c1ccc(F)cc1)C1CCNCC1
Temperature: 0 °C
Yield: 24.5 %

Procedure:
A mixture of 16.3 g (0.05 mole) of 1-acetyl-α-(4-fluorophenyl) -α-phenyl-4-piperidinemethanol and 5.6 g (0.1 mole) of potassium hydroxide in 150 ml of 95% ethanol and 20 ml of water was heated at reflux for 18 hr. The mixture was poured into 1.5 liters of ice-water and a solid precipitated. The gummy solid was collected by filtration and dried. The solid was dissolved in ethyl ether, filtered, and the filtrate slowly evaporated to 50 ml. The resulting solid was collected by filtration and recrystallized from 2-propanolisopropyl ether to yield 3.5 g (25%) of title compound as a white solid, m.p. 144.5°-146° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=2)[CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH2:6][NH2:7].C(N(CC)CC)C.C1(C(Cl)=[O:32])CC1.[C:34]1([CH3:40])[CH:39]=[CH:38][CH:37]=CC=1>>[Br:1][C:2]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=2)[CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH2:6][NH:7][C:40]([CH2:34][CH:39]1[CH2:38][CH2:37]1)=[O:32]
Reactant: NCCOc1ccc(Oc2cc(F)cc(F)c2)cc1Br
Reactant: O=C(Cl)C1CC1
Reactant: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(CC1CC1)NCCOc1ccc(Oc2cc(F)cc(F)c2)cc1Br
Reaction time: 2 h

Procedure:
To a mixture of 230 g (0,667 mol) of 2-[2-bromo-4-(3,5-difluorophenoxy)phenoxy]ethylamine, 81 g (0.80 mol) of triethylamine and 8 liter of toluene, there is added dropwise a solution of 70 g (0.67 mol) of cyclopropane carbonyl chloride in 2 liter of toluene with stirring at a temperature of from 5° C. to 10° C. After 2 hours, the reaction mixture is stirred at a room temperature for 15 hours. After the reaction is completed, the resultant mixture is washed twice with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is subjected to silica gel chromatography to give N-{2-[2-bromo-4-(3,5-difluorophenoxy)phenoxy]ethyl}-cyclopropane carboxyamide.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:16]([F:19])([F:18])[F:17])=[O:8])[CH2:3][CH2:2]1.CCN(CC)CC.Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>C(#N)C>[CH2:32]([O:31][C:29](=[O:30])[CH2:28][N:1]1[CH2:6][CH2:5][CH:4]([C:7](=[O:8])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:16]([F:17])([F:18])[F:19])[CH2:3][CH2:2]1)[CH3:33]
Reactant: O=C(c1ccccc1OC(F)(F)F)C1CCNCC1
Reactant: CCOC(=O)CBr
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)CN1CCC(C(=O)c2ccccc2OC(F)(F)F)CC1
Temperature: 85 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
To a solution of piperidin-4-yl-(2-trifluoromethoxy-phenyl)-methanone in 5 mL of acetonitrile was added Et3N (0.3 mL, 2.4 mmol, 2 eq.), followed by ethyl 2-bromoacetate (0.14 mL, 1.3 mmol, 1.1 eq.) added dropwise and heated at 85° C. overnight. After 18 h, the reaction mixture was concentrated in vacuo, diluted with saturated NaHCO3 (100 mL) and extracted with ethyl acetate (3×50 mL). The combine organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo to give a dark oil. This oil was purified by silica gel column chromatography (30-50% ethyl acetate/heptane) to give the title as a light brown oil (0.36 g, 85%). Exact mass calculated for C18H22F3N1O4 360.1. MS (ESI) m/z 360.7 (M+H)+.