Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][CH2:13][CH:14]2[O:16][CH2:15]2)[N:3]=1.[NH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:22]=[C:23]([C:27]2[CH:28]([CH3:34])[CH2:29][C:30](=[O:33])[NH:31][N:32]=2)[CH:24]=[CH:25][CH:26]=1>>[OH:1][C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:17][CH2:18][CH2:19][O:20][C:21]2[CH:22]=[C:23]([C:27]3[CH:28]([CH3:34])[CH2:29][C:30](=[O:33])[NH:31][N:32]=3)[CH:24]=[CH:25][CH:26]=2)[N:3]=1
Reactant: CC1CC(=O)NN=C1c1cccc(OCCN)c1
Reactant: OC1=Nc2cccc(OCC3CO3)c2CC1
Product: CC1CC(=O)NN=C1c1cccc(OCCNCC(O)COc2cccc3c2CCC(O)=N3)c1

Procedure:
Prepared analogously to Example 1 from 1-(3,4-dihydro-2-hydroxy-quinolin-5-yloxy)-2,3-epoxypropane and 6-[3-(2-aminoethoxy)phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:9])[CH:5]=[CH:6][C:7]=1[Cl:8].N1C(C)=CC=CC=1C.Br[CH2:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>C1(C)C=CC=CC=1>[C:24]([O:23][C:21](=[O:22])[CH2:20][CH2:19][NH:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)CCBr
Solvent: Cc1ccccc1
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)OC(=O)CCNc1ccc(Cl)c(Cl)c1
Reaction time: 30 h
Yield: 52.2 %

Procedure:
A solution of 9.61 g (59.33 mmol) of 3,4-dichloro-phenylamine and 10.21 ml (59.33 mmol) of 2,6-lutidine in 55 ml of toluene was treated slowly with 6.50 ml (59.33 mmol) of tert-butyl 3-bromopropionate and stirred 30 h at reflux temperature. The reaction was then partitioned between 10% aq. KHSO4 solution and EtOAc (3×). The organic phases were washed with 10% aq. NaCl solution, dried over Na2SO4 evaporated and purified by flash silica gel column (n-heptane:EtOAc 9:1) to yield 8.98 g (52%) of the title compound as off-white solid. MS: 290.0 (MH+, 2Cl).
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].[CH2:5]([Mg]Br)[CH3:6].C(OCC)C.[CH:14]([C@H:17]1[C:21](=[O:22])[CH2:20][CH2:19][N:18]1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])([CH3:16])[CH3:15]>>[CH2:5]([C@:21]1([OH:22])[CH2:20][CH2:19][N:18]([C:23]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:24])[C@H:17]1[CH:14]([CH3:16])[CH3:15])[CH3:6]
Reactant: CC[Mg]Br
Reactant: CC(C)[C@H]1C(=O)CCN1C(=O)OCc1ccccc1
Agent: [Ce+3]
Agent: [Cl-]
Solvent: CCOCC
Product: CC[C@]1(O)CCN(C(=O)OCc2ccccc2)[C@H]1C(C)C

Procedure:
By an operation in the same manner as in Reference Example 3 and using cerium chloride (9.25 g), 3 mol/L ethylmagnesium bromide-diethyl ether solution (11.0 mL) and benzyl (2S)-2-isopropyl-3-oxopyrrolidine-1-carboxylate (3.92 g), the title compound was obtained as colorless oil (yield: 2.21 g, yield: 51%).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]([CH2:14][N:15]3[CH:19]=[C:18]([C:20]([O:22]CC)=[O:21])[CH:17]=[N:16]3)[S:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1.C(O)C.[OH-].[Na+]>O1CCCC1>[F:26][C:2]([F:1])([F:25])[C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]([CH2:14][N:15]3[CH:19]=[C:18]([C:20]([OH:22])=[O:21])[CH:17]=[N:16]3)[S:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1cnn(Cc2nc(-c3cccc(C(F)(F)F)c3)cs2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1cnn(Cc2nc(-c3cccc(C(F)(F)F)c3)cs2)c1
Reaction time: 8 h
Yield: 67.4 %

Procedure:
To the compound (4.80 g, 12.6 mmol) obtained in Example 1c were added ethanol (40 mL), tetrahydrofuran (10 mL) and 2N aqueous sodium hydroxide solution (12.6 mL, 25.2 mmol), and the mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with water, and washed with ether. The aqueous layer was acidified with 6N hydrochloric acid, extracted with ethyl acetate, washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (3.0 g, 67%) as colorless crystals.
Reaction SMILES: [CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([O:51][CH2:52][CH2:53][O:54][CH3:55])[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:15][CH:14]=3)[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]2)=[O:6])[CH2:3][CH2:2]1.Cl.O1CCOCC1>C(Cl)Cl>[CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([O:51][CH2:52][CH2:53][O:54][CH3:55])[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:15][CH:14]=3)[CH2:11][CH2:10][NH:9][CH2:8]2)=[O:6])[CH2:2][CH2:3]1
Reactant: COCCCc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCCOC)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COCCCc1cc(CN(C(=O)[C@H]2CNCC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCCOC)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution tert-butyl (3R,4S)-3-({cyclopropyl[3-(2-methoxyethoxy)-5-(3-methoxypropyl)benzyl]amino}carbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)-ethoxy]phenyl}piperidine-1-carboxylate (1 eq.) from the previous step in DCM (0.05 M) was added 4 M HCl in dioxane (10 eq.) and stirred at rt for 5 h. The reaction was concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 5% [2 M NH3 in MeOH] in DCM) to afford the title compound as a colorless oil. 1H NMR (acetone d-6): δ 7.28 (s, 2H), 7.20 (d, 2H), 6.84 (d, 2H), 6.62 (s, 1H), 6.48 (s, 1H), 6.4 (s, 1H), 4.47-4.25 (m, 6H), 4.05 (t, 2H), 3.71 (t, 2H), 3.56 (m, 1H), 3.38 (s, 3H), 3.33 (t, 2H), 3.28 (s, 3H), 3.25 (m, 1H), 3.11 (m, 2H), 2.76 (m, 2H), 2.55 (t, 2H), 2.34 (s, 3H), 2.32 (m, 1H), 1.78 (m, 4H), 0.77 (m, 3H), 0.49 (m, 1H). LRMS [M+H]=699.0
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]#[N:8].C(N(CC)CC)C.Br[CH2:17][CH2:18][CH2:19]Br>O1CCOCC1>[N:5]1[N:6]2[CH2:17][CH2:18][CH2:19][NH:1][C:2]2=[C:3]([C:7]#[N:8])[CH:4]=1
Reactant: N#Cc1cn[nH]c1N
Reactant: BrCCCBr
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: N#Cc1cnn2c1NCCC2
Temperature: 95 °C
Reaction time: 120 h

Procedure:
To a solution of 5-aminopyrazole-4-carbonitrile (102 g) and triethylamine (316 ml) in 1,4-dioxane (2000 ml) was added 1,3-dibromopropane (115 ml), and the mixture was stirred at 95° C. for 5 days. The insoluble materials were removed by filtration, and the filtrate was concentrated in vacuo. To the residue was added 10% aqueous citric acid solution, and the mixture was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was triturated with 2-propanol and dried in vacuo to give 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile (8.0 g) as a solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:12]([OH:14])=O.C(N(CC)CC)C.ClC(OCC)=O.[CH3:28][NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1>ClCCl>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:12]([N:29]([CH3:28])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)=[O:14]
Reactant: CNc1ccccn1
Reactant: O=C(O)c1nnc2ccccc2c1O
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)c1nnc2ccccc2c1O)c1ccccn1
Reaction time: 1 h
Yield: 14 %

Procedure:
4-Hydroxy-cinnoline-3-carboxylic acid (8.8 g) is dissolved in dichloromethane (600 ml) in the presence of triethylamine (5.6 g). To this solution ethyl chloroformate (6 g) diluted with dichloromethane (50 ml) is added dropwise under stirring at a temperature varying between 0° C. and about 5° C. The mixture is allowed to react at 0°-5° C. for 1 hour, then 2-methylamino-pyridine (4.55 g) is added. The reaction mixture is kept at 0°-5° C. for 1 hour, then at room temperature for 2 hours, under stirring. The organic solution is washed with 2.5% NaHCO3 and water, then is evaporated to dryness in vacuo. The residue is purified over a SiO2 column using ethyl acetate, then ethylacetate-methanol=95:5 as eluents. Crystallization from ethanol yields 1.65 g of 4-hydroxy-N-methyl-N-(2-pyridyl)-cinnoline-3-carboxamide, m.p. 237°-239° C., NMR (DMSO d6) δ ppm: 3.43 (s) (3H, CH3), 7.0-8.3 (m) (8H, phenyl and pyridyl protons).
Reaction SMILES: C1(O)C=CC=CC=1.ClC1C(Cl)=C(C=CC=1)N(Cl)Cl.Cl[C:20]1[C:25]([NH2:26])=[C:24](Cl)[C:23]([Cl:28])=[C:22](Cl)[C:21]=1[Cl:30].Cl.[H][H]>[Ta]>[Cl:28][C:23]1[CH:24]=[C:25]([CH:20]=[C:21]([Cl:30])[CH:22]=1)[NH2:26]
Reactant: [H][H]
Reactant: Nc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Agent: [Ta]
Agent: Cl
Agent: Clc1cccc(N(Cl)Cl)c1Cl
Solvent: Oc1ccccc1
Product: Nc1cc(Cl)cc(Cl)c1
Yield: 97 %

Procedure:
200 parts of phenol, 131 parts of a tetrachloroaniline/pentachloroaniline mixture corresponding to the composition mentioned in Example 3, 1 part of ruthenium-on-charcoal catalyst (5% strength) which has already been used for 10 previous similar experiments, and 12 parts of aqueous hydrochloric acid (57% strength) are reacted in a tantalum autoclave, during the course of 3.5 hours at 165° C., whilst stirring, at a hydrogen pressure of 50 bars. After the usual working up, 90 parts of 99% strength 3,5-dichloroaniline are isolated. Yield: 97% of theory.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][C@H:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH2:25][CH2:26][N:27]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:28][CH:29]=3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.Cl.[OH:36][NH2:37].C(=O)([O-])O.[Na+]>>[CH3:1][C:2]1[CH:7]=[C:6](/[C:8](=[N:37]/[OH:36])/[CH2:9][C@H:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH2:25][CH2:26][N:27]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:28][CH:29]=3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(C3=CCN(S(C)(=O)=O)CC3)cc2)c2ccccc2C)ccn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(C[C@H](c2ccc(C3=CCN(S(C)(=O)=O)CC3)cc2)c2ccccc2C)=N/O)ccn1

Procedure:
In analogy to example 132, step 6, from (R)-1-(2-methylpyridin-4-yl)-3-(4-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-3-o-tolylpropan-1-one and hydroxyl-amine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a colourless foam, MS (ESI+): m/z=490.4 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[N:7]([CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][Si](C(C)(C)C)(C)C)=[CH:22][CH:21]=1)[C:8]1[C:17]2[C:12](=[N:13][CH:14]=[CH:15][N:16]=2)[N:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl.C1COCC1>[C:1]([O:5][C:6](=[O:34])[N:7]([CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[C:8]1[C:17]2[C:12](=[N:13][CH:14]=[CH:15][N:16]=2)[N:11]=[CH:10][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(O[Si](C)(C)C(C)(C)C)cc1)c1ncnc2nccnc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(CCc1ccc(O)cc1)c1ncnc2nccnc12
Reaction time: 18 h

Procedure:
{2-[4-(tert-Butyldimethylsilanyloxy)-phenyl]-ethyl}-pteridin-4-yl-carbamic acid tert-butyl ester (680 mg, 1.4 mmol) was dissolved in 5 mL CH2Cl2 and treated with tetrabutylammonium fluoride 3H2O in 10 mL THF. After stirring for 18 h, the solution was washed with H2O, dried (Na2SO4), suction filtered, and concentrated in vacuo to give [2-(4-hydroxyphenyl)-ethyl]-pteridin-4-yl-carbamic acid tert-butyl ester as a tan solid, mp 132-134° C. (dec.); ESIMS m/z ([M+H]+) 368.
Reaction SMILES: Cl.[CH:2]1([S:5]([C:8]2[CH:13]=[CH:12][C:11](/[C:14](/[C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:29]=[N:30][NH:31][CH:32]=4)=[C:24]([O:33][CH3:34])[N:23]=3)=[CH:15]\[C@@H:16]3[NH:20][C:19](=[O:21])[CH2:18][CH2:17]3)=[CH:10][CH:9]=2)(=[O:7])=[O:6])[CH2:4][CH2:3]1.[H][H]>CO.[Pd]>[CH:2]1([S:5]([C:8]2[CH:9]=[CH:10][C:11]([CH:14]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:29]=[N:30][NH:31][CH:32]=4)=[C:24]([O:33][CH3:34])[N:23]=3)[CH2:15][C@@H:16]3[NH:20][C:19](=[O:21])[CH2:18][CH2:17]3)=[CH:12][CH:13]=2)(=[O:6])=[O:7])[CH2:4][CH2:3]1
Reactant: COc1nc(/C(=C/[C@H]2CCC(=O)N2)c2ccc(S(=O)(=O)C3CC3)cc2)ccc1-c1cn[nH]c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1nc(C(C[C@H]2CCC(=O)N2)c2ccc(S(=O)(=O)C3CC3)cc2)ccc1-c1cn[nH]c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
10% palladium-activated carbon (175 mg) and concentrated hydrochloric acid (1 mL) were added to a solution of (5R)-5-{(E)-2-[4-(cyclopropylsulfonyl)phenyl]-2-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]ethenyl}pyrrolidin-2-one obtained in Example 4-376(1) (175 mg) in methanol (3 mL) in a hydrogen gas stream, and the mixture was stirred at room temperature for five hours. The reaction solution was filtered through celite, and then the solvent was evaporated under reduced pressure. Saturated aqueous sodium bicarbonate was added to the residue, followed by extraction with chloroform. The solvent was evaporated from the organic layer under reduced pressure to give a crude product of (5R)-5-{2-[4-(cyclopropylsulfonyl)phenyl]-2-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]ethyl}pyrrolidin-2-one as a colorless amorphous (129 mg, 73%).
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21])[CH2:16][CH2:17][CH3:18]>>[CH2:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:12](=[O:14])[CH2:10][NH:11][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[S:8][CH:9]=2)=[O:14])[CH2:24][CH2:23]1)=[O:21])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCOC(=O)N1CCNCC1
Reactant: O=C(O)c1csc(-c2ccccc2)n1
Product: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2csc(-c3ccccc3)n2)CC1

Procedure:
This compound was prepared using a method analogous to that of Example 3, step 3.2, 2-phenyl-1.3-thiazole-4-carboxylic acid replacing intermediate 3.1 and intermediate 26.2 replacing piperazine-1-carboxylic acid butyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:25]2[CH2:26][CH2:27][N:22]([C:17]3[N:16]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:23][CH2:24]2)=[O:15])=[CH:6][CH:7]=1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Product: Cc1ccc(-c2oncc2C(=O)N2CCN(c3ncccn3)CC2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 1-(2-pyrimidyl)piperazine (9.9 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (4.4 mg). Calcd for C19H19N5O2: 349.1539, found 349.1538.
Reaction SMILES: C([O:5][C:6](=[O:35])[C:7]([CH3:34])([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=3)=[CH:20][CH:19]=2)[N:14]=1)[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:34][C:7]([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=3)=[CH:20][CH:19]=2)[N:14]=1)([CH3:8])[C:6]([OH:35])=[O:5]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(-c3ccc(C(F)(F)F)cn3)cc2)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(Sc1nc(CCOc2ccc(-c3ccc(C(F)(F)F)cn3)cc2)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 58.6 %

Procedure:
2-Methyl-2-{[4-(2-{4-[5-(trifluoromethyl)pyridin-2-yl]phenoxy}ethyl)-1,3-thiazol-2-yl]thio}propionic acid tert-butyl ester (650 mg) obtained in Example 127-2 was dissolved in dichloromethane (6 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1 to 0:1) to give the title compound (340 mg) as a white solid.
Reaction SMILES: CO[C:3](=[O:20])[C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[O:9])=[CH:6][C:5]=1C1C=CC=CC=1O.CC(C[AlH]C[CH:27]([CH3:29])[CH3:28])C>C1COCC1>[OH:20][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][C:28]2[CH:27]=[CH:29][CH:6]=[CH:7][C:8]=2[OH:9])=[O:9])=[CH:11][CH:12]=1
Reactant: CC(C)C[AlH]CC(C)C
Reactant: COC(=O)c1ccc(C(N)=O)cc1-c1ccccc1O
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1O)c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution of (2-hydroxyphenyl)-terephthalamic acid methyl ester (1.31 g, 4.8 mmol) in THF (50 mL) at −78° C. was added a solution of DIBAL-H (27 mL, 1.0 M in THF). The reaction was allowed to warm to room temperature, stirred for 1 h and quenched with a saturated potassium sodium tartrate solution (15 mL). The biphasic mixture was stirred vigorously for 1 h, the phases separated and the organic layer dried (MgSO4), filtered, concentrated and purified by column chromatography on silica gel (5% MeOH/CH2Cl2) to give 4-hydroxymethyl-N-(2-hydroxyphenyl)-benzamide (0.58 g, 50%). 1H NMR (CDCl3) δ 1.83 (t, 1H (OH)), 4.82 (d, 2H, J=6.0 Hz), 6.93 (t, 1H, J=7.8 Hz), 7.08 (t, 1H, J=7.8 Hz), 7.19 (d, 2H, J=7.8 Hz), 7.53 (d, 2H, J=6.0 Hz), 7.92 (d, 2H, J=7.8 Hz), 8.07 (br, 1H), 8.62 (s, 1H).
Reaction SMILES: C([O-])(=S)C[O:3][CH2:4][C:5]([O-])=[S:6].[NH4+:10].[NH4+].[OH2:12]>>[C:4]([O-:3])(=[O:12])[CH2:5][SH:6].[C:4]([O-:3])(=[O:12])[CH2:5][SH:6].[NH4+:10].[NH4+:10]
Reactant: [O-]C(=S)COCC([O-])=S
Reactant: O
Agent: [NH4+]
Product: O=C([O-])CS

Procedure:
Four types of hair were treated for 15 minutes either with a 2.5 weight percent solution of diammonium dithiodiglycolate at pH 7.0 or with deionized water. The hair was centrifuged at 2,800 r.p.m. for 30 minutes to remove excess surface liquid and then dried in a vacuum oven at 110° C. for one hour. The weight gain corresponding to the take-up of the dithiodiglycolic acid salt was then determined by subtracting any weight gain of the control samples from the test sample weight gains.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]([O:17]C)=[O:16].O[Li].O.Cl>CO.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]([OH:17])=[O:16]
Reactant: COC(=O)[C@@H]1CCCN1c1nc2ccccc2o1
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: O
Product: O=C(O)[C@@H]1CCCN1c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1.66 G (S)-pyrrolidine-2-carboxylic acid methyl ester, hydrochloride salt and 1.15 mL of 2-chlorobenzoxazole in 6 mL CH2Cl2 was subjected to microwave heating at 120° C. for 0.5 h. Solvent was evaporated. Purification by chromatography (SiO2, EtOAc/heptane) provided 2.283 g (93% yield) of (S)-1-benzooxazol-2-yl-pyrrolidine-2-carboxylic acid, methyl ester as a waxy white solid, m/z 247.16 (MH+). A mixture of 2.0 g of (S)-1-benzooxazol-2-yl-pyrrolidine-2-carboxylic acid, methyl ester and 1.02 G LiOH H2O in 15 mL MeOH and 15 mL water was stirred overnight at room temperature. The reaction was acidified with 1N HCl, was extracted three times with MeOH/CH2Cl2, was dried over Na2SO4 and was evaporated to provide the title compound. m/z 233.17 (MH+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:10]3[N:18]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)[CH:16]=[C:15]([C:27]([O:29]C)=O)[C:11]=3[NH:12][C:13]=2[CH:14]=1.[NH3:31]>CO>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:10]3[N:18]=[C:17]([C:19]4[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=4)[CH:16]=[C:15]([C:27]([NH2:31])=[O:29])[C:11]=3[NH:12][C:13]=2[CH:14]=1
Reactant: COCCOc1ccc2c(c1)[nH]c1c(C(=O)OC)cc(-c3ccc(OC)cc3)nc12
Reactant: N
Solvent: CO
Product: COCCOc1ccc2c(c1)[nH]c1c(C(N)=O)cc(-c3ccc(OC)cc3)nc12
Temperature: 60 °C

Procedure:
A suspension of methyl 7-(2-methoxyethoxy)-2-(4-methoxyphenyl)-5H-pyrido[3,2-b]indole-4-carboxylate (28 mg, 0.069 mmol) in 7 N ammonia in MeOH (3mL) in a sealed microwave vial was heated at 60° C. for 22 hr. The solvent was removed and the residue was purified by radial chromatography (step gradient elution with DCM containing 2 to 4% MeOH) to give 7-(2-methoxyethoxy)-2-(4-methoxyphenyl)-5H-pyrido[3,2-b]indole-4-carboxamide (20 mg). MS (ESI) m/z 392.1 (M+H). 1H NMR (MeOD) δ ppm 8.26 (1H, d, J=8.55 Hz), 8.07 (1H, s), 8.01-8.06 (2H, m), 7.16 (1H, d, J=2.14 Hz), 7.06-7.11 (2H, m), 6.94 (1H, d, J=8.55 Hz), 4.21-4.29(2H, m), 3.89(3H, s), 3.83 (2H, dd), 3.45-3.51 (3H, s).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[I-].[CH2:48]([N+:52]1[N:56]=[C:55]([CH3:57])[S:54][C:53]=1[CH3:58])[CH2:49][CH2:50][CH3:51]>>[CH2:48]([N:52]1[N:56]=[C:55]([CH3:57])[S:54]/[C:53]/1=[CH:58]\[C:6]([C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:1])([F:13])[F:12])[CH:4]=1)=[O:8])[CH2:49][CH2:50][CH3:51]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: CCCC[n+]1nc(C)sc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 3-(trifluoromethyl)benzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.92 (t, 3H) 1.30-1.39 (m, 2 H) 1.72-1.80 (m, 2 H) 2.49-2.51 (m, 3 H) 4.30 (t, 2 H) 6.83-6.85 (m, 1 H) 7.69-7.74 (m, 1 H) 7.80-7.89 (m, 1 H) 8.25-8.30 (m, 1 H) 8.32-8.36 (m, 1H); MS (ESI) m/z 343 (M+H)+.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:50][N:51]1[CH:55]=[C:54]([C:56]2[CH:57]=[C:58]([NH2:62])[CH:59]=[CH:60][CH:61]=2)[CH:53]=[N:52]1>CN(C=O)C>[CH3:50][N:51]1[CH:55]=[C:54]([C:56]2[CH:57]=[C:58]([NH:62][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:59]=[CH:60][CH:61]=2)[CH:53]=[N:52]1
Reactant: Cn1cc(-c2cccc(N)c2)cn1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4cnn(C)c4)c3)c(=O)oc12
Temperature: 25 °C
Yield: 69.7 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(1-methyl-1H-pyrazol-4-yl)-phenylamine (0.011 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.017 g of product in 71% yield: LCMS (ESI) m/z 376 (MH+).