Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:11]=[CH:12][C:13]([O:16][C@H:17]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[CH3:18])=[N:14][CH:15]=1.[OH:31]OS([O-])=O.[K+].[OH2:37]>CC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:9])(=[O:31])=[O:37])[CH:5]=[CH:4][C:3]=1[C:10]1[N:11]=[CH:12][C:13]([O:16][C@H:17]([CH:19]2[CH2:20][CH2:21][N:22]([C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:24]2)[CH3:18])=[N:14][CH:15]=1
Reactant: O=S([O-])OO
Reactant: O
Reactant: CSc1ccc(-c2cnc(O[C@@H](C)C3CCN(C(=O)OC(C)C)CC3)cn2)c(F)c1
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)OC(=O)N1CCC([C@H](C)Oc2cnc(-c3ccc(S(C)(=O)=O)cc3F)cn2)CC1

Procedure:
The title compound (0.195 g) was prepared from 1-methylethyl 4-[(1S)-1-({5-[2-fluoro-4-(methylthio)phenyl]-2-pyrazinyl}oxy)ethyl]-1-piperidinecarboxylate (0.33 g, 0.76 mmol) and Oxone® (1.41 g, 2.29 mmol) in acetone (25 mL) and water (10 mL) in a manner similar to Example 166, Step 2. The crude product was purified by chromatography on an ISCO silica gel column using 0 to 50% EtOAc/hexanes, followed by chiral separation on an AS-H column with 25% MeOH in CO2, 140 bar, 40° C. at 2 mL/min. The first eluting peak was further purified by trituration with 9% EtOAc/hexanes to afford the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.64 (s, 1H), 8.27 (s, 1H), 8.20 (t, 1H, J=7.8 Hz), 7.85-7.70 (m, 2H), 5.20-5.10 (m, 1H), 4.89 (septet, 1H, J=6.2 Hz), 4.30-4.15 (m, 2H), 3.09 (s, 3H), 2.80-2.65 (m, 2H), 1.90-1.65 (m, 3H), 1.40-1.15 (m, 11H); LRMS (ESI), m/z 466 (M+H).
Reaction SMILES: C([Li])CCC.[CH3:6][CH:7]1[S:12][CH2:11][CH2:10][CH2:9][S:8]1.[CH:13](=[O:17])[CH2:14][CH2:15][CH3:16].O>CCCCCC.O1CCCC1>[OH:17][CH:13]([C:7]1([CH3:6])[S:12][CH2:11][CH2:10][CH2:9][S:8]1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCC=O
Reactant: CC1SCCCS1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CCCC(O)C1(C)SCCCS1
Temperature: -30 °C
Reaction time: 2 h

Procedure:
56 mmol of n-butyllithium (35 ml of a 1.6 M solution in hexane) were added with stirring to a solution of 2-methyl-1,3-dithian (7 g, 52.1 mmol) in 100 ml of dry tetrahydrofuran at −30° C. under argon. After stirring at −30° C. for 2 hours, the mixture was cooled to −78° C. 4.2 g (58.3 mmol) of freshly distilled n-butyraldehyde were added dropwise in the course of 15 minutes and the mixture was stirred for a further 30 minutes. After warming to 20° C., it was poured into a beaker containing 300 ml of water and 100 ml of n-hexane. The organic phase was separated off and the aqueous phase was extracted three times with 50 ml of dichloromethane in each case. The combined organic phases were washed with 10% strength by weight potassium hydroxide solution, water and concentrated sodium chloride solution, dried over anhydrous sodium sulfate and then distilled. 8.82 g of 2-(1-hydroxybutyl)-2-methyl-1,3-dithian were isolated as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[N:4][NH:5][C:6]=1[C:7]([F:10])([F:9])[F:8].C([O-])([O-])=O.[K+].[K+].Cl[CH2:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([O:41][CH3:42])[CH:35]=2)[CH2:30][CH2:29]1)=[O:27].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[Cl:40][C:37]1[CH:38]=[CH:39][C:34]([N:31]2[CH2:32][CH2:33][N:28]([C:26](=[O:27])[CH2:25][N:5]3[C:6]([C:7]([F:8])([F:9])[F:10])=[C:2]([Cl:1])[C:3]([C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=4)=[N:4]3)[CH2:29][CH2:30]2)=[CH:35][C:36]=1[O:41][CH3:42]
Reactant: COc1cc(N2CCN(C(=O)CCl)CC2)ccc1Cl
Reactant: Fc1cccc(-c2n[nH]c(C(F)(F)F)c2Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1cc(N2CCN(C(=O)Cn3nc(-c4cccc(F)c4)c(Cl)c3C(F)(F)F)CC2)ccc1Cl

Procedure:
Protocol T was followed using 4-Chloro-3-[3-Fluorophenyl]-5-trifluoromethyl-1H-pyrazole, K2CO3, 2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=2/3, Rf=0.51) afforded the title compound as a white solid. 1H NMR (400 MHz, CDCl3): 7.44–7.52 (m, 1H), 7.18–7.28 (m, 4H), 6.38–6.48 (m, 2H), 4.94 (s, 2H), 3.84 (s, 3H), 3.52–3.78 (m, 4H), 3.12 (s, 4H).
Reaction SMILES: [OH:1][CH2:2][CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1.[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[C:36]([O:1][CH2:2][CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C=CCO)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: O=C(Cl)c1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(C=CCOC(=O)c3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
Acylation of tert-butyl (3RS,4RS)-4-[4-(3-hydroxy-propenyl)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate with benzoyl chloride analogously to the procedure described in Example 22(k) yielded tert-butyl (3RS,4RS)-4-[4-(3-benzoyloxy-propenyl)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless resin; MS: 578 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:15]2([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:5]=[C:6]([O:9][CH2:10][C:11]([F:14])([F:13])[F:12])[C:7]=1I.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.[F-].[Cs+].CCOC(C)=O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:23]([O:22][C:20]([C:15]1([C:4]2[CH:5]=[C:6]([O:9][CH2:10][C:11]([F:14])([F:13])[F:12])[C:7]([C:30]3[CH:31]=[CH:32][C:27]([C:26]([F:37])([F:36])[F:25])=[CH:28][CH:29]=3)=[C:2]([Cl:1])[CH:3]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:21])[CH3:24]
Reactant: CCOC(=O)C1(c2cc(Cl)c(I)c(OCC(F)(F)F)c2)CCCC1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C1(c2cc(Cl)c(-c3ccc(C(F)(F)F)cc3)c(OCC(F)(F)F)c2)CCCC1
Yield: 80.8 %

Procedure:
A mixture of ethyl 1-(3-chloro-4-iodo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate (0.58, 1.2 mmol), 4-trifluoromethylphenylboronic acid (0.56 g, 2.4 mmol), CsF (0.46 g, 3.0 mmol) and Pd (PPh3)4 (0.14 g, 0.12 mmol) in 20 mL anhydrous 1,2-dimethoxy ethane was refluxed for 8 h under argon. The reaction mixture was cooled, and 25 mL of EtOAc and 25 mL of water were added. The organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to yellow oil. The oil was purified by column chromatography over silica gel (hexane/EtOAc, 95:5) to give ethyl-1-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclopentanecarboxylate (0.480 g) as a color less oil.
Reaction SMILES: O[CH2:2][C@@H:3]([NH2:8])[CH2:4][CH:5]([CH3:7])[CH3:6].COC(=O)[C@H](CC(C)C)N.OCCN.[Cl:23][C:24]1[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[C:26]([CH3:32])[C:25]=1[N:33]=[C:34]=[S:35]>>[Cl:23][C:24]1[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[C:26]([CH3:32])[C:25]=1[N:33]=[C:34]1[NH:8][C@@H:3]([CH2:4][CH:5]([CH3:7])[CH3:6])[CH2:2][S:35]1
Reactant: CC(C)C[C@H](N)CO
Reactant: Cc1cc(C#N)cc(Cl)c1N=C=S
Agent: COC(=O)[C@@H](N)CC(C)C
Solvent: NCCO
Product: Cc1cc(C#N)cc(Cl)c1N=C1N[C@@H](CC(C)C)CS1

Procedure:
(1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S) -1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2-Chloro-4-cyano-6-methylphenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method C1c to give (4S)-2-(2-chloro4-cyano-6-methylphenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2f to afford (4S)-2-(2-chloro-4-cyano-6-methylphenylimino)-3,4-diisobutyl-1,3-thiazolidine trifluoroacetate salt.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C(=O)(O)[O-].[Na+].[CH:10]1[C:22]2[CH:21]([CH2:23][O:24][C:25](Cl)=[O:26])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH:13]=[CH:12][CH:11]=1>O1CCCC1.O>[CH:10]1[C:22]2[CH:21]([CH2:23][O:24][C:25](=[O:26])[NH:4][CH2:3][CH2:1][OH:2])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: NCCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCCO)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.9 %

Procedure:
To a stirred mixture of ethanolamine (0.49 g, 8 mmol), tetrahydrofuran, water and sodium bicarbonate (1.5 g, 18 mmol) at 6° C., was added a solution 9-fluorenylmethylchloroformate (2.27 g, 8.8 mmol) in tetrahydrofuran in one portion, stirring was continued for 1 h allowing the mixture to warm to room temperature. The mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate filtered and evaporated to a crude product. The crude product was re-crystallised from dichloromethane to give (2-hydroxy-ethyl)-carbamic acid 9H-fluoren-9-ylmethyl ester as a white solid (1.2 g).
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[CH:8]=[C:9](Br)[CH:10]=[C:11]2[C:16]=1[O:15][C:14]([CH3:18])([CH3:17])[CH2:13][C:12]2([CH3:20])[CH3:19])=[O:6])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:29][Si:30]([C:33]#[CH:34])([CH3:32])[CH3:31].C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:1]([O:4][C:5]([C:7]1[CH:8]=[C:9]([C:34]#[C:33][Si:30]([CH3:32])([CH3:31])[CH3:29])[CH:10]=[C:11]2[C:16]=1[O:15][C:14]([CH3:18])([CH3:17])[CH2:13][C:12]2([CH3:20])[CH3:19])=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)c1cc(Br)cc2c1OC(C)(C)CC2(C)C
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)c1cc(C#C[Si](C)(C)C)cc2c1OC(C)(C)CC2(C)C
Yield: 69.4 %

Procedure:
Following General Procedure D and using 6-bromo-2,2,4,4-tetramethylchroman-8-carboxylic acid isopropyl ester (Intermediate 42, 0.32 g, 0.89 mmol), triethyl amine (2 mL), copper(I)iodide (0.060 g, 0.33 mmol), trimethylsilyl acetylene (0.5 mL, 3.56 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.16 g, 0.22 mmol) followed by flash column chromatography over silica gel (230–400 mesh) using 20% ethyl acetate in hexane as the eluent, the title compound (0.23 g, 69%) was obtained as a yellow oil.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH:5]([NH:12][C:13]([O:15][CH3:16])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)C.[Li+].[OH-]>C1COCC1.CO.C(Cl)Cl>[CH3:16][O:15][C:13]([NH:12][CH:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[C:4]([OH:17])=[O:3])=[O:14]
Reactant: CCOC(=O)C(NC(=O)OC)c1ccccn1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)NC(C(=O)O)c1ccccn1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of Methoxycarbonylamino-pyridin-2-yl-acetic acid ethyl ester (0.26 g, 1.1 mmol) in THF (6.0 mL) and MeOH (2.0 mL) was added aqueous LiOH (2.5 M, 2.2 mL, 5.5 mmol). The solution was stirred at room temperature for 1.5 h. The reaction was diluted with CH2Cl2 and washed with aqueous ammonium chloride and brine. The aqueous layers were combined and concentrated. The resulting solid was triterated with MeOH and filtered. The filtrated was concentrated and triterated a second time with MeOH. Concentration of the filtrate provided Methoxycarbonylamino-pyridin-2-yl-acetic acid which was used crude in the next step. LCMS-ESI+: calc'd for C9H10N2O4: 210.06 (M+); Found: 210.98 (M+H+).
Reaction SMILES: [CH:1](OCC)=[O:2].[H-].[Na+].[CH3:8][O:9][C:10]1[CH:18]=[C:17]2[C:13]([CH2:14][CH2:15][C:16]2=[O:19])=[CH:12][CH:11]=1.O>C1C=CC=CC=1>[OH:2][CH:1]=[C:15]1[CH2:14][C:13]2[C:17](=[CH:18][C:10]([O:9][CH3:8])=[CH:11][CH:12]=2)[C:16]1=[O:19]
Reactant: CCOC=O
Reactant: COc1ccc2c(c1)C(=O)CC2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: COc1ccc2c(c1)C(=O)C(=CO)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a mixture of ethyl formate (15.75 mL, 0.195 mol) and NaH (60%, 7.80 g, 0.195 mol) in benzene (550 mL) was added a suspension of 6-methoxy-indan-1-one (15.81 g, 0.0974 mol) in benzene (150 mL) dropwise at 0° C. The reaction mixture was stirred at room temperature overnight and treated with water. The solid was filtered, washed with water, and oven dried to give the desired product (16.86 g, 91%). The product may exist in sodium salt form, however, it was carried into the next reaction without further characterization. MS (DCI/NH3) m/z: 191.1 (M+H)+; 1H NMR (300 MHz, DMSO-D6) δ ppm 3.50 (s, 2H) 3.80 (s, 3H) 7.13-7.20 (m, 2H) 7.47 (d, J=8.14 Hz, 1H) 7.74 (s, brd, 1H).
Reaction SMILES: Cl.[C:2](N)(=[NH:5])[CH2:3][CH3:4].[CH3:7][O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([NH:15][NH2:16])=[O:14])=[CH:11][CH:10]=1>>[NH:5]=[C:2]([N:15]([C:13](=[O:14])[C:12]1[CH:11]=[CH:10][C:9]([O:8][CH3:7])=[CH:18][CH:17]=1)[NH2:16])[CH2:3][CH3:4]
Reactant: CCC(=N)N
Reactant: COc1ccc(C(=O)NN)cc1
Agent: Cl
Product: CCC(=N)N(N)C(=O)c1ccc(OC)cc1

Procedure:
Prepared from 4.90 g (45 mmol) of propioamidine hydrochloride and 5.00 g (30 mmol) of 4-methoxy-benzoic acid hydrazide analogously to the method described in P-1-a). After the ethanol has been distilled off 10.0 g of crude product are obtained which are reacted without any further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:17]([C:18]([OH:20])=O)=[C:12]2[N:13]=[CH:14][CH:15]=[CH:16][N:11]2[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:54][C:55]1[CH:56]=[CH:57][C:58]([O:67][CH:68]([F:70])[F:69])=[C:59]([C:61]2[NH:65][N:64]=[CH:63][C:62]=2[NH2:66])[CH:60]=1>CN(C=O)C.O>[Cl:54][C:55]1[CH:56]=[CH:57][C:58]([O:67][CH:68]([F:70])[F:69])=[C:59]([C:61]2[C:62]([NH:66][C:18]([C:17]3[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[N:10][N:11]4[CH:16]=[CH:15][CH:14]=[N:13][C:12]=34)=[O:20])=[CH:63][NH:64][N:65]=2)[CH:60]=1
Reactant: CC(C)(C)OC(=O)Nc1nn2cccnc2c1C(=O)O
Reactant: Nc1cn[nH]c1-c1cc(Cl)ccc1OC(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1nn2cccnc2c1C(=O)Nc1c[nH]nc1-c1cc(Cl)ccc1OC(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 76939.6 %

Procedure:
To a solution of compound 2-tert-butoxycarbonylamino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (2.78 g, 0.01 mol) in DMF (40 mL) was added DIPEA (3.9 g, 0.03 mol), HATU (3.8 g, 0.01 mol) and 5-(5-chloro-2-difluoromethoxyphenyl)-1H-pyrazol-4-ylamine (2.6 g, 0.01 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into water and the precipitate was collected to give the target compound as a solid (4 g, 77%). LCMS (Method 7) [M+Na]+=541.9, RT=1.20 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 13.13 (s, 1H), 9.58 (s, 2H), 9.2 (dd, 1H, J=7.2, 1.6 Hz), 8.58 (d, 1H, J=2), 8.27 (s, 1H), 7.60 (m, 2H), 7.23-7.04 (m, 3H), 1.48 (s, 9H).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([CH3:40])[C:27]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([Cl:39])[CH:34]=2)([OH:32])[C:28]([F:31])([F:30])[F:29])=[C:22]([Cl:41])[CH:21]=1>C(Cl)Cl>[Cl:41][C:22]1[CH:21]=[C:20]([NH:19][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:25]=[CH:24][C:23]=1[CH:26]([CH3:40])[C:27]([C:33]1[CH:38]=[CH:37][N:36]=[C:35]([Cl:39])[CH:34]=1)([OH:32])[C:28]([F:31])([F:30])[F:29]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(c1ccc(N)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(c1ccc(NC(=O)c2ccccc2)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N,N-diisopropylethylamine (0.117 ml) and benzoyl chloride (0.024 ml) were added to a solution of 3-(4-amino-2-chloro-phenyl)-2-(2-chloro-pyridin-4-yl)-1,1,1-trifluoro-butan-2-ol (25 mg) in DCM (3 ml). The mixture was stirred at room temperature for 2 h and then concentrated in vacuo. Purification by preparative HPLC (Phenomenex Gemini Axia-C18 column, solvent gradient 30-95% CH3CN in 0.1% HCOOH[aq]) gave the title compound (35 mg) as a white foam. MS (m/e)=469.2 [M+H+].
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:13]([CH3:14])[N:12]=[CH:11][C:10]=1[C:15]([O:17]CC)=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[Li].O.O>C1COCC1.CO>[CH2:1]([O:8][C:9]1[N:13]([CH3:14])[N:12]=[CH:11][C:10]=1[C:15]([OH:17])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnn(C)c1OCc1ccccc1
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cn1ncc(C(=O)O)c1OCc1ccccc1
Yield: 90.3 %

Procedure:
Ethyl 5-benzyloxy-1-methylpyrazole-4-carboxylate (755 mg, 2.9 mmol) was likewise hydrolyzed using LiOH.H2O (243 mg, 5.8 mmol) in THF (20 mL), MeOH (4 mL), and water (10 mL), to afford 608 mg of 5-benzyloxy-1-methyl-4-carboxylic acid (25) as a white solid, m.p. 117-122° C.
Reaction SMILES: [CH2:1](OC1C=CC=CC=1)[C:2]1C=CC=[CH:4][CH:3]=1.[CH2:15]([N:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:29]1([N:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:15][C:16]2[C:17]3[C:18](=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:19]=[CH:20][CH:21]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: c1ccc(CN(c2ccccc2)c2ccccc2)cc1
Reactant: c1ccc(COc2ccccc2)cc1
Product: c1ccc(N(Cc2cccc3ccccc23)c2ccccc2)cc1
Yield: 74 %

Procedure:
N-phenylnaphthaldimine (2.20 g, 0.010 mol) and benzylphenyl ether (1.84 g, 0.010 mol) were reacted as above for the preparation of benzyldiphenylamine. Aqueous work-up afforded a precipitate which was isolated by filtration and recrystallized from 95% ethanol to yield 2.3 g (74%) of needles, mp 170°-172° C. Anal. calcd. for C23H19N: C 89.28, H 6.19, N 4.53%; found: C 89.11, H 6.26, N 4.44%. 1H NMR (200 MHz, CDCl3) δ(assignment): 5.52 (s, 2H, CH2), 7.00-8.10 (m, 17H, aromatic). MS [m/e (70 ev, % of base peak)](C10H7)CH2N(C6H5)2 309 (M+., 4.8), 308 (M+--H., 29.0), 168 (M+--((C10H7)CH2)., 18.0), 141 (((C10H7)CH2)+., 100 ). FTIR (CDCl3): 3063, 3040, 1606, 1602, 1594, 1584, 1574, 1559, 1512, 1501, 1497, 1488, 1485, 1474, 1465, 1460, 1451 cm-1.
Reaction SMILES: ClCCl.[N+:4]([C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][O:12][C:13]2=[O:14])=[CH:9][CH:8]=1)([O-:6])=[O:5].[Br:17]Br.OO>O>[N+:4]([C:7]1[CH:16]=[C:15]2[C:10]([CH:11]([Br:17])[O:12][C:13]2=[O:14])=[CH:9][CH:8]=1)([O-:6])=[O:5]
Reactant: O=C1OCc2ccc([N+](=O)[O-])cc21
Reactant: BrBr
Agent: OO
Solvent: ClCCl
Solvent: O
Product: O=C1OC(Br)c2ccc([N+](=O)[O-])cc21

Procedure:
To 125 ml of a dichloromethane solution of 6-nitrophtalide (8.0 g, 0.047 mol), bromine (8.25 g, 0.052 mol, 1.15 eq) and hydrogen peroxide (5.07 g of a 35% solution in water, equivalent to 1.77 of hydrogen peroxide, 0.052 mol, 1.15 eq) were added. The mixture was gently refluxed for 11 hours, then cooled down and concentrated by solvent evaporation. The aqueous layer was separated, and the organic phase washed with water before drying up (Na2SO4).
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH3:7])[CH2:4][NH2:5])[CH3:2].[CH3:8][O:9][C:10](=[O:15])[CH2:11][C:12](=O)[CH3:13].[CH3:16][O:17][C:18](=[O:21])[C:19]#[CH:20]>CO>[CH3:16][O:17][C:18](=[O:21])[CH:19]=[CH:20][C:11](=[C:12]([NH:5][CH2:4][CH:3]([CH2:6][CH3:7])[CH2:1][CH3:2])[CH3:13])[C:10]([O:9][CH3:8])=[O:15]
Reactant: CCC(CC)CN
Reactant: COC(=O)CC(C)=O
Reactant: C#CC(=O)OC
Solvent: CO
Product: CCC(CC)CNC(C)=C(C=CC(=O)OC)C(=O)OC
Temperature: 25 °C
Yield: 57.9 %

Procedure:
A mixture of 2-ethyl-butylamine (4.5 g, 44.6 mmol) and 3-oxo-butyric acid methyl ester (5.8 mL, 53.5 mmol) in MeOH (170 mL) was refluxed for 2 h. Propynoic acid methyl ester (6 mL, 66.8 mmol) was added, and the resulting mixture was refluxed for 2 days. After cooling to r.t., the solvent was evaporated. The residue was purified by silica gel chromatography (0-30% EtOAc/hexanes) to give 7.32 g of the title compound as an orange oil. MS: (+) m/z 284.35 (M+1).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6]([NH2:15])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)=[O:5].Cl.C(N(CC)CC)C.[CH:24]([C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[S:35])=[CH:29][CH:28]=1)([CH3:26])[CH3:25]>CCOCC>[CH:24]([C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH:15][CH:6]([C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH2:7][C:8]2[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=2)=[S:35])=[CH:29][CH:28]=1)([CH3:26])[CH3:25]
Reactant: CC(C)c1ccc(N=C=S)cc1
Reactant: CCOC(=O)C(N)Cc1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)C(Cc1ccc(Cl)cc1)NC(=S)Nc1ccc(C(C)C)cc1
Temperature: 0 °C
Yield: 80 %

Procedure:
DL-4-Chlorophenylalanine ethyl ester hydrochloride(5 g, 18.9 mmol) was converted to the free base using triethylamine. A solution of the free base in 75 mL ether was added to a solution of 4-isopropylphenylisothiocyanate in 150 mL ether, cooled on an ice-salt bath. The temperature was maintained at about 0° C. during addition. The reaction was stirred for four and one-half hours, at which time the reaction temperature was 12° C.. The reaction mixture was filtered, the filtrate concentrated, and the resulting foamy residue triturated with petroleum ether while cooling on ice. This resulted in 6.1 g (15.1 mmol, 80%) N-(4-isopropylphenyl)-N'-[2-(4-chlorophenyl)-1-(ethoxycarbonyl)ethyl]thiourea, mp 73°-75° C.
Reaction SMILES: Cl.[CH3:2][C@H:3]([CH2:6][C:7]([F:10])([F:9])[F:8])[CH2:4][NH2:5].[C:11]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH3:23])[CH:18]=[C:17]2[CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][C:26]=1[O:35][CH3:36])(O)=[O:12].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:36][O:35][C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][C:25]=1[CH2:24][C:17]1[C:16]2[C:20](=[CH:21][CH:22]=[C:14]([C:11](=[O:12])[NH:5][CH2:4][C@H:3]([CH3:2])[CH2:6][C:7]([F:10])([F:9])[F:8])[CH:15]=2)[N:19]([CH3:23])[CH:18]=1)[C:29]([O:31][CH3:32])=[O:30]
Reactant: COC(=O)c1ccc(Cc2cn(C)c3ccc(C(=O)O)cc23)c(OC)c1
Reactant: C[C@@H](CN)CC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(Cc2cn(C)c3ccc(C(=O)NC[C@H](C)CC(F)(F)F)cc23)c(OC)c1
Reaction time: 18 h
Yield: 55.1 %

Procedure:
A mixture of (R)-2-methyl-4,4,4-trifluorobutylamine hydrochloride (9.79 g), methyl 4-(5-carboxy-1-methylindol-3-ylmethyl)-3-methoxybenzoate (20.55 g), 4-dimethylaminopyridine (7.45 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (15.07 g) and triethylamine (9.3 mL) was dissolved in dry methylene chloride (240 mL) and the solution was stirred under an inert atmosphere for 18 h. The mixture was diluted with methylene chloride (200 mL) and washed twice with 1N hydrochloric acid. The combined acid washes were back extracted with methylene chloride and the combined organic extracts were washed (water, brine), dried (MgSO4), and evaporated. The residue was purified by flash chromatography, eluting with 97:3 methylene chloride:ethyl acetate to give methyl (R)-3-methoxy-4-[1-methyl-5-(2-methyl-4,4,4-trifluorobutylcarbamoyl)indol-3-ylmethyl]benzoate (14.48 g, 55%) as a white solid; mp 150°-151° C.; partial NMR (300 MHz, CDCl3): 1.12 (d, 3H, CH3), 1.98-2.08 (m, 1H, CHCH3) 2.12-2.44 (m, 2H, CF3CH2), 3.30-3.58 (m, 2H, CH2N), 3.76 (s, 3H, NCH3), 3.90 (s, 3H, OCH3), 3.93 (s, 3H, OCH3), 4.13 (s, 2H, ArCH2Ar'), 6.23 (br t, 1H, NHCO).