Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H].Cl>[Pd].CO.Cl>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: COc1ccc(C2=CCN(Cc3ccccc3)CC2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1ccc(C2CCN(Cc3ccccc3)CC2)cc1
Reaction time: 8 h

Procedure:
Palladium on carbon (10%, 0.0695 g) is added to a mixture of 1-benzyl-1,2,3,6-tetrahydro-4-(4-methoxyphenyl)pyridine (XVI, Step 2, 0.6843 g, 2.4 mmol) in methanol/hydrochloric acid and the mixture is shaken overnight under approximately 40 psi of hydrogen. Additional palladium on carbon and concentrated hydrochloric acid are added and the mixture is again shaken overnight under hydrogen. The palladium on carbon then is filtered off and the filtrate is concentrated. The residue is partitioned between dichloromethane and saturated sodium bicarbonate and the combined organic phases are backwashed with saturated sodium bicarbonate, dried over magnesium sulfate, and concentrated to give 1-benzyl-4-(4-methoxyphenyl)piperidine (XVIII), NMR (CDCl3) 1.77, 2.07, 2.45, 3.00, 3.55, 3.78, 6.85, 7.16 and 7.31 δ.
Reaction SMILES: [CH2:1]([N:8]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.[CH:29]1[CH:30]=[CH:31][C:32]2[N:37](O)N=[N:35][C:33]=2[CH:34]=1.C1(N)C=CC=CC=1N>CN(C=O)C.CCOC(C)=O>[NH2:35][C:33]1[CH:34]=[CH:29][CH:30]=[CH:31][C:32]=1[NH:37][C:13](=[O:14])[C:12]1[CH:11]=[CH:10][C:9]([N:8]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:17][CH:16]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1ccc(N(Cc2ccccc2)Cc2ccccc2)cc1
Agent: Nc1ccccc1N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: Nc1ccccc1NC(=O)c1ccc(N(Cc2ccccc2)Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-(dibenzylamino)benzoic acid (50 mg, 0.16 mmol) in DMF was added EDC (181 mg, 0.95 mmol), HOBt (128 mg, 0.95 mmol) and phenylenediamine (171 mg, 1.58 mmol) were which was allowed to stir at room temperature for 12 hours. The crude reaction mixture was diluted with EtOAc (20 mL) and then washed with sat.'d aq. NaHCO3 (1×10 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by reverse-phase chromatography (20-100% MeCN/H2O with 0.05% TFA). The appropriate fractions were combined, diluted with EtOAc (20 mL) and washed with sat.'d aq. NaHCO3 (1×10 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to gave the desired N-(2-aminophenyl)-4-(dibenzylamino)benzamide: 1H NMR (600 MHz, MeOH-d4) δ 7.83 (d, J=9.0 Hz, 2H), 7.31 (m, 6H), 7.25 (m, 8H), 6.81 (d, J=9.1 Hz, 2H), 4.79 (s, 4H); cal'd 408.2 (MH+), exp 408.2 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]([CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:26])[CH2:17][CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])=[CH:12][CH:11]=1)[CH3:6].FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]([CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:26])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:12][CH:11]=1)[CH3:6]
Reactant: CN(CCOc1ccc(C(=O)CCC(=O)OC(C)(C)C)cc1)Cc1ccccc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(CCOc1ccc(C(=O)CCC(=O)O)cc1)Cc1ccccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of tert-Butyl 4-[4-(2-(N-(2-fluorobenzyl)-N-methylamine)ethoxy)phenyl]-4-oxobutyrate (Step E, 2.23 g, 5.3 mol) in dichloromethane (20 ml) was treated with trifluoroacetic acid (10 ml). The reaction mixture was stirred at ambient temperature for 2 hours, and concentrated in vacuo. The purification was done by flash chromatography on silica gel column (chloroform:methanol, 92.5:7.5-90:10 spiked with acetic acid) to provide the title compound.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].Cl[C:12]1[N:17]=[CH:16][C:15]([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26](=[O:28])[CH3:27])=[C:22]([OH:29])[C:21]=2[CH2:30][CH2:31][CH3:32])=[CH:14][CH:13]=1>CN(C)C=O.C(OCC)(=O)C>[C:26]([C:23]1[CH:24]=[CH:25][C:20]([O:19][CH2:18][C:15]2[CH:14]=[CH:13][C:12]([S:1][C:2]3[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=3)[C:5]([OH:7])=[O:6])=[N:17][CH:16]=2)=[C:21]([CH2:30][CH2:31][CH3:32])[C:22]=1[OH:29])(=[O:28])[CH3:27]
Reactant: O=C(O)c1cccc(S)c1
Reactant: CCCc1c(OCc2ccc(Cl)nc2)ccc(C(C)=O)c1O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(OCc2ccc(Sc3cccc(C(=O)O)c3)nc2)ccc(C(C)=O)c1O
Reaction time: 0.17 h

Procedure:
Dissolve 3-mercapto-benzoic acid (482 mg, 3.13 mmol, commercially available) in dimethylformamide (20 mL) at 0° C. Add washed sodium hydride (300 mg), and stir the mixture for 10 minutes. Add 1-[4-(6-chloro-pyridin-3-ylmethoxy)-2-hydroxy-3-propyl-phenyl]-ethanone (1.00 g, 3.13 mmol). Stir the mixture at room temperature for 2 hours; then stir at 65° C. for 2 hours and finally stir at 120° C. overnight. Dilute in ethyl acetate, and wash with water twice. Extract the organic layer with saturated aqueous sodium bicarbonate. Acidify the aqueous layer with 2N hydrochloric acid hydrochloric acid to pH 3. Extract with ethyl acetate, wash with brine, dry and concentrate to afford 620 mg of a crude red solid. Purify the residue via chromatography, eluting with 1:1 hexane:ethyl acetate to afford the title compound as a light yellow powder (120 mg): 1H NMR (DMSO-d6) δ 0.84 (s, 3H), 1.44 (sextet, 2H), 2.55 (t, 2H), 2.58 (s, 3H), 5.24 (s, 2H), 6.74 (d, 1H), 7.14 (d, 1H), 7.63 (t, 1H), 7.75 (d, 1H), 7.81-7.84 (m, 2H), 8.02 (d, 1H), 8.05 (s, 1H), 8.51 (s, 1H), 12.84 (s, 1H), 13.21 (bs, 1H); MS (APCI-neg mode) m/z (rel intensity) 436 (100).
Reaction SMILES: [F:1][C:2]([F:12])([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)[CH:3]=O.[CH:13](I)(I)[I:14].O>O1CCCC1.[Cl-].[Cl-].[Cr+2]>[F:1][C:2]([F:12])([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)[CH:3]=[CH:13][I:14]
Reactant: O=CC(F)(F)c1ccc(Cl)cc1
Reactant: IC(I)I
Agent: [Cr+2]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: FC(F)(C=CI)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Under a nitrogen atmosphere, a stirred suspension of 29.5 grams (0.24 mole) of anhydrous chromium(II) dichloride in 400 mL of tetrahydrofuran is cooled to 0° C., and a solution of 7.6 grams (0.04 mole) of difluoro-4-chlorophenylacetaldehyde and 31.5 grams (0.08 mole) of iodoform in 200 mL of tetrahydrofuran is added dropwise. Upon completion of addition, the reaction mixture is stirred at 0° C. for three hours. After this time the reaction mixture is poured into about 1200 mL of water, and the mixture is extracted with three 150 mL portions of diethyl ether. The combined extracts are dried with sodium sulfate and filtered. The filtrate is concentrated under reduced pressure, yielding 1,1-difluoro-1-(4-chlorophenyl)-3-iodo-2-propene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31][CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37]>>[F:1][C:2]1[CH:7]=[C:6]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31][CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:5]=[CH:4][C:3]=1[C:17]1[CH:22]=[N:21][C:20]([NH2:23])=[N:19][CH:18]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: C[Si](C)(C)CCOCSc1ccccc1Br
Product: C[Si](C)(C)CCOCSc1ccccc1-c1ccc(-c2cnc(N)nc2)c(F)c1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 6 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine and (2-(((2-bromophenyl)thio)methoxy)ethyl)trimethylsilane. MS (ESI): mass calcd. for C22H26FN3OSSi, 427.16; m/z found, 428.0 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.47 (d, J=1.4, 2H), 7.69 (dd, J=7.7, 1.1, 1H), 7.44 (m, 1H), 7.34-7.15 (m, 5H), 4.86 (s, 2H), 3.60-3.47 (m, 2H), 0.88-0.76 (m, 2H), 0.06 (s, 9H)
Reaction SMILES: [OH:1][C@H:2]([CH2:10][OH:11])[CH2:3][C:4](=[O:9])[CH2:5][C:6]([OH:8])=[O:7]>CO.C(O)C.C(O)(C)C.C(O)(C)(C)C.[Ru]>[OH:9][C@H:4]([CH2:3][C@H:2]([OH:1])[CH2:10][OH:11])[CH2:5][C:6]([OH:8])=[O:7]
Reactant: O=C(O)CC(=O)C[C@H](O)CO
Agent: [Ru]
Solvent: CO
Solvent: CC(C)O
Solvent: CCO
Product: O=C(O)C[C@H](O)C[C@H](O)CO

Procedure:
That is, the (S)-5,6-dihydroxy-3-oxohexanoic acid derivative shown by formula (2) is dissolved in an alcohol such as methanol, ethanol, iso-propanol, tert-butyl alcohol, etc., the ruthenium-optically active phosphine complex shown by formula (3) is added to the solution in an amount of from 0.0001 to 0.002 mol, and preferably from 0.0001 to 0.001 mol, per mol of the compound of formula (2), the hydrogenation is carried out under a hydrogen pressure of from 10 to 120 kg/cm2, and preferably from 20 to 50 kg/cm2 and at a reaction temperature of from 25° to 100° C., and preferably from 30° to 50° C. The solvent was removed by distillation, and the residue formed is purified by silica gel column chromatography to provide the desired (3R,5S)-3,5,6-trihydroxyhexanoic acid derivative shown by formula (1).
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[C:28]([CH3:29])=[C:27]([CH3:30])[S:26][C:16]=2[N:17]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[N:19]=1>>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:18]1[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:1][O:2][C:3]=3[CH:4]=2)[C:15]2[C:28]([CH3:29])=[C:27]([CH3:30])[S:26][C:16]=2[N:17]=1
Reactant: Cc1sc2nc(-c3ccccn3)nc(Cl)c2c1C
Reactant: NCCc1ccc2c(c1)OCO2
Product: Cc1sc2nc(-c3ccccn3)nc(NCCc3ccc4c(c3)OCO4)c2c1C

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(pyridin-2-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3,4-methylenedioxyphenethylamino)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([C:3]([C:21]1[O:22][C:23]2[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][C:24]=2[CH:25]=1)([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([OH:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[C:8]([CH3:20])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].Cl.C([O:36][C:37](=[O:41])[CH2:38][NH:39][CH3:40])C.[OH-].[Na+]>>[CH2:4]([C:3]([C:21]1[O:22][C:23]2[CH:29]=[CH:28][C:27]([C:30]([N:39]([CH2:38][C:37]([OH:41])=[O:36])[CH3:40])=[O:31])=[CH:26][C:24]=2[CH:25]=1)([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([OH:19])[C:15]([CH3:18])([CH3:16])[CH3:17])=[C:8]([CH3:20])[CH:7]=1)[CH2:1][CH3:2])[CH3:5]
Reactant: CCOC(=O)CNC
Reactant: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1cc2cc(C(=O)O)ccc2o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1cc2cc(C(=O)N(C)CC(=O)O)ccc2o1

Procedure:
2-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-benzofuran-5-carboxylic acid (152 mg, 346 mmol) HATU (145 mg, 380 mmol) DIEA (0.35 ml, 2.07 mmol) and sarcosine ethyl ester hydrochloride (63 mg, 0.415 mmol) are reacted followed by base hydrolysis with 2N NaOH in an analogous manner to example E from to yield (78 mg, 56%). MS (ES) m/e: 508.3 (M−1)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[C:13]([OH:15])=O)([O-:3])=[O:2].Cl.[CH3:17][NH:18][CH3:19].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>CN(C=O)C.O>[CH3:17][N:18]([CH3:19])[C:13]([C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:9][N:8]=1)=[O:15]
Reactant: CNC
Reactant: O=C(O)c1n[nH]c2ccc([N+](=O)[O-])cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1n[nH]c2ccc([N+](=O)[O-])cc12
Reaction time: 18 h
Yield: 96.2 %

Procedure:
To a solution of 5-nitro-1H-indazole-3-carboxylic acid (1.01 g, 4.88 mmol), dimethylamine hydrochloride (1.99 g, 24.4 mmol) and HATU (2.78 g, 7.31 mmol) in DMF at RT was added DIPEA (4.3 mL, 24 mmol) and the reaction mixture kept at RT for 18 hr and then diluted with water (150 mL). The resulting precipitate was collected by filtration and was dried in vacuo to afford N,N-dimethyl-5-nitro-1H-indazole-3-carboxamide as a pale yellow solid (1.10 g, 92%); Rt 0.26 min (Method 2, acidic); m/z 235 (M+H)+ (ES+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[NH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.CN(C)C1C=CC=CC=1.[C:25]([O:28][CH:29]([CH3:33])[C:30](Cl)=[O:31])(=[O:27])[CH3:26]>CN(C=O)C>[C:25]([O:28][CH:29]([CH3:33])[C:30]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]([CH3:15])[NH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:6][CH:7]=1)=[O:31])(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)C(=O)Cl
Reactant: CC1NC(=O)NN=C1c1ccc(N)cc1
Solvent: CN(C)C=O
Solvent: CN(C)c1ccccc1
Product: CC(=O)OC(C)C(=O)Nc1ccc(C2=NNC(=O)NC2C)cc1
Yield: 72.5 %

Procedure:
To a stirred mixture of 6-(4-aminophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (1.0 g) and N,N-dimethylaniline (0.93 ml) in DMF (10 ml) was added dropwise 2-acetoxypropionyl chloride (0.98 g) under ice cooling. The stirring was continued for one night at ambient temperature. The mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate after addition of saline solution. The extract was washed successively with 1N hydrochloric acid, water and saline solution, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (170 ml) with a mixture of chloroform and methanol (10:1) as an eluent. The eluates containing the object compound were evaporated in vacuo to give 1.13 g of 6-[4-(2-acetoxypropionylamino)phenyl]-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.[N+]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([O-])=O>C1COCC1>[CH2:11]([C:16]1[CH:21]=[CH:20][C:19]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=2)=[CH:18][CH:17]=1)[CH2:12][CH2:3][CH2:4][CH3:5]
Reactant: COc1ccc2ncccc2c1
Reactant: O=[N+]([O-])c1ccccc1
Solvent: C1CCOC1
Product: CCCCCc1ccc(-c2ccc3cc(OC)ccc3n2)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 44.8 %

Procedure:
To the resultant mixture, a solution of 2.18 ml (15.8 mM) of 6-methoxyquinoline in 13 ml of dry THF was added dropwise in 30 minutes at the same temperature. After the addition, the dry ice-acetone bath was removed and the mixture was stirred for 1 hour and 40 minutes at room temperature. After the reaction, the reaction mixture was poured into ice water and subjected to extraction with ethyl acetate. The organic layer was washed with water and dried with anhydrous sodium sulfate, followed by evaporation under reduced pressure to obtain a residue. To the residue, 5 ml of nitrobenzene was added, followed by refluxing under stirring. The reaction mixture was subjected to reduced-pressure distillation to distill off nitrobenzene as much as possible. The resultant crude product was purified by silica gel column chromatography (eluent: toluene/ethyl acetate=100/1) and recrystallized from methanol to obtain 2.16 g of 2-(4-pentylphenyl)-6-methoxyquinoline (Yield: 44.8%). This compound showed the following phase transition series.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:22](=[O:23])[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:7]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:15][CH:16]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Reactant: O=C(Cl)Oc1ccccc1
Product: CC(C)(C)c1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)cc1
Yield: 66.8 %

Procedure:
Using the procedure in Example 118A, 3-tert-butyl-1-(4-tert-butylphenyl)-1H-pyrazol-5-amine (996 mg, 3.67 mmol) and phenyl chloroformate (1.40 mL, 11.0 mmol) were reacted to give phenyl 3-tert-butyl-1-(4-tert-butylphenyl)-1H-pyrazol-5-ylcarbamate (957 mg, 2.45 mmol, 66%). 1H NMR (300 MHz, DMSO-d6) δ 10.05 (br s, 1H), 7.56-7.08 (m, 8H), 6.77 (s, 1H), 6.33 (s, 1H), 1.33 (s, 9H), 1.28 (s, 9H); LC-MS (ESI) m/z 392 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[Cl:24][C:25]1[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](O)=[O:28]>>[Cl:24][C:25]1[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([NH:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2)=[O:28]
Reactant: Cc1cccc(C(=O)O)c1Cl
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc(C)c2Cl)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 2-Chloro-3-methyl-benzoic acid.
Reaction SMILES: Cl.[CH2:2]([C@@H:4]1[C:13]2[C:8](=[C:9]([O:14]C)[CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][C@@H:5]1[N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])[CH3:3].[BrH:23]>>[BrH:23].[CH2:2]([C@@H:4]1[C:13]2[C:8](=[C:9]([OH:14])[CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][C@@H:5]1[N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])[CH3:3]
Reactant: CCCN(CCC)[C@H]1CCc2c(OC)cccc2[C@H]1CC
Agent: Br
Agent: Cl
Product: CCCN(CCC)[C@H]1CCc2c(O)cccc2[C@H]1CC

Procedure:
cis-1-Ethyl-5-methoxy-2-(di-n-propylamino) tetralin hydrochloride (150 mg, 0.46 mmol) was heated in 48% aqueous HBr for 2 h at 120° C. under N2. The volatiles were evaporated in vacuo and the residue was crystallized from MeOH-ethyl ether. Two recrystallizations from MeOH-ethyl ether gave the desired product as HBr-salt (68 mg, 42%). Isomeric purity >95% (6C, 250° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](OC)=[O:10])=[CH:5][C:4]=1[NH:13][C:14]([CH:16]1[CH2:21][CH:20]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH:19]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[CH:18]([O:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH3:78])[CH2:17]1)=[O:15].CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.Cl>C1COCC1>[OH:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([NH:13][C:14]([CH:16]2[CH2:17][CH:18]([O:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH3:78])[CH:19]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[CH:20]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:21]2)=[O:15])[CH:5]=1
Reactant: CCCCCCCCCCCCCCCCCCOC1CC(C(=O)Nc2cc(C(=O)OC)ccc2OC)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOC1CC(C(=O)Nc2cc(CO)ccc2OC)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Reaction time: 5 h
Yield: 85.7 %

Procedure:
N-(2-Methoxy-5-methoxycarbonylphenyl) 3,4,5-tris(octadecyloxy)cyclohexylcarboxamide (225 mg, 0.21 mmol) was dissolved in dehydrated THF (2.5 ml), 1M DIBAL/toluene (0.6 ml, 0.6 eq) was added dropwise, and the mixture was stirred for 5 hr. After completion of the reaction, 1N hydrochloric acid was added to quench the reaction, and the mixture was extracted with chloroform (10 ml), and washed with 1N hydrochloric acid (5 ml). The solvent was evaporated and the residue was precipitated with methanol (15 ml) and slurry-washed with acetonitrile (10 ml) and 1N hydrochloric acid (10 ml) to give N-(5-hydroxymethyl-2-methoxyphenyl) 3,4,5-tris(octadecyloxy)cyclohexylcarboxamide (200 mg, 0.18 mmol, yield 86%).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH:15]2[CH2:17][CH2:16]2)[C:4]2[CH2:5][CH2:6][CH2:7][CH2:8][C:9]=2[C:10]=1[C:11]([O:13]C)=O.C(O[C:21]([CH3:28])=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])C.CC1C=CC(S(O)(=O)=O)=CC=1.[O-]CC.[Na+].Cl>C1(C)C=CC=CC=1.O>[CH:15]1([N:3]2[C:4]3[CH2:5][CH2:6][CH2:7][CH2:8][C:9]=3[C:10]3[C:11]([OH:13])=[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:21]([CH3:28])=[N:1][C:2]2=3)[CH2:17][CH2:16]1
Reactant: COC(=O)c1c2c(n(C3CC3)c1N)CCCC2
Reactant: CCOC(=O)C=C(C)OCC
Agent: CC[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1c(C)nc2c(c1O)c1c(n2C2CC2)CCCC1
Temperature: 135 °C
Yield: 43.9 %

Procedure:
A suspension of methyl 2-amino-1-cyclopropyl-4,5,6,7-tetrahydro-1H-indole-3-carboxylate (2.29 g, 9.77 mmol) in Toluene (46 mL) was treated with ethyl 3-ethoxybut-2-enoate (3.09 g, 19.55 mmol) and pTsOH (0.093 g, 0.489 mmol), and then heated to reflux (135° C.) for 2.5 hours using Dean-Stark. The mixture was cooled to rt, slowly treated with sodium ethoxide (21 wt % in EtOH) (4.38 mL, 11.73 mmol), and refluxed at 135° C. with Dean-Stark for 4 hours. The reaction was cooled to rt and concentrated. The brown residue was diluted with water and 1N HCl until neutral (pH ˜6), extracted with EtOAc, washed with brine, dried with Na2SO4, filtered, and concentrated to give 2.9568 g crude product. Water layer still contained some product. It was acidified with 1N HCl. extracted with EtOAc, washed with brine, dried with Na2SO4, filtered, and concentrated to give 203 mg crude product. Both products were combined and purified with column chromatography (0-50% EtOAc/Hexane) to give ethyl 9-cyclopropyl-4-hydroxy-2-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-3-carboxylate (1.3474 g, 4.29 mmol, 43.8% yield) as white solid: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 12.48 (s, 1 H), 4.43 (q, J=7.1 Hz, 2 H), 3.06 (quin, J=5.4 Hz, 1 H), 2.94-2.85 (m, 2 H), 2.85-2.70 (m, 5 H), 1.96-1.75 (m, 4 H), 1.45 (t, J=7.1 Hz, 3 H), 1.11 (d, 4 H); LCMS (m/z) ES+=315 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([OH:3])=O.CC(C)N=C=NC(C)C.O[NH:22][C:23](=[NH:35])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>C(Cl)Cl>[CH2:24]([C:23]1[N:22]=[C:1]([C:4]2[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=2)[O:3][N:35]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCCCCC(=N)NO
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Product: CCCCCCCCCCCc1noc(-c2ccc(C=O)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.9 %

Procedure:
To a solution of 4-carboxybenzaldehyde (20.0 g, 133.2 mmol) in anhydrous DCM (500 mL) was added DIC (18.42 g, 146.5 mmol). The mixture was stirred at rt for 30 min then a solution of N-hydroxydodecanimidamide (31.41 g, 146.5 mmol) in anhydrous DCM (500 mL) was added in one portion. The resulting reaction mixture was stirred overnight at rt. The reaction was filtered, the collected solid washed with DCM and the solvent was concentrated in vacuo. The residue was heated at 115° C. for 5 h in a mixture of toluene (285 mL) and pyridine (115 mL). The solvents were evaporated off and the resulting residue was purified on column (SiO2, c-Hex/EtOAc 20/1) to give the title compound as a white solid (24.0 g, 55%). 1H NMR (CDCl3, 300 MHz) δ 10.1 (s, 1H), 8.18 (d, 2H, J=8.3 Hz), 7.94 (d, 2H, J=8.3 Hz), 2.33 (t, 2H, J=7.4 Hz), 1.74-1.58 (m, 2H), 1.43-1.18 (m, 16H), 0.87 (m, 3H). HPLC (Condition A), Rt: 5.83 min (HPLC purity: 99.6%).