Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[C:22]([Cl:31])[CH:21]=1>>[Cl:31][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[O:26][C:27]([F:28])([F:29])[F:30])[CH2:19][N:16]1[CH:11]([C:4]2[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:12][CH2:13][CH2:14][C:15]1=[O:17]
Reactant: FC(F)(F)Oc1ccc(CBr)cc1Cl
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc(OC(F)(F)F)c(Cl)c1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)piperidin-2-one with commercially available 4-(bromomethyl)-2-chloro-1-(trifluoromethoxy)benzene. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.83 min.; [M+H]+: 444.11 g/mol.
Reaction SMILES: [CH:1]1([NH:7][C:8]([C:10]2[CH:29]=[CH:28][C:13]([O:14][CH2:15]/[C:16](/[F:27])=[CH:17]\[CH2:18][NH:19]C(=O)OC(C)(C)C)=[CH:12][CH:11]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[ClH:37]>ClCCl>[ClH:37].[NH2:19][CH2:18]/[CH:17]=[C:16](/[F:27])\[CH2:15][O:14][C:13]1[CH:28]=[CH:29][C:10]([C:8]([NH:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:9])=[CH:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)NC/C=C(/F)COc1ccc(C(=O)NC2CCCCC2)cc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC/C=C(/F)COc1ccc(C(=O)NC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
To a stirred solution of (E)-tert-butyl 4-(4-(cyclohexyl-carbamoyl)phenoxy)-3-fluorobut-2-enylcarbamate (1.25 g, 3.1 mmol) in dichloromethane (54 mL) was added trifluoroacetic acid (6 mL). The reaction was then stirred at room temperature for 3 hours at which time TLC analysis showed no remaining starting material. Evaporation of the solvent and the remaining acid afforded a brown gum. Aqueous HCl (2 M; 5 mL) was then added and the reaction stirred for 40 minutes, upon which point an off-white solid had precipitated out of solution. Filtered, washing with ice cold aqueous HCl (1 M; 3 mL) and dried in a 60° C. oven to afford the title compound as an off-white powder (0.89 g, 85%); m.p.=210-212° C.; 1H-NMR (400 MHz, (CD3)2SO): δppm: 1.11 (1H, m), 1.15-1.33 (4H, m), 1.59 (1H, m), 1.70-1.77 (4H, m), 3.59 (2H, d, J 8.1 Hz), 3.71 (1H, m), 4.87 (2H, d, J 19.8 Hz), 5.52 (1H, dt, J 18.9, 7.8 Hz), 7.01 (2H, d, J 7.9 Hz), 7.83 (2H, d, J 7.9 Hz), 7.97-8.10 (3H, br s, NHs).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][C:23]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:24])[CH2:16][CH2:15]1)=[O:13])[CH:6]=[CH:5]2.[BH4-].[Na+].Cl.[OH-].[Na+]>C(O)C.O>[F:31][C:28]1[CH:29]=[CH:30][C:25]([CH:23]([OH:24])[CH2:22][CH2:21][CH2:20][N:17]2[CH2:16][CH2:15][CH:14]([CH:12]([C:7]3[CH:6]=[CH:5][C:4]4[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=4)[CH:8]=3)[OH:13])[CH2:19][CH2:18]2)=[CH:26][CH:27]=1
Reactant: O=C(CCCN1CCC(C(=O)c2ccc3cc(Cl)ccc3c2)CC1)c1ccc(F)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OC(CCCN1CCC(C(O)c2ccc3cc(Cl)ccc3c2)CC1)c1ccc(F)cc1
Reaction time: 1 h

Procedure:
To a stirred suspension of 4.4 g (0.01 mole) of 4-[4-(6-chloro-2-naphthoyl)-1-piperidyl]-1-(4-fluorophenyl)-1-butanone in 100 ml of absolute ethanol at 50° C. is gradually added 1.9 g (0.05 mole) sodium borohydride. Stirring is continued at 50° for one hour after the addition is completed and 20 ml of 3 N hydrochloric acid is added slowly. The mixture is diluted to 400 ml with water, made basic with sodium hydroxide, and extracted with chloroform. The organic phase is dried over MgSO4, concentrated in vacuo and recrystallized to yield α-(4-fluorophenyl)-4-[(6-chloro-2-naphthyl)hydroxymethyl]-1-piperidinebutanol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]([O:14]C)=[O:13])[CH:5]=[C:6]([Br:9])[C:7]=1[OH:8].C([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26]Br)[CH:21]=1)(=O)C>>[Br:9][C:6]1[CH:5]=[C:4]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:3]=[C:2]([Br:1])[C:7]=1[O:8][CH2:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([OH:19])[CH:21]=1
Reactant: COC(=O)CCc1cc(Br)c(O)c(Br)c1
Reactant: CC(=O)Oc1cccc(CBr)c1
Product: O=C(O)CCc1cc(Br)c(OCc2cccc(O)c2)c(Br)c1
Yield: 65 %

Procedure:
Methyl 3-(3,5-dibromo-4-hydroxyphenyl)propionate (0.15 g, 0.44 mmol) was coupled with 3-bromomethylphenyl acetate (0.20 g, 0.88 mmol) using the procedure described in Method D4. Purification on column (silica gel, dichloromethane/methanol, gradient elution from 95:5 to 90:10) gave 123 mg (78%) of 3-[3,5-dibromo-4-(3-hydroxybenzyloxy)phenyl]propionic acid. MS: m/z 430.1 (M+−1).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([CH2:8][CH2:9][O:10][CH2:11][CH3:12])[C:6]2[CH:13]=[CH:14][CH:15]=[CH:16][C:5]=2[N:4]=1.[OH:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][OH:23])=[CH:20][CH:19]=1>>[CH2:11]([O:10][CH2:9][CH2:8][N:7]1[C:6]2[CH:13]=[CH:14][CH:15]=[CH:16][C:5]=2[N:4]=[C:3]1[CH2:2][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][OH:23])=[CH:20][CH:19]=1)[CH3:12]
Reactant: CCOCCn1c(CCl)nc2ccccc21
Reactant: OCc1ccc(O)cc1
Product: CCOCCn1c(COc2ccc(CO)cc2)nc2ccccc21
Yield: 83.4 %

Procedure:
In a manner similar to that of Production Example 9, the title compound (yield: 83.4%) was obtained as pale yellow prisms by use of 2-chloromethyl-N-(2-ethoxyethyl)benzimidazole and 4-Hydroxybenzyl alcohol.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([CH:18]([CH2:29][CH2:30][CH2:31][OH:32])[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(CC)CC>C(Cl)Cl>[CH2:11]([CH:18]([CH2:29][CH2:30][CH:31]=[O:32])[C:19]([O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:20])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(OCc1ccccc1)C(CCCO)Cc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=CCCC(Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96.2 %

Procedure:
A solution of oxalyl chloride (0.9 ml, 10 mmol in 25 ml of CH2Cl2) was slowly added to a flask containing DMSO (1.5 ml, 21 mmol in 3 ml CH2Cl2 at -60° C. under N2. After 5 min, the alcohol from Example 52 (3 g, 10 mmol, 5 ml CH2Cl2) was added dropwise over 5 min period. After stirring the contents for 30 min, Et3N (6.3 ml, 45 mmol) was added and the mixture was warmed to room temperature. The suspension was stirred for 1 h and then poured to a slurry of CH2Cl2 -H2O-ice. The organic layer was washed with dilute HCl, brine, dried over MgSO4, and finally concentrated in vacuo. The crude product was purified by column chromatography (silica gel, Hexane-AcOEt, 4:1) which gave 2.85 g (95%) of the title compound: 1H NMR (CDCl3, 300 MHz) δ: 9.70 (t,J=1Hz,1H,--CHO), 7.40-7.10 (m,10H), 5.05 (s,2H), 3.95 (t,J=6Hz,1H), 2.75 (m,2H), 2.41 (m,2H), and 1.90 (m,2H); DCI-NH3 -MS, m/z 314 (MNH4+, 100%), and 297 (MH+, 20%).
Reaction SMILES: [CH:1]([C:9]1[CH:10]=[CH:11][C:12]2[O:13][CH2:14][C:15](=[O:19])[NH:16][C:17]=2[N:18]=1)=CC1C=CC=CC=1.[O:20]=[O+][O-].S(C)C>C(Cl)Cl>[O:19]=[C:15]1[CH2:14][O:13][C:12]2[CH:11]=[CH:10][C:9]([CH:1]=[O:20])=[N:18][C:17]=2[NH:16]1
Reactant: O=C1COc2ccc(C=Cc3ccccc3)nc2N1
Reactant: O=[O+][O-]
Solvent: ClCCl
Solvent: CSC
Product: O=Cc1ccc2c(n1)NC(=O)CO2
Reaction time: 24 h

Procedure:
To a solution of 6-styryl-4H-pyrido[3,2-b][1,4]oxazin-3-one (757 mg, 3.00 mmol) in CH2Cl2 (128 mL) was bubbled ozone at −78° C. with stirring until a pale blue color appeared. The excess ozone was removed by bubbling oxygen through the reaction mixture for 15 min. Me2S (1.0 mL, 14 mmol) was added, and the reaction was stirred at −78° C. for 3 h and then at RT for 24 h. The solvent was concentrated and the residue was triturated with Et2O (100 mL). The solid collected from filtration of the suspension was washed with additional Et2O and dried in vacuo to provide 340 mg (63% crude) of a solid, which was used without further purification. MS (ESI): exact mass calculated for C8H6N2O3, 178.04; m/z found, 179.2 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)O)[CH3:3].[ClH:14].S(Cl)([Cl:17])=O>C(Cl)(Cl)Cl>[ClH:17].[CH3:1][N:2]([CH2:4][CH2:5][CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[Cl:14])[CH3:3]
Reactant: O=S(Cl)Cl
Reactant: CN(C)CCC(O)c1ccccc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CN(C)CCC(Cl)c1ccccc1

Procedure:
A solution containing 442 g. of N,N-dimethyl 3-phenyl-3-hydroxypropylamine in 5 l. of chloroform was saturated with dry gaseous hydrogen chloride. 400 ml. of thionyl chloride were then added to the chloroform solution at a rate sufficient to maintain reflux. The solution was refluxed an additional 5 hours. Evaporation of the chloroform andd other volatile constituents in vacuo yielded N,N-dimethyl 3-phenyl-3-chloropropylamine hydrochloride which was collected by filtration, and the filter cake washed twice with 1500 ml. portions of acetone. The washed crystals weighed about 500 g. and melted at 181°-3° C. with decomposition. An additional 30 g. of compound were obtained from the acetone wash by standard crystallization procedures. The structure of the above compound was verified by NMR and titration.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N:9]([CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19])[CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14].[CH3:26][Mg]I>C(OCC)C>[CH2:15]([N:12]([CH2:13][CH3:14])[CH2:11][CH2:10][N:9]([CH2:17][C:18]([OH:19])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH3:26])[C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[Cl:1])[CH3:16]
Reactant: C[Mg]I
Reactant: CCN(CC)CCN(CC(=O)c1ccccc1)c1cc(Cl)ccc1Cl
Solvent: CCOCC
Product: CCN(CC)CCN(CC(C)(O)c1ccccc1)c1cc(Cl)ccc1Cl

Procedure:
A solution of 0.10 mole of 2-[N-(2,5-dichlorophenyl)-N-(β-diethylaminoethyl)amino]acetophenone in 200 ml of dry diethylether is added to a solution of 0.10 mole of methylmagnesium iodide in 500 ml of dry diethylether maintained at a temperature of from 0° to -5° C under nitrogen atmosphere. Thirty minutes after the addition the reaction mixture is washed with ice cold aqueous 2M ammonium chloride, dried over sodium sulfate, filtered and evaporated to give N-(β-diethylaminoethyl)-N-(β-hydroxy-β-phenylpropyl)-2,5-dichloroaniline.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][C:13](=[O:15])[CH:12]=[CH:11][NH:10]2)[CH:6]=[CH:7][CH:8]=1)#[N:2].C([Li])CCC.[Br:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[CH:24][C:23]=1[CH2:32][C:33](Cl)=[O:34].[Cl-].[NH4+]>C1COCC1>[Br:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[CH:24][C:23]=1[CH2:32][C:33]([N:10]1[CH:11]=[CH:12][C:13](=[O:15])[CH2:14][CH:9]1[C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[C:1]#[N:2])=[O:34]
Reactant: N#Cc1cccc(C2CC(=O)C=CN2)c1
Reactant: COc1cc(Br)c(CC(=O)Cl)cc1OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc(Br)c(CC(=O)N2C=CC(=O)CC2c2cccc(C#N)c2)cc1OC
Temperature: -75 °C
Reaction time: 0.17 h
Yield: 27.4 %

Procedure:
To 75 mg of 2-(3-cyanophenyl)-2,3-dihydro-pyridin-4-one in 8 ml THF at −75° C. was added 0.2 ml 2.5M n-butyl lithium. The mixture is stirred under argon at −75° C. for 10 minutes and then 106 mg 2-(2-bromo-4,5-dimethoxy-phenyl)acetyl chloride in 2 ml THF was added slowly. The reaction mixture was then stirred at −75° C. for 30 minutes, then allowed to warm to room temperature and was stirred for an additional 30 minutes. To this mixture was added 10 ml saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. Chromatography of the residue gave 45 mg 3-{1-[2-(2-bromo-4,5-dimethoxy-phenyl)-acetyl]-4-oxo-1,2,3,4-tetrahydro-pyridin-2-yl}-benzonitrile. MS (M+H) 457.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21][NH2:22])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:23](=[N-])(=[O:25])=[O:24].N1C=CC=CC=1.[ClH:33]>C(O)C.C(OCC)(=O)C>[ClH:33].[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH2:21][NH:22][S:23]2(=[O:25])=[O:24])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=S(=O)=O
Reactant: NCc1ccccc1NC1CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=S1(=O)NCc2ccccc2N1C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C

Procedure:
In this reference example, 33.0 g (112.4 m.mols) of 1-benzyl-4-[N-(o-aminomethylphenyl)-amino]-piperidine, 21.6 g (224.8 m.mols) of sulfuryl amide and 250 ml of pyridine are mixed and refluxed with heating for 8 hours. The reaction solution is cooled to room temperature, concentrated to 70 ml and poured into 500 ml of ice water. The mixture is mixed with 300 ml of chloroform, stirred and adjusted to pH 9 with 2 N aqueous sodium hydroxide. The chloroform layer is separated with separating funnel and the remaining water layer is further extracted with chloroform (300 ml×3). The chloroform layers are combined, washed with water (300 ml×4), dried and concentrated to obtain an oily residue. This residue is dissolved in 150 ml of ethanol. To the solution, 50 ml of 5.7 N hydrogen chloride in ethyl acetate is added. The resultant solution is concentrated under reduced pressure. The crystalline residue is mixed with 50 ml of ethanol and filtered to obtain 29.0 g of the desired product. This compound is tested for NMR after it has been freed from hydrochloric acid, and it is tested for IR in its unaltered form of hydrochloride.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=2[C:16]2[N:17]([CH3:21])[N:18]=[CH:19][CH:20]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[N:30]=[C:31]=[O:32]>ClCCl>[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[NH:30][C:31]([NH:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[C:10]([C:16]2[N:17]([CH3:21])[N:18]=[CH:19][CH:20]=2)[CH:11]=1)=[O:32]
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: Cn1nccc1-c1cc(N)ccc1OCCn1ccnc1
Solvent: ClCCl
Product: Cn1nccc1-c1cc(NC(=O)Nc2ccc(F)cc2F)ccc1OCCn1ccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a solution of 4-(2-imidazol-1-yl-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (0.08 g, 0.256 mmol) in 2.0 mL of dichloromethane was added 2,4-difluoro phenyl isocyanate (0.042 g, 0.280 mmol), and the mixture was stirred at ambient temperature overnight. The DCM was evaporated from the reaction mixture, the crude residue was dissolved in 5.0 mL of DMSO and purified by RP-HPLC. The proper fractions were collected and lyophilized to afford the 1-(2,4-difluoro-phenyl)-3-[4-(2-imidazol-1-yl-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea as an off-white solid in 75% yield. LCMS m/z (%)=439 (M+H). 1H NMR (400 MHz, Acetone-d6) δ: 8.46 (bs, 1H), 7.96-8.02 (m, 1H), 7.48 (dd, J=8.9 and 2.72 Hz, 1H), 7.39-7.41 (m, 2H), 7.31 (d, J=1.81 Hz, 1H), 7.17 (t, J=1.42 Hz, 1H), 6.94 (d, J=8.94 Hz, 1H), 6.7-6.8 (m, 2H), 6.01 (d, J=1.78 Hz, 1H), 4.62 (t, J=4.74 Hz, 2H), 4.33 (t, J=5.07 Hz, 2H), 3.48 (s, 3H).
Reaction SMILES: [CH2:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH:2]([CH3:4])[CH3:3].CCN(CC)CC.[C:28](Cl)(=[O:30])[CH3:29]>C(Cl)Cl>[C:28]([N:18]1[CH2:19][CH2:20][N:15]([C:12]2[CH:11]=[CH:10][C:9]([S:6]([NH:5][CH2:1][CH:2]([CH3:4])[CH3:3])(=[O:8])=[O:7])=[CH:14][CH:13]=2)[CH2:16][CH2:17]1)(=[O:30])[CH3:29]
Reactant: CC(=O)Cl
Reactant: CC(C)CNS(=O)(=O)c1ccc(N2CCNCC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(c2ccc(S(=O)(=O)NCC(C)C)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
A solution of N-isobutyl-4-piperazin-1-yl-benzenesulfonamide (1.14 g, 3.83 mmol) and Et3N (795 μL, 5.75 mmol) in DCM (25 mL) was treated with acetyl chloride (340 mL, 4.79 mmol) and stirred at room temperature for 30 minutes. The mixture was diluted with DCM, washed with 1 N aqueous HCl, saturated aqueous NaHCO3, water and brine, dried over Na2SO4 and concentrated under vacuum. Purification by silica gel column chromatography (60-75% EtOAc in DCM) gave 4-(4-acetyl-piperazin-1-yl)-N-isobutyl-benzenesulfonamide (1.23 g, 95%) as a white solid. 1H NMR (400 MHz, DMSO) δ 7.58 (d, J=8.8 Hz, 2H), 7.27 (t, J=6.2 Hz, 1H), 7.04 (d, J=8.8 Hz, 2H), 3.62-3.54 (m, 4H), 3.38-3.26 (m, 8H), 2.49-2.43 (m, 2H), 2.04 (s, 3H), 1.65-1.54 (m, 1H), 0.80 (d, J=6.7 Hz, 6H). LCMS (m/z, Method B) ES+ 340.0 [M+1]+.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([CH2:17][C:18]#[N:19])[CH2:12]1)=O)C1C=CC=CC=1.Cl>C(O)C.[Pd]>[C:18]([CH2:17][CH:13]1[CH2:14][CH2:15][CH2:16][NH:11][CH2:12]1)#[N:19]
Reactant: N#CCC1CCCN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: N#CCC1CCCNC1
Reaction time: 2.5 h

Procedure:
1-Benzyloxycarbonyl-3-cyanomethylpiperidine (Method 22; 12.5 g) was dissolved in ethanol (20 ml) and ethereal HCl (1 ml) and 5% palladium on charcoal (2.0 g) was added. The mixture was shaken under an atmosphere of hydrogen for 2.5 hours. The catalyst was filtered and the filtrate evaporated in vacuo. The crude product was dissolved in ethanol and recrystallized from ether. M/z 124 [M+].
Reaction SMILES: S1[CH:5]=[CH:4][C:3]([C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9]2)=[O:7])=[CH:2]1.[C:19]1(C(C)C(O)=O)[CH:24]=CC=[CH:21][CH:20]=1.Cl.CN(C)CCCN=C=NCC.N1CCC[C@H](C(OCC)=O)C1>>[C:4]1([CH:3]([CH3:2])[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9]2)=[O:7])[CH:21]=[CH:20][CH:19]=[CH:24][CH:5]=1
Reactant: CC(C(=O)O)c1ccccc1
Reactant: CCOC(=O)C1CCCN(C(=O)c2ccsc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: CCOC(=O)[C@H]1CCCNC1
Agent: Cl
Product: CCOC(=O)C1CCCN(C(=O)C(C)c2ccccc2)C1

Procedure:
This reaction was run in the same manner as ethyl 1-(3-thiophenecarbonyl)-3-piperidinecarboxylate, starting with commercially available 2-phenylpropionic acid (265 μl; 1.94 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (371.3 mg; 1.94 mmol) and (S)-ethyl nipecotate (300 μl; 1.94 mmol). Crude product was purified by chromatography on silica eluting with 25% ethyl acetate/75% hexane, giving (S)±ethyl 1-(2-phenylpropionyl)-3-piperidinecarboxylate (268.9 mg) as a colorless oil. MS m/z (positive ion) 290 (MH+; 100), 142 (55), 115 (50).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].C([Li])CCC.[CH3:15][C:16]1[CH:21]=[C:20]([CH3:22])[N:19]=[C:18]([S:23](F)(=[O:25])=[O:24])[N:17]=1>C(COC)OC>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH:4][S:23]([C:18]1[N:17]=[C:16]([CH3:15])[CH:21]=[C:20]([CH3:22])[N:19]=1)(=[O:24])=[O:25]
Reactant: Nc1c(Cl)cccc1Cl
Reactant: Cc1cc(C)nc(S(=O)(=O)F)n1
Agent: [Li]CCCC
Solvent: COCCOC
Product: Cc1cc(C)nc(S(=O)(=O)Nc2c(Cl)cccc2Cl)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2,6-dichloroaniline (1.0 g, 6.2 mmol) in dimethoxyethane (25 mL) was added butyl lithium (3.9 mL, 6.24 mmol). After 15 minutes, the solution was cooled to -30° and 4,6-dimethyl-2-pyrimidinesulfonyl fluoride (1.18 g, 6.2 mmol) was added. The mixture stirred for 12 hours with warming to 25° C. The mixture was concentrated and the residue was treated with 1N NaOH (2 mL) and extracted with ethyl acetate. The aqueous layer was acidified with 1N HCl and a solid was collected, m.p. 261°-263° C. NMR (90 MHZ) D6 -Acetone: δ 7.5 (m, 4H) and 2.5 (s, 6H).
Reaction SMILES: [CH2:1]([C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[C:20]([C:25]([OH:27])=[O:26])[CH:19]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].F[B-](F)(F)F.[H+]>O1CCCC1.C(O)C.[Pt]=O>[CH2:1]([CH:16]1[CH2:24][C:23]2[C:18](=[CH:19][C:20]([C:25]([OH:27])=[O:26])=[CH:21][CH:22]=2)[NH:17]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCCCCCCc1cc2ccc(C(=O)O)cc2[nH]1
Agent: O=[Pt]
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCC1Cc2ccc(C(=O)O)cc2N1
Yield: 45.4 %

Procedure:
2-(n-Pentadecyl)indole-6-carboxylic acid (16.0 g) was dissolved in a mixture of tetrahydrofuran (400 ml) and ethanol (100 ml), containing aqueous fluoroboric acid (100 ml, of strength 40% w/v). The stirred mixture was hydrogenated over platinum oxide (2.0 g) at room temperature and atmospheric pressure. After 6 hours the mixture was filtered, the residue was washed with diethyl ether (100 ml) and the combined filtrates were concentrated in vacuo until a solid separated. The mixture was adjusted to pH 7 by treatment with an aqueous solution of sodium hydroxide (strength 50% w/v) and was then adjusted to pH 4-5 with glacial acetic acid. The mixture was extracted with diethyl ether (3×100 ml), and the ether solution was dried over magnesium sulphate and, on evaporation in vacuo, gave a solid. The solid was recrystallised from a mixture of toluene and hexane (equal parts by volume) to give (RS)-2-(n-pentadecyl)-indoline-6-carboxylic acid (7.3 g), in the form of a colourless solid, m.p. 119°-122° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:4]=1[CH2:5][NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[N+:16]([O-])=O)[CH2:12][N:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1[O:28][CH3:29])[CH2:10]2.S(S([O-])=O)([O-])=O.[Na+].[Na+].[OH-].[NH4+].[OH-].[Na+].[Cl-].[Na+]>O.O1CCCC1>[CH3:1][O:2][C:3]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:4]=1[CH2:5][NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[NH2:16])[CH2:12][N:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1[O:28][CH3:29])[CH2:10]2
Reactant: COc1ccc(CNc2cc3c(cc2[N+](=O)[O-])CN(Cc2ccc(OC)cc2OC)C3)c(OC)c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CNc2cc3c(cc2N)CN(Cc2ccc(OC)cc2OC)C3)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of N,2-bis(2,4-dimethoxybenzyl)-6-nitroisoindolin-5-amine T-03 (2.7 g, 5.6 mmol) and sodium hydrosulfite (15.6 g, 90 mmol) was added a solution of tetrahydrofuran (40 mL), water (40 mL) and ammonium hydroxide (40 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was basified with sodium hydroxide and saturated with sodium chloride. The reaction mixture was filtered and extracted with ethyl acetate. The organic layer was dried over sodium sulfate. Solvent was evaporated under reduced pressure to afford the desired N5,2-bis(2,4-dimethoxybenzyl)isoindoline-5,6-diamine T-04 (2.5 g, 5.6 mmol). The crude product was used in the next step without further purification.
Reaction SMILES: [CH:1]([N:3]([CH2:12][C@@H:13]([CH2:40][CH2:41][CH2:42][CH3:43])[C:14]([N:16]1[C@H:20]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][N:27]=[CH:26][N:25]=2)=[O:22])[CH2:19][CH2:18][N:17]1C(OCC1C=CC=CC=1)=O)=[O:15])[O:4]CC1C=CC=CC=1)=[O:2]>C(O)C.[OH-].[OH-].[Pd+2]>[CH:1]([N:3]([CH2:12][C@@H:13]([CH2:40][CH2:41][CH2:42][CH3:43])[C:14]([N:16]1[C@H:20]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][N:27]=[CH:26][N:25]=2)=[O:22])[CH2:19][CH2:18][NH:17]1)=[O:15])[OH:4])=[O:2]
Reactant: CCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)N1[C@H](C(=O)Nc2ccncn2)CCN1C(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCCC[C@H](CN(O)C=O)C(=O)N1NCC[C@H]1C(=O)Nc1ccncn1
Reaction time: 1 h
Yield: 80.7 %

Procedure:
To a solution of phenylmethyl (3S)-2-[(2R)-2-({formyl[(phenylmethyl)oxy]amino}methyl)hexanoyl]-3-[(4-pyrimidinylamino)carbonyl]-1-pyrazolidinecarboxylate (80 mg, 0.136 mmol) in ethanol (30 mL) was added Pd(OH)2/C (40 mg). The mixture was stirred under an H2 atmosphere for 1 h and the catalyst was filtered off. The filtrate was concentrated and the residue was purified by pre-HPLC to provide the title compound (40 mg, 70%). LCMS: (M+H)+: 365.2.