Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[CH:12]=2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].C(N(CC)CC)C.[C:32]([O:36][C:37](=[O:42])[NH:38][CH2:39][CH2:40]Br)([CH3:35])([CH3:34])[CH3:33]>CC#N.CCOC(C)=O>[C:32]([O:36][C:37]([NH:38][CH2:39][CH2:40][N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[CH:12]=2)=[O:8])[CH2:2][CH2:3]1)=[O:42])([CH3:35])([CH3:34])[CH3:33]
Reactant: O=C(OCc1cc(Cl)cc(Cl)c1)N1CCNCC1
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCN1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
3,5-Dichlorobenzyl piperazine-1-carboxylate (Example 26, step 2) (3.466 mg, 11.99 mmol), potassium carbonate (4.97 g, 36 mmol) and triethlyamine (5.01 ml, 36 mmol) were suspended in MeCN (60 ml). tert-Butyl(2-bromoethyl)carbamate (3.49 g, 15.58 mmol) was added and the reaction mixture was refluxed for 18 hrs at 80° C. A further portion of tert-butyl(2-bromoethyl)carbamate (1.05 g, 4.69 mmol) was added and heating continued at 80° C. for 3 hrs. After cooling to RT, the reaction mixture was diluted with EtOAc and filtered. The organic portion was evaporated under reduced pressure. The crude product was solubilised in EtOAc and washed with 2M NaOH. The organic portion was dried over MgSO4 (anh) filtered and evaporated under reduced pressure. Purification by chromatography on silica using a gradient solvent system of DCM to 10% MeOH with ammonia in DCM afforded product fractions that were concentrated to give the title compound;
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[N:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[S:48](Cl)(=[O:50])=[O:49]>C(#N)C>[N:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[S:48]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:50])=[O:49]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: O=S(=O)(Cl)c1ccccn1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3ccccn3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 733 %

Procedure:
In a similar manner to Step 1 of Example 227, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0728 g, 0.158 mmol) was dissolved in acetonitrile (2.0 mL), and the solution was treated with triethylamine (0.0660 mL, 0.473 mmol) and 2-pyridinesulfonyl chloride (0.0680 g, 0.315 mmol) to obtain 4-(2-pyridinesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.698 g, yield 73%).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][C:14]2([N:18]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:17][O:16][CH2:15]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:33])[CH:8]=2)[N:3]=1.[F:34][C:35]1([F:46])[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[CH2:39][NH:38][CH2:37][CH2:36]1.C(N(CC)CC)C.O>CN(C)C=O>[CH2:19]([N:18]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:14]1([CH2:13][NH:12][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([CH3:33])[CH:8]=3)[N:3]=[C:2]([N:38]3[CH2:37][CH2:36][C:35]([F:34])([F:46])[C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=4[CH2:39]3)[N:11]=2)[CH2:17][O:16][CH2:15]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1ccc2nc(Cl)nc(NCC3(N(Cc4ccccc4)Cc4ccccc4)COC3)c2c1
Reactant: FC1(F)CCNCc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc2nc(N3CCC(F)(F)c4ccccc4C3)nc(NCC3(N(Cc4ccccc4)Cc4ccccc4)COC3)c2c1
Temperature: 120 °C
Yield: 71.9 %

Procedure:
To a solution of 2-chloro-N-{[3-(dibenzylamino)oxetan-3-yl]methyl}-6-methylquinazolin-4-amine (200 mg, 0.436 mmol) in N,N-dimethylformamide (3 mL) was added 5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepine (80 mg, 0.436 mmol) and triethylamine (89 mg, 0.872 mmol). The mixture was heated at 120° C. for 30 minutes under microwave irradiation. The reaction was poured into water (10 mL) and extracted with dichloromethane (15 mL×3). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (eluting with 20% ethyl acetate in petroleum ether) to afford 190 mg of the product as a brown solid (yield was 72%).
Reaction SMILES: [C:1](O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:13]([C:14]([OH:16])=[O:15])[C:12]=1[NH2:20]>O>[C:2]1([C:1]2[O:10][C:11]3[C:12](=[C:13]([C:14]([OH:16])=[O:15])[CH:17]=[CH:18][CH:19]=3)[N:20]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1c(O)cccc1C(=O)O
Reactant: O=C(O)c1ccccc1
Solvent: O
Product: O=C(O)c1cccc2oc(-c3ccccc3)nc12
Temperature: 180 °C
Reaction time: 2 h

Procedure:
Benzoic acid (122 mg, 1.0 mmol) and 3-hydroxyanthranilic acid (153 mg, 1.0 mmol) were added to PPA (1 g), the mixture was stirred at 180° C. for 2 hr. After cooled to room temperature, water (50 mL) was added and filtered; the cake was washed with water and dried in vacuum to obtain 2-phenylbenzo[d]oxazole-4-carboxylic acid. LC-MS (ESI) m/z 240 [M+1]+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@H:10]([O:13][C:14]3[CH:19]=[C:18]([N:20]4[C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[N:22]=[C:21]4[CH:29]([F:31])[F:30])[N:17]=[C:16]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)[N:15]=3)[CH2:9][CH2:8]2)[C:3]1=[O:38].C(N(C(C)C)C(C)C)C.[CH3:48][S:49](Cl)(=[O:51])=[O:50].C(=O)(O)[O-].[Na+]>ClCCCl>[F:30][CH:29]([F:31])[C:21]1[N:20]([C:18]2[N:17]=[C:16]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)[N:15]=[C:14]([O:13][C@H:10]3[CH2:11][CH2:12][C@H:7]([N:4]4[CH2:5][CH2:6][C@H:2]([NH:1][S:49]([CH3:48])(=[O:51])=[O:50])[C:3]4=[O:38])[CH2:8][CH2:9]3)[CH:19]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=1
Reactant: N[C@H]1CCN([C@H]2CC[C@H](Oc3cc(-n4c(C(F)F)nc5ccccc54)nc(N4CCOCC4)n3)CC2)C1=O
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CS(=O)(=O)N[C@H]1CCN([C@H]2CC[C@H](Oc3cc(-n4c(C(F)F)nc5ccccc54)nc(N4CCOCC4)n3)CC2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To (3S)-3-amino-1-[trans-4-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)cyclohexyl]pyrrolidin-2-one (75 mg), N-ethyl-N-isopropylpropan-2-amine (73 μL), and 1,2-dichloroethane (750 μL) was added methanesulfonyl chloride (17 μL), followed by stirring at room temperature for 1 hour. After the completion of the reaction, a saturated aqueous sodium bicarbonate solution was added thereto, followed by extraction with chloroform. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol) to obtain N-{(3S)-1-[trans-4-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)cyclohexyl]-2-oxopyrrolidin-3-yl}methanesulfonamide (82 mg) as a pale yellow powder.
Reaction SMILES: CC(=[N:4][C@@H:5]([C:16]12[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][C:18]([OH:26])([CH2:19]3)[CH2:17]1)[CH2:23]2)[C:6]([N:8]1[C@H:13]([C:14]#[N:15])[CH2:12][C@H:11]2[C@@H:9]1[CH2:10]2)=[O:7])C>O>[CH2:12]1[C@@H:13]([C:14]#[N:15])[N:8]([C:6]([C@@H:5]([NH2:4])[C:16]23[CH2:17][C:18]4([OH:26])[CH2:24][CH:22]([CH2:21][CH:20]([CH2:19]4)[CH2:25]2)[CH2:23]3)=[O:7])[C@@H:9]2[C@H:11]1[CH2:10]2.[OH2:7]
Reactant: CC(C)=N[C@H](C(=O)N1[C@H](C#N)C[C@@H]2C[C@@H]21)C12CC3CC(CC(O)(C3)C1)C2
Solvent: O
Product: N#C[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)[C@@H](N)C12CC3CC(CC(O)(C3)C1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
The Schiff base (Compound M, 7.27 g) was suspended in 25 ml of water. The obtained suspension was stirred overnight at room temperature in a closed flask. The product was filtered off and dried at 40° C./0 mbar for 2 hours. (Yield=80.1%) HPLC 100%, Powder XRD—H-1
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:7][CH2:6][CH:5]([CH2:8][C@@H:9]2[CH2:14][C@H:13]([C:15]3[O:19][NH:18][C:17](=[O:20])[CH:16]=3)[CH2:12][CH2:11][N:10]2C(OC)=O)[CH2:4][CH2:3]1.Br>>[F:25][C:2]1([F:1])[CH2:7][CH2:6][CH:5]([CH2:8][C@@H:9]2[CH2:14][C@H:13]([C:15]3[O:19][NH:18][C:17](=[O:20])[CH:16]=3)[CH2:12][CH2:11][NH:10]2)[CH2:4][CH2:3]1
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@H]1CC1CCC(F)(F)CC1
Agent: Br
Product: O=c1cc([C@@H]2CCN[C@H](CC3CCC(F)(F)CC3)C2)o[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.8 %

Procedure:
(2R,4R)-Methyl 2-((4,4-difluorocyclohexyl)methyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)-piperidine-1-carboxylate (0.752 g, 2.10 mmol) (from example 89, step 3) was dissolved in hydrogen bromide (33% in acetic acid, 16.54 mL, 94.42 mmol) and the mixture stirred at room temperature overnight. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2R,4R)-2-((4,4-difluorocyclohexyl)methyl)piperidin-4-yl)isoxazol-3(2H)-one (415 mg, 66%). HRMS Calculated for [C15H22F2N2O2+H]+: 301.1728. Found: 301.1741
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:18][C:19]([F:24])([F:23])[CH:20]([F:22])[F:21])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[CH:33]1[CH2:37][CH2:36][CH2:35][O:34]1.S(Cl)(Cl)(=O)=O>O1CCCC1>[C:12]1([C:11]2[N:10]=[C:9]([S:18][C:19]([F:23])([F:24])[CH:20]([F:22])[F:21])[N:8]([CH:33]3[CH2:37][CH2:36][CH2:35][O:34]3)[C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClC1CCCO1
Reactant: FC(F)C(F)(F)Sc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=S(=O)(Cl)Cl
Product: FC(F)C(F)(F)Sc1nc(-c2ccccc2)c(-c2ccccc2)n1C1CCCO1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a stirred solution of 1.8 g (0.005 mole) of 4,5-diphenyl-2-(1,1,2,2-tetrafluoroethylthio)imidazole and 5 g (0.05 mole) triethylamine in 20 ml tetrahydrofuran, was added dropwise at room temperature a solution of 2-chlorotetrahydrofuran, which had been prepared by adding 2.4 g (0.018 mole) of sulfuryl chloride to 30 ml tetrahydrofuran and waiting until the exothermic reaction mixture had returned to room temperature. The reaction mixture was stirred at room temperature for four days, then poured into ice water containing excess sodium bicarbonate. The aqueous mixture was extracted with methylene chloride, which was dried and concentrated. The crystalline residue was purified by chromatography on silica gel, eluting with toluene, to give 1.6 g of product, mp 145°-6° (from methylcyclohexane).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][CH:9]2[CH2:12][N:11]([C:13]([N:15]3[CH2:21][CH2:20][CH2:19][N:18]([CH:22]4[CH2:25][CH2:24][CH2:23]4)[CH2:17][CH2:16]3)=[O:14])[CH2:10]2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:30]I>C1COCC1>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([N:8]([CH:9]2[CH2:12][N:11]([C:13]([N:15]3[CH2:21][CH2:20][CH2:19][N:18]([CH:22]4[CH2:23][CH2:24][CH2:25]4)[CH2:17][CH2:16]3)=[O:14])[CH2:10]2)[CH3:30])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(NC1CN(C(=O)N2CCCN(C3CCC3)CC2)C1)c1ccc(Cl)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C(=O)c1ccc(Cl)cc1)C1CN(C(=O)N2CCCN(C3CCC3)CC2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 949.8 %

Procedure:
To a solution of 4-chloro-N-{1-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]azetidin-3-yl}benzamide (15 mg, 38 μmol) in THF (2 ml) was added NaH (3 mg of a 60% dispersion in mineral oil, 76 μmol). The reaction was stirred at room temperature for 30 minutes and then MeI (2.6 μmol, 46 μmol) was added. The reaction was heated in a sealed tube at 50° C. for 3 hours and then concentrated at reduced pressure, diluted with dichloromethane (30 ml), washed twice with saturated NaHCO3 (15 ml), dried (MgSO4), filtered and concentrated at reduced pressure. The residue was purified by FCC (DCM/MeOH/NH3 with gradient, 95:5:1 to 90:10:1) to provide the title compound as colourless oil (10 mg, 66%).
Reaction SMILES: [CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:21])=[CH:10][CH2:11][CH2:12][C:13]([CH3:20])=[CH:14][CH2:15][CH2:16][C:17](=[O:19])[CH3:18])[C:3](O)=O.O.[NH3:23].[C:24](Cl)(=[O:27])[CH2:25][CH3:26]>>[CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:21])=[CH:10][CH2:11][CH2:12][C:13]([CH3:20])=[CH:14][CH2:15][CH2:16][C:17](=[O:19])[CH3:18])[CH2:3][NH:23][C:24](=[O:27])[CH2:25][CH3:26]
Reactant: CCC(=O)Cl
Reactant: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O
Reactant: N
Solvent: O
Product: CCC(=O)NCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=O

Procedure:
Starting materials: 2,6,10-trimethyl-14-oxo-2,6,10-pentadecatrienoic acid; ammonia water (28% ammonia water); and propionyl chloride.
Reaction SMILES: [CH:1]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:10]([N:13]1[C:17]([NH2:18])=[N:16][N:15]=[N:14]1)[CH2:11][CH3:12]>>[CH2:10]([N:13]1[C:17]([NH:18][C:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[O:9])=[N:16][N:15]=[N:14]1)[CH2:11][CH3:12]
Reactant: O=C(O)C1CCCCC1
Reactant: CCCn1nnnc1N
Product: CCCn1nnnc1NC(=O)C1CCCCC1
Yield: 49 %

Procedure:
Employing 0.30 g (2.3 mmol) of cyclohexane carboxylic acid and 0.29 mg (2.3 mmol) of 1-propyl-1H-tetrazol-5-amine in the procedure described above and elution with CH2Cl2/MeOH/Et31NT (9.3:0.5:0.2) gave the product in 49% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24](O)=[O:25])[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.[N:50]1[CH:55]=[CH:54][CH:53]=[C:52]([CH2:56][N:57]2[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]2)[CH:51]=1>C(Cl)Cl.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:19][CH2:20][CH:21]([C:24]([N:60]3[CH2:61][CH2:62][N:57]([CH2:56][C:52]4[CH:51]=[N:50][CH:55]=[CH:54][CH:53]=4)[CH2:58][CH2:59]3)=[O:25])[CH2:22][CH2:23]2)=[O:17])=[CH:4][CH:3]=1
Reactant: O=C(O)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Reactant: c1cncc(CN2CCNCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(c1cc2ccccc2n1Cc1ccc(Cl)cc1)N1CCC(C(=O)N2CCN(Cc3cccnc3)CC2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-(1-(4-chlorobenzyl)-1H-indole-2-carbonyl)piperidine-4-carboxylic acid (100 mg, 0.252 mmol), 1-hydroxybenzotriazole (68.1 mg, 0.504 mmol) and EDCI (97 mg, 0.504 mmol) were dissolved in DCM (Volume: 4.0 ml). The suspension was stirred at room temperature for 10 minutes where it turned clear. Hunig'sBase (0.088 ml, 0.504 mmol) and 1-(pyridin-3-ylmethyl)piperazine (100 mg, 0.564 mmol) were added. The reaction was stirred at room temperature overnight. It was diluted with water and ethyl acetate. The water layer was washed with another portion of ethyl acetate. The combined organic layer was washed with saturated sodium bicarbonate and saturated sodium chloride. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The dark brown oil crude material was purified using 5% Methanolic ammonia/DCM resulting in a white solid as a product. (Yield: 105 mg, white solid) 1H-NMR (400 MHz, DMSO-d6) 8.51-8.45, 7.74-7.68, 7.62, 7.53, 7.39-7.30, 7.24-7.18, 7.13-7.07, 6.73, 5.49, 4.58-3.85, 3.55-3.42, 3.13-2.80, 2.40-2.27, 1.60, 1.36
Reaction SMILES: [N+:1]([C:4]1[CH:29]=[CH:28][C:7]([CH2:8][S:9][CH:10]([S:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=2)[CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:6][CH:5]=1)([O-])=O.[Cl-:30].[NH4+]>O.C(O)C.[Fe]>[ClH:30].[ClH:30].[ClH:30].[ClH:30].[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][S:17][CH:10]([S:9][CH2:8][C:7]2[CH:28]=[CH:29][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:20][CH:21]=1
Reactant: O=[N+]([O-])c1ccc(CSC(Cn2ccnc2)SCc2ccc([N+](=O)[O-])cc2)cc1
Reactant: [Cl-]
Agent: [Fe]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cl
Product: Nc1ccc(CSC(Cn2ccnc2)SCc2ccc(N)cc2)cc1

Procedure:
A stirred mixture of 1-[2,2-bis(4-nitrobenzylthio)ethyl]-1H-imidazole (924 mg), iron powder (1.08 g) and ammonium chloride (862 mg) in water (30 ml) was refluxed for 2 hours. The cooled mixture was thoroughly extracted with CH2Cl2 and the combined CH2Cl2 extracts were washed with water and dried over Na2SO4. Removal of the CH2Cl2 left 360 mgs. of the crude amine as a viscous oil. The black residue, which resisted extraction with CH2Cl2, was extracted with dilute aqueous oxalic acid. The aqueous mixture was filtered, and the filtrate was made basic with aqueous potassium hydroxide. Extraction of the filtrate with CH2Cl2 gave another crop of the crude amine which was combined with the 360 mg. fraction. The crude amine was chromatographed on silicic acid (20 g) with CH2Cl2 /CH3OH/diethyl amine (500:25:2) to afford 340 mg. of the pure amine. Treatment of a solution of the pure base in ethanol with hydrogen chloride afforded the title compound as a light tan amorphous solid which melted indistinctly with decomposition.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:25])[C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C([O:33][C:34]([C@H:36]1[CH2:41][CH2:40][C@H:39]([C:42](O)=[O:43])[CH2:38][CH2:37]1)=[O:35])C1C=CC=CC=1.C(C1C=C(NC(C2C=CC(N3CCN(C([C@H]4CCC[C@@H]4C(O)=O)=O)CC3)=NC=2)=O)C=CC=1)(C)(C)C>>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([C:13]2[CH:14]=[CH:15][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:42]([CH:39]4[CH2:38][CH2:37][CH:36]([C:34]([OH:35])=[O:33])[CH2:41][CH2:40]4)=[O:43])[CH2:21][CH2:20]3)=[CH:17][CH:18]=2)=[O:25])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc(C3CCNCC3)cc2)c1
Reactant: O=C(O)[C@H]1CC[C@H](C(=O)OCc2ccccc2)CC1
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(C(=O)[C@H]4CCC[C@@H]4C(=O)O)CC3)nc2)c1
Product: CC(C)(C)c1cccc(NC(=O)c2ccc(C3CCN(C(=O)C4CCC(C(=O)O)CC4)CC3)cc2)c1

Procedure:
4-{4-[4-(3-tert-Butyl-phenylcarbamoyl)-phenyl]-piperidine-1-carbonyl}-cyclohexanecarboxylic acid was prepared from N-(3-tert-butyl-phenyl)-4-piperidin-4-yl-benzamide and trans-1,4-cyclohexane dicarboxylic acid monobenzyl ester in a manner similar to the one described in the synthesis of (1S,2S)-2-{4-[5-(3-tert-butyl-phenylcarbamoyl)-pyridin-2-yl]-piperazine-1-carbonyl}-cyclopentanecarboxylic acid above. LCMS calcd for C30H38N2O4 (m/e) 490, obsd 491 (M+H).
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][C:8]2[N:16]([C:17]3[CH:25]=[CH:24][C:20]([CH2:21][CH2:22][NH2:23])=[CH:19][CH:18]=3)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([Si]([O:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][CH2:51][CH:52]2[CH2:54][O:53]2)=[CH:46][CH:45]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[CH:1]1([CH2:6][CH2:7][C:8]2[N:16]([C:17]3[CH:25]=[CH:24][C:20]([CH2:21][CH2:22][NH:23][CH2:54][C@H:52]([OH:53])[CH2:51][O:50][C:47]4[CH:48]=[CH:49][C:44]([OH:43])=[CH:45][CH:46]=4)=[CH:19][CH:18]=3)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCc1ccc(-n2c(CCC3CCCC3)nc3cccnc32)cc1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Oc1ccc(OC[C@@H](O)CNCCc2ccc(-n3c(CCC4CCCC4)nc4cccnc43)cc2)cc1
Yield: 43.1 %

Procedure:
4-[2-(2-Cyclopentylethyl)-3H-imidazo[4,5-b]pyridin-3-yl]phenethylamine (0.22 g, 0.658 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.266 g, 0.656 mmol) according to Procedure G (eluant: 20:1 going to 5:1 chloroform-methanol) to give the title compound (0.209 g, 0.283 mmol).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:17][C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([OH:25])=[C:20]([Cl:26])[CH:19]=1>>[CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:17][C:18]3[CH:23]=[C:22]([Cl:24])[C:21]([OH:25])=[C:20]([Cl:26])[CH:19]=3)=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cc(NC2CCCCC2)ncn1
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Product: O=C(Nc1cc(Cl)c(O)c(Cl)c1)c1cc(NC2CCCCC2)ncn1

Procedure:
Following the general method as outlined in Example 1, starting from 6-(cyclohexylamino)pyrimidine-4-carboxylic acid (Intermediate 4) and 4-amino-2,6-dichlorophenol (ABCR), the title compound was obtained as a yellow solid after purification by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[S:8]/[C:9]/1=[N:10]\[C:11]([C:13]1([CH3:23])[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=O)[C:14]1([CH3:22])[CH3:21])=[O:12])[CH2:2][CH2:3][CH3:4].Cl.[F:29][C:30]1([F:34])[CH2:33][NH:32][CH2:31]1>>[CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:25])([CH3:26])[CH3:27])[S:8]/[C:9]/1=[N:10]\[C:11]([C:13]1([CH3:23])[CH2:17][CH2:16][CH:15]([C:18]([N:32]2[CH2:33][C:30]([F:34])([F:29])[CH2:31]2)=[O:20])[C:14]1([CH3:21])[CH3:22])=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)C1(C)CCC(C(=O)O)C1(C)C
Reactant: FC1(F)CNC1
Agent: Cl
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)C1(C)CCC(C(=O)N2CC(F)(F)C2)C1(C)C

Procedure:
The product from Example 96 and 3,3-difluoroazetidine hydrochloride (Oakwood)) were processed using the method described in Example 99 to afford the title compound. 1H NMR (DMSO-d6) δ 0.51 (s, 3H), 0.90 (t, J=7.3 Hz, 3H), 1.22 (s, 3H), 1.25 (s, 3H), 1.26-1.36 (m, 2H), 1.39-1.48 (m, 1H), 1.57 (s, 9H), 1.57-1.78 (m, 3H), 1.93-2.07 (m, 1H), 2.62-2.67 (m, 2H), 2.72-2.83 (m, 1H), 2.88-2.94 (m, 1H), 4.14-4.37 (m, 2H), 4.41-4.52 (m, 1H), 4.73-4.86 (m, 1H), 8.50 (s, 1H). MS (ESI+) m/z 470 (M+H)+. Anal. calcd. for C24H37F2N3O2S: C, 61.38; H, 7.94; N, 8.95. Found: C, 61.35; H, 7.84; N, 8.96.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH:3]([CH2:7][CH2:8][CH2:9][CH3:10])[C:4](O)=[O:5].C(Cl)(=O)C([Cl:16])=O>>[F:1][C:2]([F:12])([F:11])[CH:3]([CH2:7][CH2:8][CH2:9][CH3:10])[C:4]([Cl:16])=[O:5]
Reactant: CCCCC(C(=O)O)C(F)(F)F
Reactant: O=C(Cl)C(=O)Cl
Product: CCCCC(C(=O)Cl)C(F)(F)F
Yield: 89.7 %

Procedure:
2-Trifluoromethylhexanoic acid (2.3 g.) was added dropwise to 10 g. oxalyl chloride (10 g.) and the mixture heated to reflux for 2 hours. Distillation of the reaction mixture after this time yielded 2-trifluoromethylhexanoyl chloride (2.27 g.; 90%), b.p. 67°-70°/43 mmHg.
Reaction SMILES: [C:1]([Si:5]([O:8][C@@H:9]1[CH2:14][C@@H:13]([O:15][Si](CC)(CC)CC)[CH2:12][CH:11]=[C:10]1[CH2:23]I)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[In].[CH2:26]=[O:27]>O.O1CCCC1>[Si:5]([O:8][C@H:9]1[C:10](=[CH2:23])[C@H:11]([CH2:26][OH:27])[CH2:12][C@H:13]([OH:15])[CH2:14]1)([C:1]([CH3:2])([CH3:3])[CH3:4])([CH3:6])[CH3:7]
Reactant: C=O
Reactant: CC[Si](CC)(CC)O[C@H]1CC=C(CI)[C@H](O[Si](C)(C)C(C)(C)C)C1
Agent: [In]
Solvent: C1CCOC1
Solvent: O
Product: C=C1[C@H](CO)C[C@H](O)C[C@H]1O[Si](C)(C)C(C)(C)C
Yield: 68.5 %

Procedure:
The compound of Example 16G (2.5 g, 5.2 mmol) was dissolved in 20 mL of water and 30 mL of tetrahydrofuran. Indium powder (0.90 g) was added followed by formaldehyde (37% aqueous solution, 1.6 mL, 21 mmol). Two additional portions of indium (0.3 g each) were added to drive the reaction toward completion. The reaction was diluted with 180 mL of water and extracted twice with 250 mL each of ethyl acetate. The combined organic layers were washed sequentially with 5% NaHCO3 and brine, then dried over MgSO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (200 mL of SiO2, elution with a gradient of 1:1 to 3:1 ethyl acetate:hexanes) afforded the titled compound (0.97 g, 68%).