Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[Cl:13]Cl>C(O)(=O)C>[Cl:13][C:7]1[C:8]([F:9])=[C:2]([F:1])[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]=1[NH2:6]
Reactant: ClCl
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Solvent: CC(=O)O
Product: Nc1c([N+](=O)[O-])cc(F)c(F)c1Cl
Temperature: 0 °C

Procedure:
Into a solution of 4,5-difluoro-2-nitroaniline (20 g) in acetic acid (200 ml) was boubled chlorine gas at 13° to 15° C. during 45 minutes. The reaction mixture was poured into ice water (500 ml) and extracted with dichloromethane. The organic layer was washed with 6% aqueous sodium carbonate and with water successively, dried over anhydrous sodium sulfate and then concentrated. The residue was purified with silica gel chromatography eluting with dichloromethane-n-hexane (1:4) and further recrystallized from hexane to give the title compound (2.91 g) as yellow needles, mp 86°-88° C.
Reaction SMILES: [C:1](/[CH:4]=[CH:5]/[S:6][C:7]1[CH2:13][CH:12]2[N:9]([C:10](=[O:30])[CH:11]2[CH:14]([O:16]C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)[CH3:15])[C:8]=1[C:31]([O:33]CC1C=CC([N+]([O-])=O)=CC=1)=[O:32])(=[O:3])[NH2:2].C(=O)([O-])O.[Na+:48]>[Pd].O1CCOCC1.O>[C:1](/[CH:4]=[CH:5]/[S:6][C:7]1[CH2:13][CH:12]2[N:9]([C:10](=[O:30])[CH:11]2[CH:14]([OH:16])[CH3:15])[C:8]=1[C:31]([O-:33])=[O:32])(=[O:3])[NH2:2].[Na+:48]
Reactant: CC(OC(=O)OCc1ccc([N+](=O)[O-])cc1)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S/C=C/C(N)=O)CC12
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(O)C1C(=O)N2C(C(=O)[O-])=C(S/C=C/C(N)=O)CC12
Reaction time: 0.33 h

Procedure:
10% Palladium/charcoal catalyst (15 mg), suspended in 50% aqueous dioxan (4 ml) was pre-hydrogenolysed for 20 mins. To this was then added a solution of p-nitrobenzyl 3-[E-2-carbamoylethenyl thio]-6-[1-p-nitrobenzyloxycarbonyloxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (11 mg) in 50% aqueous dioxan (6 ml). After hydrogenolysis for 21/2 hr., sodium hydrogen carbonate (1.5 mg) in water (1 ml) was added. The dioxan was removed in vacuo and the aqueous phase extracted with ethyl acetate. The aqueous solution was shown to contain 3.75 mgs; (65%), of sodium 3-[E-2-carbamoylethenylthio]-6-[1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate, νmax. (H2O) 316 nm.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[CH:18][C:19]([F:23])=[C:20]([NH2:22])[CH:21]=2)[CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.[CH3:30][N:31]1[CH:35]=[C:34]([S:36](Cl)(=[O:38])=[O:37])[N:33]=[CH:32]1>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[CH:18][C:19]([F:23])=[C:20]([NH:22][S:36]([C:34]3[N:33]=[CH:32][N:31]([CH3:30])[CH:35]=3)(=[O:38])=[O:37])[CH:21]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: CC(C)c1nc(-c2ccc(F)c(N)c2)c(-c2ccnc(Cl)n2)s1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3cn(C)cn3)c2)c(-c2ccnc(Cl)n2)s1
Temperature: 45 °C
Reaction time: 0.08 h
Yield: 66.3 %

Procedure:
{5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}amine (160 mg, 0.459 mmol) was dissolved in DMF (3 mL) and added pyridine (0.074 mL; 0.917 mmol). The reaction was stirred 5 min and added 1-methylimidazole-4-sulfonyl chloride (83 mg, 0.459 mmol). The reaction mixture was heated at 45° C. for two days. The reaction mixture was cooled to rt, added silica gel, and concentrated. The crude product was chromatographed on silica gel eluting with 100% DCM to 100% EtOAc to obtained the title compound as a white solid (150 mg, 66% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.12 (br. s., 1H), 8.49 (d, J=5.4 Hz, 1H), 7.52-7.83 (m, 2H), 7.51 (d, J=1.8 Hz, 1H), 7.28-7.43 (m, 1H), 7.25 (t, J=9.3 Hz, 1H), 7.05 (d, J=5.3 Hz, 1H), 3.58 (s, 3H), 3.00-3.23 (m, 1H), 1.35 (d, J=6.9 Hz, 6H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][C:8]2[C:9](=[O:18])[N:10]=[C:11]([NH:14][N+:15]([O-:17])=[O:16])[NH:12][CH:13]=2)[CH:4]=[N:3]1.[CH3:19]CN(C(C)C)C(C)C.CI>C(Cl)(Cl)Cl>[CH3:19][N:12]1[CH:13]=[C:8]([CH2:7][C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)[C:9](=[O:18])[N:10]=[C:11]1[NH:14][N+:15]([O-:17])=[O:16]
Reactant: Cn1cc(Cc2c[nH]c(N[N+](=O)[O-])nc2=O)cn1
Reactant: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: CI
Product: Cn1cc(Cc2cn(C)c(N[N+](=O)[O-])nc2=O)cn1
Temperature: 23 °C
Reaction time: 8 h
Yield: 19.5 %

Procedure:
A solution of 5-[(1-methyl-1H-pyrazol-4-yl)methyl]-2-(nitroamino)-4(1H)-pyrimidinone (500 mg, 1.998 mmol) and DIPEA (1.745 mL, 9.99 mmol) in chloroform (5 mL) was mixed with methyl iodide (0.150 mL, 2.398 mmol). The reaction mixture was stirred at 23° C. overnight. Purification via HPLC then afforded the title compound (103 mg, 19.51% yield). LCMS: rt=1.46 min, [M+H+]=265.1
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=O)=[CH:9][CH:8]=1.[CH2:18]([SH:22])[CH2:19][CH2:20][SH:21].[F:23][C:24]([F:30])([F:29])[S:25]([OH:28])(=[O:27])=[O:26]>C(CC(C)(C)C)(C)C.C1(C)C=CC=CC=1>[F:23][C:24]([F:30])([F:29])[S:25]([O-:28])(=[O:27])=[O:26].[F:1][C:2]([F:17])([F:16])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]2[S:22][CH2:18][CH2:19][CH2:20][S+:21]=2)=[CH:9][CH:8]=1
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: SCCCS
Reactant: O=C(O)c1ccc(OCCCC(F)(F)F)cc1
Solvent: Cc1ccccc1
Solvent: CC(C)CC(C)(C)C
Product: FC(F)(F)CCCOc1ccc(C2=[S+]CCCS2)cc1
Product: O=S(=O)([O-])C(F)(F)F
Yield: 94.9 %

Procedure:
60 g (242 mmol) of 4-(4,4,4-trifluorobutoxy)benzoic acid, 31.8 ml (314 mmol) of propane-1,3-dithiol and 27.9 ml (314 mmol) of trifluoromethanesulfonic acid are refluxed in 1.61 of a mixture 1/1 isooctane/toluene for 18 hours. The mixture is cooled down and the product is precipitated by addition of 1.5 l of TBME to yield 108 g of 2-[4-(4,4,4-trifluorobutoxy)phenyl]-5,6-dihydro-4H-1,3-dithiin-1-ium trifluoromethanesulfonate as yellow crystals.
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[CH:13]=[C:14]3[N:27]=[C:26]([NH:28][C:29]4[C:34]([Cl:35])=[C:33]([F:36])[CH:32]=[C:31]([CH2:37][NH:38]C(OC(C)(C)C)=O)[C:30]=4[Cl:46])[NH:25][C:15]3=[N:16][C:17]=2[N:18]2[CH2:23][CH2:22][CH:21]([F:24])[CH2:20][CH2:19]2)=[O:11])[CH2:5][CH2:4]1.Cl>O1CCOCC1>[F:47][C:2]([F:1])([F:48])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[CH:13]=[C:14]3[N:27]=[C:26]([NH:28][C:29]4[C:34]([Cl:35])=[C:33]([F:36])[CH:32]=[C:31]([CH2:37][NH2:38])[C:30]=4[Cl:46])[NH:25][C:15]3=[N:16][C:17]=2[N:18]2[CH2:19][CH2:20][CH:21]([F:24])[CH2:22][CH2:23]2)=[O:11])[CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)NCc1cc(F)c(Cl)c(Nc2nc3cc(C(=O)N[C@H]4CC[C@H](C(F)(F)F)CC4)c(N4CCC(F)CC4)nc3[nH]2)c1Cl
Agent: Cl
Solvent: C1COCCO1
Product: NCc1cc(F)c(Cl)c(Nc2nc3cc(C(=O)N[C@H]4CC[C@H](C(F)(F)F)CC4)c(N4CCC(F)CC4)nc3[nH]2)c1Cl
Reaction time: 8 h

Procedure:
A mixture of N-(trans-4-trifluoromethyl-cyclohexyl)-2-{2,6-dichloro-5-fluoro-3-[(tert.butoxycarbonylamino)-methyl]-phenylamino}-5-[4-fluoro-piperidinyl]-3H-imidazo[4,5-b]pyridine-6-carboxamide (180 mg, 0.250 mmol), 4N HCl in dioxane (5.0 mL) and dioxane (10 mL) is stirred overnight, concentrated, dissolved in water, filtered, basicified with aq NH3-solution and extracted with DCM. The organic phase is dried with MgSO4, filtered and concentrated.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=[O:12])[CH:9]=2)[NH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:19][Si:20]([CH3:27])([CH3:26])[CH2:21][CH2:22][O:23][CH2:24]Cl>CN(C=O)C>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=[O:12])[CH:9]=2)[N:4]([CH2:24][O:23][CH2:22][CH2:21][Si:20]([CH3:27])([CH3:26])[CH3:19])[N:3]=1
Reactant: O=Cc1ccc2[nH]nc(I)c2c1
Reactant: C[Si](C)(C)CCOCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1nc(I)c2cc(C=O)ccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.5 %

Procedure:
21.6 g (79.5 mmol) 3-iodo-1H-indazole-5-carbaldehyde (Example 3A), dissolved in DMF (100 ml), and 31.1 g (95.4 mmol) cesium carbonate were slowly treated with 15.9 g (95.4 mmol) 2-(trimethylsilyl)ethoxymethyl chloride at 0° C. The mixture was warmed to room temperature, and stirring was continued for 12 h. The solids were then filtered off, and the filtrate was evaporated to dryness yielding the title compound (26.4 g, 82% of th.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)=[CH:5][CH:4]=1.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(O)(=[O:41])C>CC(O)(C)C.C(O)C.C(O)(=O)C.[Zn]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:41])[NH:13]3)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2cccc3[nH]ccc23)cc1
Reactant: CC(=O)O
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: CC(C)(C)O
Product: COc1ccc(-c2cccc3c2CC(=O)N3)cc1
Temperature: 27 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
To the suspension of 4-(4-methoxy-phenyl)-1H-indole (1.84 g, 8.24 mmol) in t-BuOH-ethanol-acetic acid (3:2:1) (99 mL) was added pyridinium tribromide (90% purity from Aldrich, 8.78 g, 24.72 mmol)) portionwise. The mixture was stirred at 27° C. for 3 hours, and then to the mixture was added acetic acid (40 mL). Zinc dust was added to the reaction mixture portionwise until the color changed from deep red to light yellow, and the reaction mixture was stirred at room temperature for one hour. The unreacted zinc dust was filtered off and washed with ethanol. The filtrate was concentrated, and the syrupy residue was dissolved in ethyl acetate, which was washed with water, 0.5 N HCl, sat. NaHCO3 and brine, and dried over Na2SO4. After filtration and evaporation, the crude product was triturated with diethyl ether to provide product 4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one (1.66 g, 84%) as a tan solid.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1.C(N(CC)CC)C>ClCCl>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:31](=[O:32])[C:30]4[CH:34]=[CH:35][C:27]([C:26]([F:25])([F:36])[F:37])=[CH:28][CH:29]=4)=[CH:24][CH:23]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1)c1ccc(C(F)(F)F)cc1
Yield: 88.5 %

Procedure:
As described for Example 9, 0.314 g of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine is reacted with 0.269 g (1.29 mmol) of 4-trifluoromethylbenzoyl chloride and 0.130 g (1.29 mmol) of triethylamine in 9 ml of dichloromethane for 1.5 hours at room temperature. The product is triturated with ethyl acetate-hexane to give 0.43 g of crystals, m.p. 205°-207° C.
Reaction SMILES: C([O:8][NH:9][C:10](=[O:28])[CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH:16]=1)C1C=CC=CC=1>C1COCC1.[Pd]>[F:27][C:24]1[CH:23]=[CH:22][C:21]([C:17]2[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=2)[O:14][CH2:13][CH2:12][CH2:11][C:10]([NH:9][OH:8])=[O:28])=[CH:26][CH:25]=1
Reactant: O=C(CCCOc1cccc(-c2ccc(F)cc2)c1)NOCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C(CCCOc1cccc(-c2ccc(F)cc2)c1)NO
Reaction time: 8 h
Yield: 25.6 %

Procedure:
To a solution in THF (15 mL) of O-benzyl-4-[3-(4-fluorophenyl)phenoxy]butanohydroxamic acid (0.29 g, 0.77 mmol), prepared as in step 3, was added 10% palladium on carbon (0.107 g) and the mixture was stirred overnight under a positive H2 pressure. Purification by reverse phase high performance liquid chromatography gave 4-[3-(4-fluorophenyl)phenoxy]butanohydroxamic acid (57 mg) as a white solid. 1H NMR (DMSO-d6) δ 1.94 (m, 2H), 2.16 (t, 2H, J=7 Hz), 4.03 (t, 2H, J=6 Hz), 6.92 (dd, 1H, J=2, 8 Hz), 7.16 (m, 1H), 7.20 (d, 1H, J=7 Hz), 7.28 (t, 2H, J=9 Hz), 7.37 (t, 1H, J=8 Hz), 7.71 (dd, 2H, J=5, 8 Hz), 8.71 (s, 1H), 10.42 (s, 1H). MS (DCI/NH3) 307 (M+NH4+, 100), 290 (M+H+, 30). Anal. Calcd for: C16H16FNO3 : C, 66.43; H, 5.57; N, 4.84. Found: C, 66.04; H, 5.48; N, 4.78.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([C@@H:13]([NH:15][C:16](=[O:19])[CH2:17][CH3:18])[CH3:14])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[CH2:20]([Br:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC(C)=O>[Br-:27].[CH2:20]([N+:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([C@@H:13]([NH:15][C:16](=[O:19])[CH2:17][CH3:18])[CH3:14])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCC(=O)N[C@@H](C)c1ccc(-c2ccncc2)cc1
Reactant: BrCc1ccccc1
Solvent: CC(C)=O
Product: CCC(=O)N[C@@H](C)c1ccc(-c2cc[n+](Cc3ccccc3)cc2)cc1
Product: [Br-]

Procedure:
To 9.60 g (37.7 mmol) (S)—N-[1-(4-pyridin-4-yl-phenyl)-ethyl]-propionamide (IV.6) in 120 mL acetone are added 4.91 mL (41.5 mmol) benzyl bromide. The mixture is refluxed for 12 h. After that time, the precipitate is filtered off, washed with acetone and dried at 50° C. to yield the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15](OS(C(F)(F)F)(=O)=O)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:25]([OH:28])[C:26]#[CH:27]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:27]#[C:26][CH2:25][OH:28])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(Oc1ccc2c(-c3ccc(Cl)cc3)nsc2c1)C(F)(F)F
Reactant: C#CCO
Product: OCC#Cc1ccc2c(-c3ccc(Cl)cc3)nsc2c1

Procedure:
In analogy to example 14.1, Trifluoro-methanesulfonic acid 3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl ester and 2-propyn-1-ol were converted to yield 3-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-yn-1-ol as yellow solid, MS: 299 (M, 1 Cl).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[F:27])[N:13]=[C:12]2[CH3:28])[CH:5]=1.[Cl:30]N1C(=O)CCC1=O>C(O)(C)C.ClC(Cl)C(O)=O>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[C:15]([Cl:30])=[C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[F:27])[N:13]=[C:12]2[CH3:28])[CH:5]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3ccc(F)cc3F)cc2=O)c1
Agent: O=C(O)C(Cl)Cl
Solvent: CC(C)O
Product: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3ccc(F)cc3F)c(Cl)c2=O)c1
Temperature: 60 °C
Yield: 81.4 %

Procedure:
To a solution of 3-[4-(2,4-difluoro-benzyloxy)-2-methyl-6-oxo-6H-pyrimidin-1-yl]-4-methyl-benzoic acid methyl ester from Example 1, Step A (260 mg, 0.65 mmol) in isopropanol (5 mL) was added N-chlorosuccinimide (95 mg, 0.71 mmol) and 3 drops of dichloroacetic acid. The solution was heated at 60° C. for three hours. The solution was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulfate. The slurry was filtered and concentrated to provide the chlorinated product as a light yellow semi-solid (230 mg, 82%). MS (M+H): 435
Reaction SMILES: [Cl:1][C:2]1[CH:42]=[C:41]([N+:43]([O-])=O)[CH:40]=[CH:39][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][Si:9]([CH3:38])([CH3:37])[O:10][Si:11]([CH3:36])([CH3:35])[O:12][Si:13]([CH3:34])([CH3:33])[O:14][Si:15]([CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][C:24]=1[Cl:32])([CH3:17])[CH3:16].[H][H]>[Pd]>[NH2:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][CH2:21][CH2:20][CH2:19][CH2:18][Si:15]([CH3:16])([CH3:17])[O:14][Si:13]([CH3:34])([CH3:33])[O:12][Si:11]([CH3:36])([CH3:35])[O:10][Si:9]([CH2:8][CH2:7][CH2:6][CH2:5][O:4][C:3]2[CH:39]=[CH:40][C:41]([NH2:43])=[CH:42][C:2]=2[Cl:1])([CH3:37])[CH3:38])=[C:24]([Cl:32])[CH:25]=1
Reactant: [H][H]
Reactant: C[Si](C)(CCCCOc1ccc([N+](=O)[O-])cc1Cl)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)CCCCOc1ccc([N+](=O)[O-])cc1Cl
Agent: [Pd]
Product: C[Si](C)(CCCCOc1ccc(N)cc1Cl)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)CCCCOc1ccc(N)cc1Cl
Yield: 91.9 %

Procedure:
0.936 g of the above (2h) (1.38 mmol) and 10 mL of a 10 wt % Pd/C (0.0469 g) ethyl acetate solution were mixed, and stirred for 2 days in a hydrogen atmosphere at room temperature. The solution was filtrated by Celite and then concentrated to obtain a brown oily material of 1,7-bis[4-(4-amino-2-chlorophenoxy)butyl]-1,1,3,3,5,5,7,7-octamethyltetrasiloxane (3h) (0.860 g, 99% of yield) represented by the following formula. Various measurements were carried out with regard to the obtained (3h), and results are shown below.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([CH3:14])=[C:12]([C:15]([OH:17])=O)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([N:27]2[CH2:32][CH2:31][CH:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH2:29][CH2:28]2)=[C:23]([CH:26]=1)[C:24]#[N:25]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([CH3:14])=[C:12]([C:15]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([N:27]4[CH2:32][CH2:31][CH:30]([N:33]5[CH2:34][CH2:35][O:36][CH2:37][CH2:38]5)[CH2:29][CH2:28]4)=[C:23]([C:24]#[N:25])[CH:26]=3)=[O:17])[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N#Cc1cc(N)ccc1N1CCC(N2CCOCC2)CC1
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(F)c(Cl)c1
Product: Cc1c(C(=O)Nc2ccc(N3CCC(N4CCOCC4)CC3)c(C#N)c2)cnn1-c1ccc(F)c(Cl)c1
Yield: 42.2 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(3-chloro-4-fluorophenyl)-5-methylpyrazole-4-carboxylic acid (1.5 g) and 5-amino-2-(4-morpholinopiperidin-1-yl) benzonitrile (1.9 g), the title compound (1.3 g) was obtained, melting point: 266° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([NH2:13])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C)(C)C.[C:19]([O:23][C:24](OC([O-])=O)=[O:25])([CH3:22])([CH3:21])[CH3:20]>[OH-].[Na+]>[C:19]([O:23][C:24](=[O:25])[NH:13][CH:11]1[CH2:10][CH2:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12]1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: NC1CCN(Cc2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)NC1CCN(Cc2ccccc2)C1
Yield: 96.8 %

Procedure:
1-benzylpyrrolidin-4-ylamine (10 g, 57 mmol) was dissolved in 3M sodium hydroxide aqueous solution (21 ml) and t-butanol (114 ml) in a 500 ml vessel, and t-butyl-dicarbonate ((t-Boc)2O; 13.07 g, 59.9 mmol) wad added thereto while stirring. The resulting mixture was reacted at room temperature for 12 hrs, extracted with ethyl acetate twice. The organic layer was separated, washed with 0.1N hydrochloric acid solution and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography to obtain 15.25 g of the title compound as a white solid (yield 97%).
Reaction SMILES: [NH2:1]/[C:2](/[C:9]([F:12])([F:11])[F:10])=[CH:3]\[C:4]([O:6]CC)=O.C[O-].[Na+].C([O:18][C:19]([NH:21][C:22]1[C:23]([F:36])=[CH:24][C:25]2[O:30][CH2:29][C:28](=[O:31])[N:27]([CH2:32][C:33]#[CH:34])[C:26]=2[CH:35]=1)=O)C>CN(C)C=O>[F:36][C:23]1[C:22]([N:21]2[C:4](=[O:6])[CH:3]=[C:2]([C:9]([F:10])([F:11])[F:12])[NH:1][C:19]2=[O:18])=[CH:35][C:26]2[N:27]([CH2:32][C:33]#[CH:34])[C:28](=[O:31])[CH2:29][O:30][C:25]=2[CH:24]=1
Reactant: C#CCN1C(=O)COc2cc(F)c(NC(=O)OCC)cc21
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCN1C(=O)COc2cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)cc21
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 8.7 %

Procedure:
1.10 g of ethyl 3-amino-4,4,4-trifluorocrotonate was added to a mixture of 0.33 g of sodium methoxide and 5 ml of dimethylformamide at room temperature. After standing for 20 minutes, the mixed solution was added with 1.76 g of 6-ethoxycarbonylamino-7-fluoro-3-oxo-4-propargyl-2H-1,4-benzoxazine and heated at 130° C. for 4 hours. After cooling the solution to room temperature, the solution was poured into ice water and the resultant solution was extracted twice with diethyl ether. The aqueous layer was made acidic with dilute hydrochloric acid and extracted three times with ethyl acetate. The ethyl acetate extract was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. After distilling off ethyl acetate, the residue was purified by column chromatography using chloroform as developing solvent to obtain 0.20 g of the objective compound as pale yellow crystals.
Reaction SMILES: [OH:1][C@H:2]([C@H:6]1[CH2:11][C@H:10]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])[CH2:9][CH2:8][C@H:7]1[NH:17][C:18](=[O:33])[CH2:19][NH:20][C:21](=[O:32])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1)[CH:3]([CH3:5])[CH3:4].C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-][Cr](O[Cr]([O-])(=O)=O)(=O)=O>C(Cl)Cl>[C:2]([C@H:6]1[CH2:11][C@H:10]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])[CH2:9][CH2:8][C@H:7]1[NH:17][C:18](=[O:33])[CH2:19][NH:20][C:21](=[O:32])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1)(=[O:1])[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)[C@H](O)[C@H]1C[C@H](N(C)C(C)C)CC[C@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)C(=O)[C@H]1C[C@H](N(C)C(C)C)CC[C@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of N-(2-((1R,2S,4R)-2-((S)-1-hydroxy-2-methylpropyl)-4-(isopropyl(methyl)amino)cyclohexylamino)-2-oxoethyl)-3-(trifluoromethyl)benzamide (250 mg, 0.53 mmol; See Example 81, Step 6) in CH2Cl2 (15 mL) was added PDC (599 mg, 1.5 mmol), and 4A molecular sieves (excess). The reaction was stirred for 16 h at RT and then filtered, and concentrated in vacuo. The residue was purified by HPLC to N-(2-((1R,2S,4R)-2-isobutyryl-4-(isopropyl(methyl)amino)cyclohexylamino)-2-oxoethyl)-3-(trifluoromethyl)benzamide. MS found: (M+H)+=470.
Reaction SMILES: [CH2:1]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=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][CH3:14].[CH:21]([S:35]([OH:38])(=[O:37])=[O:36])=[CH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>>[CH2:1]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][S:35]([OH:38])(=[O:37])=[O:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCC=CS(=O)(=O)O
Reactant: CCCCCCCCCCCCCCc1ccccc1
Product: CCCCCCCCCCCCCCc1ccccc1CCCCCCCCCCCCCCS(=O)(=O)O

Procedure:
(Tetradecylphenyl) tetradecylsulfonic acid was prepared according to procedures described in U.S. U.S. Pat. No. 6,043,391 from tetradecylbenzene and tetradecenylsulfonic acid.
Reaction SMILES: [CH:1]([OH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][N:16]1[CH:20]2[CH2:21][CH:22](O)[CH2:23][CH:17]1[CH2:18][CH2:19]2.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:2]1([CH:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:14][CH:22]2[CH2:21][CH:20]3[N:16]([CH3:15])[CH:17]([CH2:18][CH2:19]3)[CH2:23]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC(c1ccccc1)c1ccccc1
Reactant: CN1C2CCC1CC(O)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CN1C2CCC1CC(OC(c1ccccc1)c1ccccc1)C2
Reaction time: 2 h

Procedure:
The starting material is prepared as follows. The intimate mixture of 9.20 g of benzhydrol 7.05 g of tropine and 10 g of p-toluenesulfonic acid monohydrate is placed in a flask which is fitted with an air condensor and a vacuum take-off. The flask is evacuated and maintained in vacuo while being heated in an oil bath to 165°-170°, whereby the liberated water is removed. After 2 hours, the mixture is cooled and partitioned between 100 ml of water and diethyl ether each. The aqueous solution is separated, washed once more with diethyl ether and made basic with 50% aqueous sodium hydroxide. It is extracted repeatedly with diethyl ether, the extract washed with brine and evaporated to give 3-diphenylmethoxy-8-methyl-8-azabicyclo[3.2.1]octane, which is sufficiently pure to be used in the next step.