Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH2:10][C@@H:9]([N+:11]([O-:13])=[O:12])[C@H:8]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[CH2:7][CH:6]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[C@H:8]1[C@H:9]([N+:11]([O-:13])=[O:12])[CH2:10][C:5]([CH2:4][NH2:1])=[CH:6][CH2:7]1
Reactant: [N-]=[N+]=NCC1=CC[C@@H](c2ccc(Cl)cc2Cl)[C@H]([N+](=O)[O-])C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCC1=CC[C@@H](c2ccc(Cl)cc2Cl)[C@H]([N+](=O)[O-])C1
Temperature: 65 °C

Procedure:
To a solution of Example 12B (700 mg, 2.14 mmol) in mixture of tetrahydrofuran/H2O (15 mL/1.5 mL), triphenylphosphine (1.12 mg, 4.28 mmol) was added at room temperature. The reaction mixture was heated to 65° C. for five hours. It was cooled to room temperature, concentrated under reduced pressure, azeotroped with toluene, and purified by flash chromatography (eluting with 10% methanol/CH2Cl2) to provide the title compound. 1H NMR (500 MHz, methanol-d4) δ ppm 7.41-7.48 (m, 2H), 7.28-7.35 (m, 1H), 5.72 (m, 1H), 5.26-5.38 (m, 1H), 3.93-4.04 (m, 1H), 3.17-3.42 (m, 4H), 2.72-2.84 (m, 2H). MS (DCI) m/z 301 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:18](Cl)(=[O:20])[CH3:19]>ClCCl>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:18](=[O:20])[CH3:19])=[CH:3][CH:4]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(N)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc(C(C)=O)cc1
Temperature: 0 °C
Yield: 73.8 %

Procedure:
Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 1-(4-aminophenyl)ethanone (3.1 g, 22.96 mmol, 1.00 equiv) in dichloromethane (30 mL), triethylamine (4.64 g, 45.94 mmol, 2.00 equiv). This was followed by the addition of acetyl chloride (1.79 g, 22.95 mmol, 1.00 equiv) dropwise with stirring at 0° C. The resulting solution was stirred for 30 min at 0° C. The reaction was then quenched by the addition of 2 mL of water. The resulting mixture was washed with 3×50 mL of saturated aqueous sodium chloride. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to give 3.0 g (74%) of N-(4-acetylphenyl)acetamide as a white solid.
Reaction SMILES: C[N:2]1[CH2:7][CH2:6][C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH2:8]2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:23][S:24]([Cl:27])(=[O:26])=[O:25].C(=O)(O)[O-].[Na+]>ClCCl>[ClH:27].[CH3:23][S:24]([N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]2([CH2:6][CH2:7][NH:2][CH2:3][CH2:4]2)[CH2:8]1)(=[O:26])=[O:25]
Reactant: CN1CCC2(CC1)CNc1ccccc12
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CC2(CCNCC2)c2ccccc21
Product: Cl
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a solution of 1.20 g (5.8 mmol) of 1'-methyl-1,2-dihydro-spiro[3H-indole-3,4'-piperidine] (prepared as described in H. Ong et al J. Med. Chem. 1983, 23,981-986) in 20 mL of dry dichloromethane at 0° C. was added triethylamine (0.90 mL; 6.4 mmol) and methanesulfonyl chloride (0.49 mL; 6.35 mmol) and stirred for 30 min. The reaction mixture was poured into 15 mL of saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (2×10 mL). The combined organics were washed with brine (20 mL), dried over anhydrous potassium carbonate, filtered and the solvent removed under reduced pressure to yield 1.44 g of the methanesulfonamide derivative as pale yellow oil which was used without purification.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O[I:12](OC(=O)C(F)(F)F)[C:13]([F:43])([F:42])[C:14]([F:41])([F:40])[C:15]([F:39])([F:38])[C:16]([F:37])([F:36])[C:17]([F:35])([F:34])[C:18]([F:33])([F:32])[C:19]([F:31])([F:30])[C:20]([F:29])([F:28])[C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])=O.FC(F)(F)C(O)=O.[F:60][C:61]([F:67])([F:66])[S:62]([OH:65])(=[O:64])=[O:63]>>[F:60][C:61]([F:67])([F:66])[S:62]([O-:65])(=[O:64])=[O:63].[F:26][C:21]([F:27])([C:22]([F:23])([F:24])[F:25])[C:20]([F:28])([F:29])[C:19]([F:31])([F:30])[C:18]([F:32])([F:33])[C:17]([F:35])([F:34])[C:16]([F:37])([F:36])[C:15]([F:39])([F:38])[C:14]([F:41])([F:40])[C:13]([F:43])([F:42])[I+:12][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccccc1
Reactant: O=C(OI(OC(=O)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Reactant: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)[I+]c1ccccc1
Product: O=S(=O)([O-])C(F)(F)F
Yield: 73.1 %

Procedure:
0.92 ml (10 mmol) of benzene was added to a mixture of 6.0 g (6.9 mmol) of di(trifluoroacetoxy)iodoheneicosafluoro-n-decane and 32 ml of trifluoroacetic acid under cooling in an ice bath with stirring, and then 0.61 ml (6.9 mmol) of trifluoromethanesulfonic acid was added dropwise thereto. After completion of the addition, the mixture was stirred for 1.5 hours and the solvent was distilled off to obtain a crystalline solid. The solid was washed with hot chloroform to obtain 4.4 g of heneicosafluoro-n-decylphenyliodonium trifluoromethanesulfonate. Yield, 73%. Melting Point 162°-166° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][P:11](=[O:18])(OCC)[O:12][CH2:13][CH3:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].P(Cl)(Cl)(Cl)(Cl)[Cl:20]>C(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][P:11]([Cl:20])(=[O:18])[O:12][CH2:13][CH3:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])cc1)OCC
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOP(=O)(Cl)Cc1ccc([N+](=O)[O-])cc1
Temperature: 30 °C
Reaction time: 24 h
Yield: 84.3 %

Procedure:
This method is a modification of that outlined by Doak and Freedman (Ref. 178). Diethyl (p-nitrophenyl)methylphosphonate (7.16) (1.0 g, 3.6 mmol) in DCM (10 ml) was added dropwise to a solution of PCl5 (0.9 g, 4.32 mmol) in CCl4 (20 ml) under an inert atmosphere. The reaction was stirred at 30° C. and the progress of the chlorination was followed by 31P NMR which showed the reaction was complete after 24 h. Solvent and phosphoryl chloride were removed in vacuo to yield a pale yellow, moisture-sensitive oil (0.8 g, 90%) which was used without further purification. δH (250 MHz, CDCl3) 1.40 (3H, t, J 7.5 Hz, CH3), 3.60 (2H, d, 2JPH 22.5 Hz, Ar--CH2), 4.25-4.43 (2H, m, JHP 8.5 Hz, J 7.5 Hz,CH2), 7.5 (2H, d, J 7.5 Hz, Ar--H), 8.20 (2H, d, J 7.5 Hz, Ar--H); δP (101 MHz, CDCl3) 35.94 (s).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([C:10]1[CH:11]=[C:12]([NH:25][C:26]([NH:28][C@@H:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C@H:32]([O:39][C:40]3[CH:41]=[CH:42][C:43]4[N:44]([C:46]([N:49]5[C@H:54]([CH3:55])[CH2:53][CH2:52][CH2:51][C@@H:50]5[CH3:56])=[N:47][N:48]=4)[CH:45]=3)[CH2:31][CH2:30]2)=[O:27])[N:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][OH:24])[CH:16]=2)[N:14]=1)([CH3:9])([CH3:8])[CH3:7].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:6]([C:10]1[CH:11]=[C:12]([NH:25][C:26]([NH:28][C@@H:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C@H:32]([O:39][C:40]3[CH:41]=[CH:42][C:43]4[N:44]([C:46]([N:49]5[C@H:54]([CH3:55])[CH2:53][CH2:52][CH2:51][C@@H:50]5[CH3:56])=[N:47][N:48]=4)[CH:45]=3)[CH2:31][CH2:30]2)=[O:27])[N:13]([C:15]2[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=2)[O:21][CH2:22][CH2:23][O:24][S:2]([CH3:1])(=[O:4])=[O:3])[N:14]=1)([CH3:9])([CH3:7])[CH3:8]
Reactant: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCO)c4)c4ccccc43)cn12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCOS(C)(=O)=O)c4)c4ccccc43)cn12
Temperature: 0 °C
Yield: 99.8 %

Procedure:
Methane sulfonylchloride (11.0 μL, 0.13 mmol) was added to an ice cold solution of Intermediate 96e (89.0 mg, 0.13 mmol) and DIPEA (27.0 μL, 0.15 mmol) in DCM (1.5 mL). After 1 hour additional DIPEA (27.0 μL, 0.15 mmol) and methane sulfonylchloride (11.0 μL, 0.13 mmol) was added. After a further 1 hour additional DIPEA (27.0 μL, 0.15 mmol) and methane sulfonylchloride (11.0 μL, 0.13 mmol) was added. After 1 hour the reaction was partitioned between DCM and water. The aqueous layer was then extracted with DCM (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo to give the title compound (100 mg, 99%). LCMS (Method 1): Rt 3.73 min, in/z 771 [MH+].
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10](N=C=S)[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7](COC(=O)C)[O:6]1)(=[O:3])[CH3:2].FC(F)(F)CN>CC#N>[C:1]([O:4][CH:5]1[CH2:10][CH:9]([O:14][C:15](=[O:17])[CH3:16])[CH:8]([O:18][C:19](=[O:21])[CH3:20])[CH2:7][O:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N=C=S)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: NCC(F)(F)F
Solvent: CC#N
Product: CC(=O)OC1CC(OC(C)=O)C(OC(C)=O)CO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 153.7 %

Procedure:
To a stirred solution of (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-isothiocyanato-tetrahydro-2H-pyran-2,4,5-triyl triacetate (0.56 g, 1.44 mmol) in CH3CN, was added neat 2,2,2-trifluoroethylamine (0.236 g, 1.74 mmol), dropwise. The reaction was stirred at room temperature until complete by TLC (3 h). The reaction was quenched with saturated aqueous NaHCO3 (15 mL). The aqueous layer was then extracted three times with DCM, and the organic layers were combined, dried with MgSO4, filtered and concentrated. The concentrated mixture was purified via flash column chromatography in a solvent system of 1:1 EtOAc and hexanes, providing (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-(3,2,2,2-trifluoroethyl)thioureido)-tetrahydro-2H-pyran-2,4,5-triyl triacetate (0.576 g, 81% yield). 1H NMR (500 MHz, CDCl3) δ 2.00 (6H, s), 2.04 (s, 3H), 3.87-3.90 (m, 1H), 4.03-4.11 (m, 1H), 4.20-4.26 (m, 2H), 4.36 (s, 1H), 5.07 (t, 1H, J=9.6 Hz), 5.27 (t, 1H, J=9.8 Hz), 5.73 (d, 1H, J=8.5 Hz), 6.75 (s, 2H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])=[CH:10][C:9]=1[NH:22][C:23](=[O:35])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][N:30]=[C:29]([C:33]#[N:34])[CH:28]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:25]([C:27]3[CH:32]=[CH:31][N:30]=[C:29]([C:33]#[N:34])[CH:28]=3)[CH2:24][C:23](=[O:35])[NH:22][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2F)cc1NC(=O)CC(=O)c1ccnc(C#N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(C2=Nc3ccc(-c4ccc(F)cc4F)cc3NC(=O)C2)ccn1

Procedure:
Prepared from {3-[3-(2-cyano-pyridin-4-yl)-3-oxo-propionylamino]-2′,4′-difluoro-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K73) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (24 mg).
Reaction SMILES: Br[C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7].C([O-])([O-])=O.[Na+].[Na+].[C:32]1(B(O)O)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>COCCOC>[F:25][C:23]1[CH:22]=[CH:21][C:3]([O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])=[C:2]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:24]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1ccc(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1ccc(F)cc1-c1ccccc1
Yield: 88.7 %

Procedure:
A solution of benzoic acid N′-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N′-isopropyl-hydrazide (50 mg, 0.122 mmol) in DME (3 ml)/2M Na2CO3 (0.215 ml, 0.427 mmol) was treated with phenylboronic acid (22 mg, 0.183 mmol) and Pd[PPh3]4 (28 mg, 0.0244 mmol) for 12 hours at 90° C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 30-50% ethyl acetate/hexanes gradient to afford the product as a white solid (44 mg, 89%). MS m/e 407.22 (M+H+)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[CH3:20])[C:5]([C:7]1([OH:16])[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[C:13]([OH:15])=[O:14])=[O:6].[CH2:21]([NH:24][CH2:25][CH2:26][CH3:27])[CH2:22][CH3:23]>CC(C)=O>[CH2:21]([NH2+:24][CH2:25][CH2:26][CH3:27])[CH2:22][CH3:23].[CH3:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[CH3:20])[C:5]([C:7]1([OH:16])[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[C:13]([O-:15])=[O:14])=[O:6]
Reactant: Cc1ccc(C(=O)C2(O)CCCCC2C(=O)O)cc1C
Reactant: CCCNCCC
Solvent: CC(C)=O
Product: CCC[NH2+]CCC
Product: Cc1ccc(C(=O)C2(O)CCCCC2C(=O)[O-])cc1C
Yield: 98 %

Procedure:
5.53 g (0.02 mol) of 2-(3,4-dimethyl-benzoyl)-2-hydroxy-cyclohexanecarboxylic acid (=compound of example 3) are dissolved in 30 ml of acetone. A solution of 2.02 g (0.02 mol) of dipropylamine in 30 ml of acetone and the reaction mixture are stirred at room temperature for 30 minutes. The solvent is evaporated in vacuum and the remaining residue is dried in vacuum. 7.4 g of 2-(3,4-dimethyl-benzoyl)-2-hydroxy-cyclohexanecarboxylate dipropyl-ammonium are obtained as slightly yellowish crystals with a melting range of 122-129° C.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH:25]=O)[C:5]1=[O:29])[CH:2]=[CH2:3].[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][NH2:40])=[CH:35][CH:34]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25][NH:40][CH2:39][C:36]2[CH:37]=[CH:38][C:33]([O:32][CH3:31])=[CH:34][CH:35]=2)[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: COc1ccc(CN)cc1
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](C=O)CC)C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: C=CC[C@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CNCc2ccc(OC)cc2)C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (S)-2-((3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanal (300 mg, 0.675 mmol; Example 91, Step C) and (4-methoxyphenyl)methanamine (131 μL, 1.01 mmol) in DCE (4.5 mL) was added sodium triacetoxyborohydride (429 mg, 2.03 mmol) at 0° C. in several portions. After being stirred at 25° C. for 18 h, the reaction was quenched by adding ice-cold saturated aqueous NaHCO3 and extracted (2×DCM). The combined organic layers were washed (1×sat. aq. NaCl solution) and concentrated under reduced pressure to provide the title compound as a yellow film. The product was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20]([OH:22])=O)[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[N:23]1([NH2:31])[CH2:28][CH2:27][S:26](=[O:30])(=[O:29])[CH2:25][CH2:24]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([C:20]([NH:31][N:23]3[CH2:28][CH2:27][S:26](=[O:30])(=[O:29])[CH2:25][CH2:24]3)=[O:22])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: NN1CCS(=O)(=O)CC1
Product: O=C(NN1CCS(=O)(=O)CC1)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid (CAN 1018782-82-5) and 4-thiomorpholinamine 1,1-dioxide (CAN 26494-76-8) as starting materials; MS (EI) 464.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:18][CH2:19][C:20](Cl)=[O:21].Cl.[CH3:24][NH2:25]>C(Cl)Cl.[OH-].[Na+]>[CH3:24][NH:25][C:20](=[O:21])[CH2:19][O:18][C:3]1[CH:4]=[CH:5][C:6]2[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])=[N:8][O:9][C:10]=2[C:2]=1[Cl:1]
Reactant: O=C(Cl)COc1ccc2c(-c3ccccc3F)noc2c1Cl
Reactant: CN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CNC(=O)COc1ccc2c(-c3ccccc3F)noc2c1Cl
Reaction time: 18 h

Procedure:
A solution of 4.0 g of {[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetyl chloride in methylene chloride is added dropwise to a solution of 0.9 g of methylamine hydrochloride in 50 ml methylene chloride and 25 ml of 15% sodium hydroxide solution at 0° C. After 18 hr at room temperature the reaction mixture is acidified, filtered, and the filtrate partitioned. The aqueous solution is washed with methylene chloride. The organic solutions are combined, washed with saturated sodium chloride solution and dried over magnesium sulfate. Removal of the solution gives N-methyl{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetamide, mp 164° C.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([O:11][CH:12]([CH3:14])[CH3:13])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[NH2:15][CH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[CH:12]([O:11][C:5]1[CH:4]=[C:3]([NH:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:2]=[CH:7][C:6]=1[N+:8]([O-:10])=[O:9])([CH3:14])[CH3:13]
Reactant: NC1CCOCC1
Reactant: CC(C)Oc1ccc(F)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)Oc1cc(NC2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 8 h
Yield: 65.4 %

Procedure:
A mixture of 0.75 g of 5-fluoro-1-nitro-2-(propan-2-yloxy)benzene, 0.42 g of 4-aminotetrahydropyran and 0.8 g of potassium carbonate in 6 ml of DMSO is stirred at 50° C. overnight. The mixture is diluted with 100 ml of water and extracted three times with 50 ml of ethyl acetate. The organic phases are combined and then dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue is purified by chromatography on a 50 g silica column, elution being carried out with a dichloromethane/methanol (95/5 v/v) mixture, so as to obtain 0.69 g of (3-isopropoxy-4-nitrophenyl)(tetrahydropyran-4-yl)amine in the form of a yellow foam.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[N:19]=[N:20][C:21](Cl)=[CH:22][CH:23]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([C:21]2[N:20]=[N:19][C:18]([Cl:17])=[CH:23][CH:22]=2)[CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1ccc(Cl)nn1
Reactant: CNCC1CCN(C(=O)OC(C)(C)C)CC1
Product: CN(CC1CCN(C(=O)OC(C)(C)C)CC1)c1ccc(Cl)nn1

Procedure:
From 1-t-butoxycarbonyl-4-[(methylamino)methyl]piperidine and 3,6-dichloropyridazine.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([CH2:32][C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)[C:8](=[O:9])[N:7]([CH2:10][CH:11]2[CH2:16][CH:15]3[CH2:17][CH:13]([C:14]3([CH3:19])[CH3:18])[CH:12]2[CH3:20])[C:6](=[CH:21][C:22]([C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=2)=[O:23])[NH:5]1.C(NC(C)C)(C)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>C(Cl)Cl>[C:28]([C:27]1[CH:26]=[CH:25][C:24]([C:22](=[O:23])[CH:21]=[C:6]2[NH:5][C:4]([CH2:3][CH2:2][O:1][S:47]([CH3:46])(=[O:49])=[O:48])([CH2:32][C:33]3[CH:34]=[CH:35][N:36]=[CH:37][CH:38]=3)[C:8](=[O:9])[N:7]2[CH2:10][CH:11]2[CH2:16][CH:15]3[CH2:17][CH:13]([C:14]3([CH3:18])[CH3:19])[CH:12]2[CH3:20])=[CH:31][CH:30]=1)#[N:29]
Reactant: CC1C(CN2C(=O)C(CCO)(Cc3ccncc3)NC2=CC(=O)c2ccc(C#N)cc2)CC2CC1C2(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: CC1C(CN2C(=O)C(CCOS(C)(=O)=O)(Cc3ccncc3)NC2=CC(=O)c2ccc(C#N)cc2)CC2CC1C2(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
4-{[4-(2-Hydroxy-ethyl)-5-oxo-4-pyridin-4-ylmethyl-1-((+)-(2,6,6-trimethyl-bicyclo[3.1.1]hept-3-ylmethyl))-imidazolidin-2-ylidene]-acetyl}-benzonitrile (1.76 g, 3.44 mMol) and diisopropylamine (0.90 mL, 5.16 mMol) were dissolved in CH2Cl2 (20 mL) under an atmosphere of dry N2. To this solution was added methanesulfonyl chloride (0.41 mL, 5.16 mMol) and the mixture was stirred at ambient temperature for 20 minutes. The mixture was concentrated under vacuum and was partitioned between Et2O-EtOAc (50:50) and water. The organic layer was washed succesively with saturated aquoeus NaHCO3 solution, brine and then dried over MgSO4, filtered and concentrated under vacuum to give the titled compound as an oil as a 1:1 mixture of diastereomers.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]3[NH2:19])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[BH4-].[Na+].CC(C)=O>C(O)C.[OH-].[Na+]>[ClH:1].[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C@H:13]3[CH2:18][CH2:17][CH2:16][CH2:15][C@@H:14]3[NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: NC1CCCCC1Nc1ccnc2cc(Cl)ccc12
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CCO
Product: Cl
Product: Clc1ccc2c(N[C@H]3CCCC[C@@H]3NCc3ccccc3)ccnc2c1

Procedure:
0.39 g of N-(7-chloro-quinolin-4-yl)-cyclohexane-1,2-diamine and 0.13 ml of benzaldehyde were stirred at 20° C. in 3 ml of ethanol for 3 hrs. The solvent was evaporated in order to complete the reaction. The resulting Schiff's base was again dissolved in 3 ml of ethanol, cooled in ice under argon and then treated portionwise with 0.3 g of sodium borohydride and stirred without cooling for a further 20 hrs. Excess reducing agent was decomposed by the addition of 3 ml of acetone. Thereafter, the mixture was diluted with 30 ml of 0.3N NaOH and extracted twice with 30 ml of dichloromethane each time. The crude product obtained from these extracts was purified by flash chromatography on silica gel with ethyl acetate and ethyl acetate/methanol 5:1. The purified product was converted into the hydrochloride with ethanolic hydrochloric acid and precipitated by dilution with 2-butanone. Yield: 260 mg (54%), m.p. >200° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.C([Li])CCC.CN([CH:17]=[O:18])C>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:17]=[O:18]
Reactant: Fc1ccc(F)cc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cc(F)ccc1F
Reaction time: 0.08 h
Yield: 60.4 %

Procedure:
A solution of 1,4-difluorobenzene (10 g, 87.6 mmol, 1 wt) in THF (175 mL, 17.5 vol) was stirred under nitrogen and cooled to −75 to −78° C. n-Butyllithium (82 mL of 1.6 M solution in hexanes, 131.4 mmol, 1.5 eq) was added to the reaction mixture over approximately 20 minutes while maintaining the temperature at <−65° C. After a further hour, DMF (10.16 mL, 131.4 mmol, 1.5 eq) was added over approximately 10 minutes while maintaining the temperature <−65° C. The reaction mixture was quenched after 10 minutes by the addition of acetic acid (17.5 mL, 1.75 mL) directly followed by water (440 mL, 36.4 vol). This caused the reaction to exotherm to 5° C. The cold bath was then removed, TBME (220 mL, 22 vol) added and the reaction stirred for 5 minutes. The phases were separated and the aqueous phase extracted with TBME (2×220 mL, 22 vol). The organic phases were combined, washed with 0.2 M HCl (220 mL, 22 vol), 2 M Na2CO3 (220 mL, 22 vol) then saturated brine (220 mL, 22 vol), dried over magnesium sulphate (50 g, 5 wt) and concentrated on a rotary evaporator to afford the crude product (11.07 g). Purification by Kugelrohr distillation gave the product as a clear, colourless oil (7.52 g, 60%)