Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].CN(C=O)C.C(Cl)(C([Cl:23])=O)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([Cl:23])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc(Br)cc(C(=O)O)c1Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(Br)cc(C(=O)Cl)c1Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of compound 56 (3.82 g, 14.3 mmol) in CH2Cl2 (63 mL) was added dropwise DMF (0.20 mL) and (COCl)2 (1.63 mL, 18.7 mmol) at 0° C. under an atmosphere of nitrogen. After being stirred for 20 hours at room temperature, the mixture was concentrated in vacuo to provide the crude acid chloride 59, which was used for the next reaction without further purification.
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([C:13]([CH3:43])([CH3:42])[C:14]([N:16]([CH3:41])[C:17]2[C:18]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH3:40])=[CH:19][C:20]([N:23]3[CH2:27][C@H:26](O)[CH2:25][C@H:24]3[CH2:29][O:30][C:31](=[O:33])[CH3:32])=[N:21][CH:22]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(N(S(F)(F)[F:52])CC)C>ClCCl.[OH-].[Na+]>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([C:13]([CH3:43])([CH3:42])[C:14]([N:16]([CH3:41])[C:17]2[C:18]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH3:40])=[CH:19][C:20]([N:23]3[CH2:27][C@@H:26]([F:52])[CH2:25][C@H:24]3[CH2:29][O:30][C:31](=[O:33])[CH3:32])=[N:21][CH:22]=2)=[O:15])[CH:4]=[C:3]([C:2]([F:1])([F:44])[F:45])[CH:8]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(=O)OC[C@@H]1C[C@@H](O)CN1c1cc(-c2ccccc2C)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(=O)OC[C@@H]1C[C@H](F)CN1c1cc(-c2ccccc2C)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Yield: 36.7 %

Procedure:
To a solution of 0.14 g (0.21 mmol) (2S,4R)-acetic acid 1-(5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-o-tolyl-pyridin-2-yl)-4-hydroxy-pyrrolidin-2-ylmethyl ester in 2 ml dichloromethane were added dropwise at 0° C. 0.03 ml (0.2 mmol) (diethylamino)sulfur trifluoride. After 1 h the reaction mixture was diluted with a 0.5 M aqueous sodium hydroxide solution and extracted with four portions of dichloromethane. The combined organic extracts were dried over sodium sulfate and concentrated in vacuo. Flash column chromatography gave 47 mg (35%) of the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([Cl:11])[S:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]=1.[F-:14].[K+]>[Br-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.CN1CCCC1=O>[Cl:11][C:9]1[S:10][C:5]2[S:4](=[O:13])(=[O:12])[N:3]=[C:2]([F:14])[NH:7][C:6]=2[CH:8]=1
Reactant: O=S1(=O)N=C(Cl)Nc2cc(Cl)sc21
Reactant: [F-]
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Br-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=S1(=O)N=C(F)Nc2cc(Cl)sc21
Temperature: 130 °C
Reaction time: 20 h

Procedure:
A mixture of 3,6-dichloro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (1.02 g, 3.95 mmol), potassium fluoride (688 mg, 11.9 mmol) and hexadecyltrimethylammonium bromide (43 mg, 0.12 mmol) in dry 1-methyl-2-pyrrolidinone (4 ml) was stirred for 20 h at 130° C. under nitrogen to form 6-chloro-3-fluoro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide. The mixture was allowed to cool to room temperature and then reacted directly with 1-ethylcyclohexylamine hydrochloride (0.8 g, 5.93 mmol) and triethylamine (1.65 ml, 11.9 mmol) for 30 h at 75° C. in the sealed flask. The cooled mixture was poured into water, acidified to pH <2 with 1N hydrochloric acid and extracted with ethyl acetate. The organic phase was dried with sodium sulphate and evaporated to dryness to give the pure title compound; mp 244-246° C.; 1H-NMR (DMSO-d6): δ0.79 (t, 3H), 1.70-1.93 (m, 8H), 1.96-2.08 (m, 2H), 2.13-2.25 (m, 2H), 7.09 (s, 1H), 7.24 (br s, 1 H), 10.57 (br s, 1 H).
Reaction SMILES: [F:1]C(F)(N(CC)CC)C(F)C(F)(F)F.[N:15]1([C:19]([C@@H:21]2[CH2:25][C@H:24](O)[CH2:23][N:22]2[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:20])[CH2:18][CH2:17][CH2:16]1.[F-].[Na+].C(=O)([O-])[O-].[K+].[K+]>ClCCl.C(OCC)(=O)C>[N:15]1([C:19]([C@@H:21]2[CH2:25][CH:24]([F:1])[CH2:23][N:22]2[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:20])[CH2:18][CH2:17][CH2:16]1
Reactant: CCN(CC)C(F)(F)C(F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@H]1C(=O)N1CCC1
Agent: O=C([O-])[O-]
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(F)C[C@H]1C(=O)N1CCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2.68 g of a mixture (approximately 3:1) of 1,1,2,3,3,3-hexafluoro-1-(diethylamino)propane and 1,2,3,3,3-pentafluoro-1-(diethylamino)-2-propene was added dropwise over a period of 10 minutes under ice cooling to a suspension of 2.71 g of the compound obtained in step 7-1 and 505 mg of sodium fluoride in 27 mL of dichloromethane, after which the reaction mixture was stirred for 16 hours at room temperature. 100 mL of a 5% potassium carbonate aqueous solution was added under ice cooling to the reaction solution, and the reaction mixture was stirred for 30 minutes at the same temperature. After liquid separation, the aqueous layer thus obtained was extracted with chloroform (30 mL×2), and the combined organic layer was washed with 50 mL of saturated brine and dried with magnesium sulfate, after which the drying agent was filtered off and the solvent was distilled off under reduced pressure. The residue thus obtained was subjected to column chromatography (silica gel 60, mobile phase: ethyl acetate) to obtain 2.30 g of the titled compound (colorless oil).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[CH2:24]O)[CH:7]=1)[CH3:2].P(Br)(Br)[Br:28]>COCCOC>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[CH2:24][Br:28])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc([N+](=O)[O-])cc2CO)c1
Reactant: BrP(Br)Br
Solvent: COCCOC
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc([N+](=O)[O-])cc2CBr)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [3-(2-hydroxymethyl-4-nitro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester (15.14 g, 41.9 mmol) in DME was added phosphorus tribromide (5.92 mL, 62.8 mmol), and the reaction was stirred at room temperature overnight. After cooling to 0° C., the mixture was quenched with saturated aqueous NaHCO3 and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: [CH3:1][S-:2].[Na+].[CH:4]1([O:9][C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=2[N+]([O-])=O)[C:13]([O:15][CH3:16])=[O:14])[CH2:8][CH2:7][CH2:6][CH2:5]1.[Cl-].[Na+]>CN1CCN(C)C1=O.O>[CH:4]1([O:9][C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=2[S:2][CH3:1])[C:13]([O:15][CH3:16])=[O:14])[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: C[S-]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(OC2CCCC2)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN1CCN(C)C1=O
Solvent: O
Product: COC(=O)c1ccc(SC)c(OC2CCCC2)c1
Reaction time: 4 h
Yield: 91.6 %

Procedure:
Sodium thiomethoxide (8.05 g, 0.115 mol) is added portionwise to a stirred solution of methyl 3-cyclopentyloxy-4-nitrobenzoate (26.5 g, 0.1 mol) in N,N'-dimethylimidazolidinone (200 mL) at ambient temperature under an atmosphere of nitrogen and stirring continued for 4 hours. The mixture is then diluted with water (1200 mL) containing sodium chloride (200 g) and extracted with ethyl acetate (2×300 mL). The combined extract is washed with saturated brine (2×300 mL) and then evaporated under reduced pressure to give methyl 3-cyclopentyloxy-4-(methylthio)benzoate (24.4g, 91.7%) as an orange brown solid which is used without further purification.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([NH:16][S:17]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)(=[O:19])=[O:18])=[CH:15][C:10]=3[N:9]=[C:8]2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:35][O:36][C:37](=[O:44])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]Br.O>CN(C)C=O>[CH3:35][O:36][C:37](=[O:44])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][N:16]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[C:14]1[CH:13]=[CH:12][C:11]2[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:8]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[N:9][C:10]=2[CH:15]=1
Reactant: COC(=O)CCCCCBr
Reactant: O=S(=O)(Nc1ccc2c(c1)nc(-c1ccccc1)n2-c1ccccc1)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCCCCN(c1ccc2c(c1)nc(-c1ccccc1)n2-c1ccccc1)S(=O)(=O)c1ccc(F)cc1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
150 mg of N-(1,2-diphenyl-1H-benzimidazol-5-yl)-4-fluorobenzenesulfonamide was suspended in 0.5 ml of N,N-dimethylformamide, mixed with 12 mg of sodium hydride and stirred for 30 minutes at 20° C. 98 mg of 6-bromohexanoic acid methyl ester was added, allowed to stir for 15 hours, mixed with water, extracted three times with ethyl acetate, the extracts were dried on sodium sulfate, concentrated by evaporation in a vacuum, and the residue was chromatographed on silica gel.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH2:19][CH2:20][C:21](=[O:24])[NH:22][N:23]=3)=[CH:14][CH:13]=2)(=[O:11])=[O:10])C(=O)C2=CC=CC=C12>C1(C)C=CC=CC=1.CN>[NH2:5][CH2:6][CH2:7][CH2:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH2:19][CH2:20][C:21](=[O:24])[NH:22][N:23]=2)=[CH:16][CH:17]=1)(=[O:10])=[O:11]
Reactant: O=C1CCC(c2ccc(S(=O)(=O)CCCN3C(=O)c4ccccc4C3=O)cc2)=NN1
Agent: CN
Solvent: Cc1ccccc1
Product: NCCCS(=O)(=O)c1ccc(C2=NNC(=O)CC2)cc1

Procedure:
30.0 g (70.7 mmol) of 6-[4-(3-phthalimidopropylsulphonyl)phenyl]-4,5-dihydro-3(2H)-pyridazinone are stirred vigorously for two hours at ambient temperature in a mixture of 200 ml of toluene and 300 ml of 40% aqueous methylamine solution. Then the solid matter precipitated is suction filtered, washed successively with 100 ml of water, 50 ml of acetone and 50 ml of diethylether and then dried over phosphorus pentoxide in a vacuum drying cupboard.
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:10][O:11][N:12]=[C:13]([C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[N:16]=1)[CH3:14].N1C=CC=CC=1.[C:29](Cl)(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:29]([O:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:10][O:11][N:12]=[C:13]([C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[N:16]=1)[CH3:14])(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31]
Reactant: COc1cccc(CON=C(C)c2cc(C)cc(C)n2)c1O
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cccc(CON=C(C)c2cc(C)cc(C)n2)c1OC(=O)C(C)(C)C
Reaction time: 5 h

Procedure:
0.2 g (0.67 mmol) of 1-(4,6-dimethyl-2-pyridinyl)ethanone O-[(2-hydroxy-3-methoxyphenyl)methyl]oxime was dissolved in 5 ml of methylene chloride. The resultant solution was added with 0.11 g (1.34 mmol) of pyridine, 5 mg of 4-(N,N-dimethylamino)pyridine and 0.12 g (1.00 mmol) of pivalic chloride. The obtained mixture was heated to reach the reflux temperature and stirred for 5 hours to complete a reaction. The reacted solution was washed with water and saturated saline solution in sequence, and the resultant nonaqueous layer was dried with anhydrous magnesium sulfate. The mixture was then condensed under reduced pressure to obtain a crude product. The crude product was then purified by means of silica gel column chromatography (eluate; hexane:ethyl acetate=9:1 (v/v)) to obtain the target compound in an amount of 0.2 g.
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([N+:22]([O-])=O)[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([OH:17])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.Cl[CH2:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]1>>[F:1][C:2]1[CH:21]=[C:20]([CH:19]=[CH:18][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH2:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1)[NH2:22]
Reactant: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1O
Reactant: CN1CCN(CCCCl)CC1
Product: COc1cc2c(Oc3ccc(N)cc3F)ccnc2cc1OCCCN1CCN(C)CC1

Procedure:
S1 was prepared from 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-quinolin-7-ol and 1-(3-chloropropyl)-4-methylpiperazine following the general procedure reported in Preparative Example 54 Step 1-2. 1H NMR (400 MHz, d6-DMSO, 300K) δ 1.95 (quint., J=6.8 Hz, 2H), 2.14 (s, 3H), 2.22-2.47 (m, 10H), 3.94 (s, 3H), 4.17 (t, J=6.5 Hz, 2H), 5.48 (br.s, 2H), 6.38 (d, J=5.2 Hz, 1H), 6.46 (dd, J=8.7 Hz, J=2.4 Hz, 1H), 6.55 (dd, J=13.2 Hz, J=2.4 Hz, 1H), 7.07 (t, J=9.0 Hz, 1H), 7.36 (s, 1H), 7.50 (s, 1H), 8.44 (d, J=5.2 Hz, 1H). MS (ES) C24H29FN4O3 requires: 440. Found: 441 (M+H)+.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH2:28]([N:31]([CH2:39][C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[CH:42][CH:41]=1)[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH3:30]>>[CH2:28]([N:31]([CH2:39][C:40]1[CH:41]=[CH:42][C:43]([NH:44]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:45][CH:46]=1)[C:32]([O:34][C:35]([CH3:38])([CH3:36])[CH3:37])=[O:33])[CH2:29][CH3:30]
Reactant: CCCN(Cc1ccc(N)cc1)C(=O)OC(C)(C)C
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: CCCN(Cc1ccc(N/C(=C2\C(=O)Nc3cc(C(=O)OC)ccc32)c2ccccc2)cc1)C(=O)OC(C)(C)C

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(N-propyl-N-tert.butoxycarbonyl-aminomethyl)-aniline Rf value: 0.5 (silica gel, methylene chloride/methanol=9:1) C32H35N3O5
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][C@H:17](O)[CH2:18][C@@H:19]([OH:21])[CH3:20].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([O:21][C@@H:19]([CH3:20])[CH2:18][C@H:17]([CH3:16])[O:14]2)[C@H:10]([CH3:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Reactant: C[C@H](O)C[C@H](C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: C[C@@H]1CN(Cc2ccccc2)CCC12O[C@@H](C)C[C@H](C)O2

Procedure:
To a solution of 1-benzyl-3-methylpiperidin-4-one (Acros, 62.09 g, 305.4 mmol) and (2S,4S)-pentane-2,4-diol (TCI-US, 34.06 g, 327.0 mmol) in benzene (800 mL) was added p-toluenesulfonic acid mono hydrate (69.72 g, 404.9 mmol). The flask was fitted with a Dean-Stark trap and heated to reflux. The reaction mixture was cooled after 16 hours of reflux, concentrated to a total volume of about 500 mL and transferred to an Erlenmeyer flask with ethyl acetate. A sodium bicarbonate solution (500 mL) added with stirring and the mixture was further neutralized with solid Na2CO3 (35 g). The layers were partitioned, the organic phase washed with sodium bicarbonate, dried (Na2SO4) and concentrated to yield approximately 95 g of crude material. The residue was purified in 15 g batches by silica gel chromatography (Analogix SF-65-600 g; 35 micron silica; elution with 10% ethyl acetate-hexane) at 50 mL/min to provide 42.33 g of the first eluting isomer, (2S,4S,7R)-9-benzyl-2,4,7-trimethyl-1,5-dioxa-9-azaspiro[5.5]undecane. 1H NMR (300 MHz, DMSO-d6) δ 7.33-7.19 (m, 5H), 4.07-3.86 (m, 2H), 3.40 (ABq, 2H, JAB=13.5 Hz, δνAB=23.3 Hz), 2.41-2.20 (m, 4H), 1.90-1.76 (m, 2H), 1.59-1.47 (m, 3H), 1.12 (d, 3H, J=6.4 Hz), 1.11 (d, 3H, J=6.4 Hz), 0.90 (d, 3H, J=7.1 Hz); MS (DCI/NH3) m/e 290 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH:20]=[CH:19][C:18]3[N:14]([C:15]4[N:29]=[CH:28][CH:27]=[CH:26][C:16]=4[C:17]=3[CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(Cl)Cl>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:20][CH2:19][C:18]3[N:14]([C:15]4[N:29]=[CH:28][CH:27]=[CH:26][C:16]=4[C:17]=3[CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH2:13]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1c2n(c3ncccc13)C[C@H](NS(=O)(=O)c1ccc(F)cc1)C=C2
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)Cc1c2n(c3ncccc13)C[C@H](NS(=O)(=O)c1ccc(F)cc1)CC2
Yield: 101 %

Procedure:
To a solution of methyl ((8R)-8-{[(4-fluorophenyl)sulfonyl]amino}-8,9-dihydropyrido[3,2-b]indolizin-5-yl)acetate (0.46 g, 1.1 mmol) in ethyl acetate (20 mL) was added under nitrogen Pd—C 10% (0.02 g, 0.19 mmol, 0.17 equiv.). After a period of 1 h under 1 atmosphere of H2, DCM was added to the reaction mixture which in turn was filtered over a micro filter and the solvents were evaporated to afford 464 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][NH2:16])[N:9]=[CH:8][CH:7]=[C:6]2[O:17][C:18]1[C:19]([CH3:28])=[N:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2.[C:29]([NH:36][C:37]([NH:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])=NS(C(F)(F)F)(=O)=O)([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>ClCCl.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][NH:16][C:37]([NH:36][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[N:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[N:9]=[CH:8][CH:7]=[C:6]2[O:17][C:18]1[C:19]([CH3:28])=[N:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCN
Reactant: CC(C)(C)OC(=O)NC(=NS(=O)(=O)C(F)(F)F)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCNC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 39.9 %

Procedure:
A solution of 2-[6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-yloxy]-ethylamine (compound 354) (340 mg) in dichloromethane (1 ml) and N,N-dimethylformamide (0.5 ml) were added to 1,3-diboc-2-(trifluoromethylsulfonyl)guanidine (355 mg), and the mixture was stirred at room temperature for 4 hr. The solvent was removed from the reaction solution under the reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give N-{2-[6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-yloxy]-ethyl}-N′,N″-diboc-guanidine (223 mg, yield 33%).
Reaction SMILES: CO[C:3](=[O:17])[C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:7]([F:14])=[CH:6][C:5]=1[CH2:15]Br.[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[CH3:27])[CH2:22][NH2:23].C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[F:14][C:7]1[CH:6]=[C:5]2[C:4](=[C:9]([C:10]([F:11])([F:12])[F:13])[CH:8]=1)[C:3](=[O:17])[N:23]([CH2:22][C:21]1[CH:24]=[CH:25][C:26]([CH3:27])=[C:19]([F:18])[CH:20]=1)[CH2:15]2
Reactant: COC(=O)c1c(CBr)cc(F)cc1C(F)(F)F
Reactant: Cc1ccc(CN)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: Cc1ccc(CN2Cc3cc(F)cc(C(F)(F)F)c3C2=O)cc1F
Temperature: 100 °C
Reaction time: 2 h
Yield: 31.1 %

Procedure:
A mixture of 4-fluoro-2-bromomethyl-6-trifluoromethyl-benzoic acid methyl ester (0.100 g, 0.32 mmol), 3-fluoro-4-methyl-benzylamine (0.060 mL, 0.42 mmol), and K2CO3 (0.088 g, 0.64 mmol) in toluene (4 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-fluoro-2-(3-fluoro-4-methyl-benzyl)-7-trifluoromethyl-2,3-dihydro-isoindol-1-one (0.034 g, 31%). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.25 (s, 3H), 4.28 (s, 2H), 4.74 (s, 2H) 6.98 (t, 2H), 7.16 (t, 1H), 7.27 (d, 1H), 7.51 (d, 1H). GC-MS: m/z 341 (M)+, 320 (M−21)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[NH:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:25][C@H:14]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[N:13]1([C:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][N:2]=[CH:3]3)=[O:12])[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:25][C@H:14]12
Reactant: O=C(O)c1ccc2[nH]ncc2c1
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc2[nH]ncc2c1)N1CCC[C@@H]2c3ccccc3C[C@@H]21
Yield: 31 %

Procedure:
The title compound is prepared from 1H-indazole-5-carboxylic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 31% of theory; LC (method 4): tR=1.91 min; Mass spectrum (ESI+): m/z=318 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5](O)=[O:6].C(C1NC=CN=1)([C:16]1[NH:17][CH:18]=CN=1)=O.CNC>CN(C=O)C>[CH3:16][N:17]([CH3:18])[C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: CNC
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N(C)C)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
3-Methyl-4-nitrobenzoic acid (3.0 g, 16.56 mmol) in DMF (30 mL) was stirred with carbonyl diimidazole (3.22 g, 1.2 Eq.) for 90 mins. The reaction mixture was cooled in an icebath, and dimethylamine (2 M in THF, 25 mL, 3 Eq.) was added. The mixture was then allowed to warm to room temperature and stirred for 2 hours. The mixture was poured onto ice water (200 ml) and extracted with EtOAc (×6). The combined extracts were washed with brine, dried over MgSO4, filtered and evaporated. Tritration with ether followed by filtration gave N,N,3-trimethyl-4-nitrobenzamide (2.6 g, colourless solid); MS (ES+) 209.
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:7]2=[O:12].N([O-])=O.[Na+].CS(C)=O.[IH:29].C([O-])([O-])=O.[Na+].[Na+]>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:6]2[CH:5]=[CH:4][C:3]3[C:8](=[CH:9][CH:10]=[CH:11][C:2]=3[I:29])[C:7]2=[O:12])=[CH:15][CH:16]=1
Reactant: I
Reactant: Nc1cccc2c(=O)n(Cc3ccc(F)cc3)ccc12
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=c1c2cccc(I)c2ccn1Cc1ccc(F)cc1
Temperature: 35 °C
Reaction time: 1 h

Procedure:
5-Amino-2-(4-fluorobenzyl)isoquinolin-1(2H)-one (0.6 g, 0.002 mol) was added to a solution of sodium nitrite (0.5 g, 0.008 mol) in dimethyl sulfoxide (10 mL, 0.1 mol) at 35° C. Aqueous hydrogen iodide (2 mL, 0.02 mol) in dimethyl sulfoxide (10 mL, 0.1 mol) was added. The reaction mixture was stirred at 35° C. for 1 hour. The cooled reaction mixture was neutralized with saturated aq. Na2CO3 and extracted with methylene chloride (3×20 mL). The combined methylene chloride extracts were washed with brine and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was chromatographed on 12 g of silica gel column (0-50% EtOAc/Hexane) gave the desired product as a brown solid. MS m/z (M+H) 379.7.