Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[CH:13]([OH:16])[CH:14]=[CH2:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:26](OC)([CH3:28])[CH3:27].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[C@@H:12]([CH2:17][CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)[CH:13]([CH:14]=[CH2:15])[O:16][C:26]1([CH3:28])[CH3:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(O)[C@H](CC1CCCCC1)NC(=O)OCc1ccccc1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=CC1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1CC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
983 mg of (3RS,4S)-4-(benzyloxycarbonyl)amino-5-cyclohexylpentene-3-ol was dissolved in 5 ml of dichloromethane, and 4 ml of 2,2-dimethoxypropane and 30 mg of dry p-toluenesulfonic acid were added thereto. The mixture was stirred at room temperature overnight. Then, 100 ml of ethyl acetate was added to the reaction mixture. The mixture was washed with a saturated sodium hydrogencarbonate aqueous solution and with a saturated sodium chloride aqueous solution. Then, the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=20/1) to obtain 967 mg of (4S,5RS)-3-benzyloxycarbonyl-4-cyclohexylmethyl-5-ethenyl-2,2-dimethyloxazolidine as colorless oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH2:15]([S:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=O)[CH3:16].S(=O)(O)[O-].[Na+].C(=O)(O)[O-].[Na+]>O.CC(N(C)C)=O>[CH2:15]([S:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[C:20]1[NH:6][C:4](=[O:5])[C:3]2[C:2](=[CH:10][C:9]([C:11]([F:12])([F:13])[F:14])=[CH:8][CH:7]=2)[N:1]=1)[CH3:16]
Reactant: NC(=O)c1ccc(C(F)(F)F)cc1N
Reactant: CCSc1ccccc1C=O
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCSc1ccccc1-c1nc2cc(C(F)(F)F)ccc2c(=O)[nH]1
Temperature: 150 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
A mixture of 1.0 g of 2-amino-4-trifluromethylbenzamide, 813 mg of 2-ethylsulfanylbenzaldehyde, 764 mg of sodium bisulfite and 4 ml of DMA was stirred at 150° C. for 8 hours. A saturated aqueous sodium bicarbonate solution and water were added to the cooled reaction mixture, and the precipitated solid was filtered. The resulting solid was washed with water and n-hexane and then dried to obtain 1.49 g of 2-(2-ethylsulfanylphenyl)-7-trifluoromethyl-3H-quinazolin-4-one.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[CH3:13][C:14]([CH3:58])([CH2:56][CH3:57])[CH2:15][C:16]1[N:17]=[C:18]([CH2:40][CH:41]([C:43]2[CH:48]=[CH:47][C:46]([C:49]3[CH:54]=[CH:53][C:52]([F:55])=[CH:51][N:50]=3)=[CH:45][CH:44]=2)O)[N:19]([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=1.C1(P([N:73]=[N+:74]=[N-:75])(C2C=CC=CC=2)=O)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[N:73]([CH:41]([C:43]1[CH:44]=[CH:45][C:46]([C:49]2[CH:54]=[CH:53][C:52]([F:55])=[CH:51][N:50]=2)=[CH:47][CH:48]=1)[CH2:40][C:18]1[N:19]([C:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[C:16]([CH2:15][C:14]([CH3:13])([CH3:58])[CH2:56][CH3:57])[N:17]=1)=[N+:74]=[N-:75]
Reactant: CCC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(O)c2ccc(-c3ccc(F)cn3)cc2)n1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(N=[N+]=[N-])c2ccc(-c3ccc(F)cn3)cc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
DEAD (72 μL, 0.46 mmol) was added to an ambient temperature solution of 2-[4-(2,2-dimethylbutyl)-1-trityl-1H-imidazol-2-yl]-1-[4-(5-fluoropyridin-2-yl)phenyl]ethanol (140 mg, 0.23 mmol), diphenylphosphoryl azide (0.1 mL, 0.46 mmol) and triphenylphosphine (150 mg, 0.57 mmol) in tetrahydrofuran (5 mL). After stirring at ambient temperature overnight, the reaction mixture was concentrated. Chromatography over silica eluting with 0-60% ethyl acetate/hexane afforded 2-(4-{1-azido-2-[4-(2,2-dimethylbutyl)-1-trityl-1H-imidazol-2-yl]ethyl}phenyl)-5-fluoropyridine.
Reaction SMILES: COC1C=C(C=CC=1OC)C[N:7]1[CH:12]=[CH:11][C:10](=O)[C:9]([C:14]#[N:15])=[CH:8]1.[Li+].[Cl-].O=P(Cl)(Cl)[Cl:25]>>[Cl:25][C:10]1[C:9]([C:14]#[N:15])=[CH:8][N:7]=[CH:12][CH:11]=1
Reactant: COc1ccc(Cn2ccc(=O)c(C#N)c2)cc1OC
Reactant: O=P(Cl)(Cl)Cl
Agent: [Cl-]
Agent: [Li+]
Product: N#Cc1cnccc1Cl

Procedure:
Alternatively, as shown in Scheme 3 below, the bisdimethylaminemethylene intermediate iii obtained by reaction of 3-oxo-butyronitrile ii with DMF-DMA can be reacted with 3,4-dimethoxybenzylamine at reflux in a solvent such as toluene to give 1-(3,4-dimethoxybenzyl)-4-oxo-1,4-dihydro-pyridine-3-carbonitrile viii. Reaction of viii with excess LiCl in refluxing POCl3 results in removal of the dimethoxybenzyl group and conversion to the corresponding 4-chloro-nicotinonitrile v.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH:11]=[C:10]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17](=[O:22])[CH2:16]4)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1COCC1.CO.[Pd]>[C:1]1([N:7]2[CH2:12][CH2:11][CH:10]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17](=[O:22])[CH2:16]4)[CH2:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1Cc2cc(C3=CCN(c4ccccc4)CC3)ccc2N1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: O=C1Cc2cc(C3CCN(c4ccccc4)CC3)ccc2N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
To a solution of 5-(1-phenyl-1,2,3,6-tetrahydropyridin-4-yl)indolin-2-one (75.8 mg, 0.261 mmol) in THF (3 ml) and MeOH (3 ml) was added 10% Pd/C (210 mg) and stirred at room temperature under H2 (1 atom) atmosphere for 2 h. The reaction mixture was filtered through a Celite pad and concentrated. The residue was purified by column chromatography (CHCl3/MeOH) to afford 5-(1-phenylpiperidin-4-yl)indolin-2-one (51.2 mg) as mixture of triphenylphosphine oxide.
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C@H:22]2[N:29]3[C:25]([S:26][C:27]([C:33]([N:35]4[CH2:49][C@H:48]([F:50])[CH2:47][C@H:36]4[C:37]([N:39]4[CH2:46][C:43]5([CH2:45][CH2:44]5)[NH:42][CH2:41][CH2:40]4)=[O:38])=[O:34])=[C:28]3[CH:30]([CH3:32])[CH3:31])=[N:24][C@:23]2([C:52]2[CH:53]=[N:54][C:55]([Cl:58])=[CH:56][CH:57]=2)[CH3:51])=[CH:18][C:17]=1[F:59].C=O.C(=O)(O)[O-].[Na+]>O1CCOCC1>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C@H:22]2[N:29]3[C:25]([S:26][C:27]([C:33]([N:35]4[CH2:49][C@H:48]([F:50])[CH2:47][C@H:36]4[C:37]([N:39]4[CH2:46][C:43]5([CH2:44][CH2:45]5)[N:42]([CH3:1])[CH2:41][CH2:40]4)=[O:38])=[O:34])=[C:28]3[CH:30]([CH3:31])[CH3:32])=[N:24][C@:23]2([C:52]2[CH:53]=[N:54][C:55]([Cl:58])=[CH:56][CH:57]=2)[CH3:51])=[CH:18][C:17]=1[F:59]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)C1=C(C(=O)N2C[C@H](F)C[C@H]2C(=O)N2CCNC3(CC3)C2)SC2=N[C@@](C)(c3ccc(Cl)nc3)[C@@H](c3ccc(Cl)c(F)c3)N21
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)C1=C(C(=O)N2C[C@H](F)C[C@H]2C(=O)N2CCN(C)C3(CC3)C2)SC2=N[C@@](C)(c3ccc(Cl)nc3)[C@@H](c3ccc(Cl)c(F)c3)N21
Reaction time: 17 h
Yield: 89.1 %

Procedure:
Sodium triacetoxyborohydride (267 mg, 1.26 mmol) was added to a 1,4-dioxane (10 ml) solution of the compound (340 mg, 0.503 mmol) obtained in Step 2 of Example 1 and 37% aqueous paraformaldehyde solution (0.41 ml, 5.05 mmol) at room temperature and the resulting mixture was stirred for 17 hours. Saturated aqueous sodium bicarbonate solution was added, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate and the solvent was concentrated under reduced pressure. The residue obtained was purified by silica gel chromatography [chloroform:methanol=50:1 (v/v)) to give the title compound (309 mg, 89%) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:11](=[O:13])[N:10]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH2:9][CH2:8][C:7]=2[C:6]([C:23]([O:25]CC)=[O:24])=[N:5][CH:4]=1.O.Cl>C1COCC1>[CH3:1][O:2][C:3]1[C:12]2[C:11](=[O:13])[N:10]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH2:9][CH2:8][C:7]=2[C:6]([C:23]([OH:25])=[O:24])=[N:5][CH:4]=1
Reactant: CCOC(=O)c1ncc(OC)c2c1CCN(Cc1ccc(OC)cc1)C2=O
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN2CCc3c(C(=O)O)ncc(OC)c3C2=O)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of ethyl 4-methoxy-6-(4-methoxybenzyl)-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate (15.2 g) in THF (150 mL) was added LiOH monohydrate (5.16 g) and sufficient water to dissolve the solids. The reaction was allowed to stir at room temperature for 1.5 hours. The reaction was neutralized with 125 mL of 1N HCl and the THF was removed in vacuo. The resulting slurry was partitioned between CHCl3 and 10% aqueous KHSO4. The combined organics were dried over sodium sulfate, filtered, and concentrated to dryness to afford the desired product as a pale tan foam. LRMS (M+1)=343.0
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=2[N:7]([C:15]([CH3:17])=[CH2:16])[C:6]1=[O:18].[NH:19]1[CH2:24][CH2:23][CH:22]([N:25]2[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[NH:27][C:26]2=[O:34])[CH2:21][CH2:20]1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[O:34]=[C:26]1[N:25]([CH:22]2[CH2:21][CH2:20][N:19]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=4[N:7]([C:15]([CH3:17])=[CH2:16])[C:6]3=[O:18])[CH2:24][CH2:23]2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[NH:27]1
Reactant: C=C(C)n1c(=O)n(CCCCl)c2ccc(C)cc21
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: C=C(C)n1c(=O)n(CCCN2CCC(n3c(=O)[nH]c4ccccc43)CC2)c2ccc(C)cc21
Yield: 67 %

Procedure:
A mixture of 5.3 parts of 1-(3-chloropropyl)-1,3-dihydro-5-methyl-3-(1-methylethenyl)-2H-benzimidazol-2-one, 4.3 parts of 1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 6.4 parts of sodium carbonate and 200 parts of 4-methyl-2-pentanone is stirred and refluxed overnight with water-separator. After cooling, water is added and the layers are separated. The 4-methyl-2-pentanone-phase is dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 6 parts (67%) of 1-{3-[4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]propyl}-1,3-dihydro-5-methyl-3-(1-methylethenyl)-2H-benzimidazol-2-one as an oily residue.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH:4]([CH:5]=[O:6])[CH:3]1[C:7]([O:9][CH3:10])=[O:8].[Cl:12][C:13](Cl)([Cl:18])[C:14]([F:17])([F:16])[F:15].[Cl-].[NH4+]>CN(C)C=O.[Zn]>[CH3:1][C:2]1([CH3:11])[CH:4]([CH:5]([OH:6])[C:13]([Cl:18])([Cl:12])[C:14]([F:17])([F:16])[F:15])[CH:3]1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)C1C(C=O)C1(C)C
Reactant: FC(F)(F)C(Cl)(Cl)Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CN(C)C=O
Product: COC(=O)C1C(C(O)C(Cl)(Cl)C(F)(F)F)C1(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 75.1 %

Procedure:
To a solution of 156 mg (1.00 mmol) of methyl 2,2-dimethyl-3-formylcyclopropane carboxylate and 0.226 ml (2.00 mmol) of 1,1,1-trichlorotrifluoroethane in 1 ml of dimethylformamide (DMF), 98 mg (1.50 mmol) of zinc powder was added at 0° C., and the mixture was stirred at 0° C. for 20 minutes, and at 50° C. for 7 hours. Then, 1 ml of a saturated ammonium chloride aqueous solution was added, and the mixture was extracted with diethyl ether (2 ml×5 times). The extract was dried over anhydrous magnesium sulfate, then filtered and concentrated under reduced pressure. The product was purified by thin layer chromatography (silica gel, dichloromethane/hexane=1/2) to obtain 232 mg of methyl 2,2-dimethyl-3-(1-hydroxy-2,2-dichloro-3,3,3-trifluoropropyl)cyclopropanecarboxylate (a mixture of two stereoisomers in a ratio of 55:45) as a colorless oil.
Reaction SMILES: COC[O:4][C:5]1[CH:44]=[CH:43][C:8]2[CH:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][S:32][CH2:33][CH2:34][CH2:35][C:36]([F:42])([F:41])[C:37]([F:40])([F:39])[F:38])[C:10]([C:14]3[CH:19]=[CH:18][C:17]([O:20]COC)=[CH:16][CH:15]=3)([CH3:13])[CH2:11][O:12][C:7]=2[CH:6]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>CO>[OH:4][C:5]1[CH:44]=[CH:43][C:8]2[CH:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][S:32][CH2:33][CH2:34][CH2:35][C:36]([F:42])([F:41])[C:37]([F:38])([F:39])[F:40])[C:10]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)([CH3:13])[CH2:11][O:12][C:7]=2[CH:6]=1
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCCCCCSCCCC(F)(F)C(F)(F)F)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: O
Product: CC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCSCCCC(F)(F)C(F)(F)F
Temperature: 25 °C
Yield: 60.1 %

Procedure:
(3RS,4RS)-7-Methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-3-methyl-4-[8-(4,4,5,5,5-pentafluoropentylthio)octyl]-2,3-dihydro-4H-benzopyran (120 mg, 0.19 mmol) and pyridinium p-toluenesulfonate (580 mg, 2.3 mmol) were dissolved in methanol (8 ml) and then refluxed for 7 hours. The reaction solution was cooled to room temperature and, after adding water, extracted with ethyl acetate. The organic layer was separated, washed with water, dried over magnesium sulfate and then concentrated. The residue was subjected to column chromatography (n-hexane:ethyl acetate=4:1) to obtain 64 mg (yield: 69%) of the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[CH2:9][C:10]#[N:11])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-:19].[K+]>C(O)(C)(C)C.Cl>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[CH2:9][C:10]([NH2:11])=[O:19])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: [OH-]
Reactant: CC(CC#N)c1ccc(-c2ccccc2)c(F)c1
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC(CC(N)=O)c1ccc(-c2ccccc2)c(F)c1
Temperature: 70 °C
Yield: 75 %

Procedure:
To a solution of 3-(2-fluoro-biphenyl-4-yl)butyronitrile in tert-butyl alcohol was added 1.87 g of finely powdered potassium hydroxide. The resulting suspension was stirred and heated to 70° C. for 2.5 hours and cooled to room temperature. The reaction suspension was diluted with 1.0 N HCl solution (100 mL) and extracted with ethyl acetate (2×100 mL). The ethyl acetate extracts were combined and washed with 5% bicarbonate solution (100 mL) and then with H2O (100 mL). The organics were then dried over MgSO4, and concentrated to a white solid which was re-crystallized several times with EtOAc/Hex to give white flaky prisms (1.62 g, 75% yield).
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17](=O)/[CH:18]=[CH:19]/[N:20](C)C)=[N:11]2)=[CH:6][CH:5]=1.[F:25][C:26]1[CH:27]=[C:28]([NH:32]N)[CH:29]=[CH:30][CH:31]=1.N([O-])=O.[Na+].[Sn](Cl)Cl>>[F:1][CH:2]([F:24])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17]3[N:32]([C:28]4[CH:29]=[CH:30][CH:31]=[C:26]([F:25])[CH:27]=4)[N:20]=[CH:19][CH:18]=3)=[N:11]2)=[CH:6][CH:5]=1
Reactant: NNc1cccc(F)c1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)F)cc2)ccc1=O
Agent: Cl[Sn]Cl
Agent: O=N[O-]
Agent: [Na+]
Product: O=c1ccn(-c2ccc(OC(F)F)cc2)nc1-c1ccnn1-c1cccc(F)c1
Yield: 62 %

Procedure:
The product was obtained starting from 1-(4-Difluoromethoxy-phenyl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-9) and (3-fluoro-phenyl)-hydrazine (prepared from the corresponding amino derivative using sodium nitrite and tin(II) chloride as described in J. Med. Chem. 2003, 46, 4676-4686) according to the method described for Example 91 in 62% yield. MS: M=399.1 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7]C)=[O:6].CN1CCOCC1.[N+:19]([C:22]1[CH:23]=[C:24]([S:28](Cl)(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1)([O-:21])=[O:20]>C(Cl)Cl>[N+:19]([C:22]1[CH:23]=[C:24]([S:28]([NH:1][C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([OH:7])=[O:6])(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: COC(=O)c1cccc(N)c1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(O)c1cccc(NS(=O)(=O)c2cccc([N+](=O)[O-])c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.6 %

Procedure:
To 1.51 g (10 mmol) of the methyl 3-aminobenzoate prepared in Example 1 in 40 mL of methylene chloride containing 2 mL of N-methylmorpholine was added 2.21 g (10 mmol) of 3-nitrobenzenesulfonyl chloride. After stirred at room temperature for 3 hours, methylene chloride (200 mL) was added and washed with saturated NaHCO3 (2×50 mL), 1N HCl (2×50 mL) and brine (2×50 mL) and dried over Na2SO4. After evaporation of the solvent, the residue was dissolved in THF (50 mL), 2N NaOH (10 mL) was added and the mixture heated to 60° C. for 2 hours. After neutralization with 1N HCl, the mixture was extracted with ethyl acetate (4×50 mL) and the organic phase was washed with brine (2×50 mL), dried over Na2SO4 and evaporated to give 3.05 g (94%) of the title compound as a white solid: 1H-NMR (300 MHz, DMSO-d6): δ 7.38 (m, 2H), 7.65 (t, 1H), 7.70 (s, 1H), 7.87 (t, 1H), 8.13 (dd, 1H), 8.47 (dd, 1H), 8.50 (t, 1H), 10.81 (s, 1H), 13.11 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([CH2:7]OS(C)(=O)=O)[CH2:4][CH2:3]1.[CH2:13]([NH:20][CH2:21][CH2:22][OH:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([N:20]([CH2:7][C@H:5]1[NH:6][C:2](=[O:1])[CH2:3][CH2:4]1)[CH2:21][CH2:22][OH:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCCNCc1ccccc1
Reactant: CS(=O)(=O)OC[C@@H]1CCC(=O)N1
Product: O=C1CC[C@@H](CN(CCO)Cc2ccccc2)N1
Temperature: 130 °C
Yield: 96.4 %

Procedure:
A mixture of (+)-methanesulfonic acid (S)-5-oxo-pyrrolidin-2-ylmethyl ester (500 mg, 2.59 mmol) and 2-(benzylamino)ethanol (1.56 g, 10.36 mmol) was heated at 130° C. in a microwave oven (Personal Chemistry Emrys™ Optimizer) for 40 minutes. The residue was partitioned between water and DCM, the organic phase was washed with brine, dried (Na2SO4) and evaporated under vacuum. The crude was purified by flash chromatography (DCM/MeOH from 95/5 to 90/10 respectively) to afford the title compound as yellow oil (620 mg, 96% yield).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])(=[O:10])=[O:9].[F:24]C1C=CC(S(Cl)(=O)=O)=CC=1>>[F:24][C:6]1[CH:5]=[CH:4][C:3]([S:8]([NH:11][C@H:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[C:13]([OH:15])=[O:14])(=[O:10])=[O:9])=[CH:2][CH:7]=1
Reactant: O=C(O)[C@@H](Cc1ccc(O)cc1)NS(=O)(=O)c1ccccc1F
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Product: O=C(O)[C@@H](Cc1ccc(O)cc1)NS(=O)(=O)c1ccc(F)cc1

Procedure:
Following 17a synthetic method, using 4-fluorobenzenesulfonyl chloride (214.08 mg, 1.1 mmol) instead of 2-fluorobenzenesulfonyl chloride gave the final compound 19a; as a colorless oil; (93.99 mg, 55.4%). [α]D25: +12.8 (c=0.26, CHCl3); 1H-NMR (300 MHz, CDCl3): δ 7.77-7.73 (m, 2H), 7.24-7.21 (m, 7H), 6.92 (d, J=9 Hz, 1H), 4.21-4.14 (m, 1H), 3.15-2.90 (m, 2H); 13C NMR (300 MHz, acetone-d6): δ 171.55, 166.28, 162.95, 137.53, 136.53, 129.74, 129.62, 129.39, 128.24, 126.68, 115.93, 115.63, 57.29, 38.49; HRMS (ESI): calcd for: C15H14FNO4S [M+Na]+=346.0520, obsd [M+Na]+=346.0513.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C@H:12]([NH:14][C:15]([C@@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:34])[C@@H:24]([NH:26][C:27](=[O:33])[C@@H:28]([OH:32])[CH:29]([CH3:31])[CH3:30])[CH3:25])[NH:18]3)=[O:16])[CH3:13])=[N:9]2)=[CH:4][CH:3]=1.[F:35][CH:36]([F:46])[O:37][CH2:38][C@@:39]([CH3:45])([CH:43]=[CH2:44])[C:40]([OH:42])=[O:41].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:35][CH:36]([F:46])[O:37][CH2:38][C@@:39]([CH3:45])(/[CH:43]=[CH:44]/[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C@H:12]([NH:14][C:15]([C@@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:34])[C@@H:24]([NH:26][C:27](=[O:33])[C@@H:28]([OH:32])[CH:29]([CH3:30])[CH3:31])[CH3:25])[NH:18]3)=[O:16])[CH3:13])=[N:9]2)=[CH:4][CH:3]=1)[C:40]([OH:42])=[O:41]
Reactant: C=C[C@](C)(COC(F)F)C(=O)O
Reactant: CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(Br)cc3n2)N1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(/C=C/[C@](C)(COC(F)F)C(=O)O)cc3n2)N1
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of (S)-1-[(S)-2-((S)-2-hydroxy-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid [(R)-1-(7-bromo-quinolin-2-yl)-ethyl]-amide (160 mg, 0.3 mmol), (R)-2-difluoromethoxymethyl-2-methyl-but-3-enoic acid (54 mg, 0.3 mmol), tri(o-tolyl)phosphine (18 mg, 0.06 mmol) and triethylamine (91 mg, 0.125 mL, 0.9 mmol) in 1,4-dioxane (6 mL) was stirred at 50° C. under nitrogen. Tris(dibenzylideneacetone)dipalladium(0) (27 mg, 0.03 mmol) was added and the reaction mixture was heated at reflux for 40 minutes. The reaction mixture was cooled to room temperature and the mixture was filtered through a hydrophobic frit and the filtrate was evaporated to afford crude (E)-(R)-2-difluoromethoxymethyl-4-{2-[(R)-1-({(S)-1-[(S)-2-((S)-2-hydroxy-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carbonyl}-amino)-ethyl]-quinolin-7-yl}-2-methyl-but-3-enoic acid (0.3 mmol) which was used in the next step. LCMS (m/z) 634.2 [M+H], Tr=2.04 min.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=3)[N:18]([CH3:29])[N:17]=2)[CH2:9]1.[CH3:31][N:32]([CH3:47])[C:33]1[CH:34]=[C:35]([C:39]2([OH:46])[CH2:44][CH2:43][C:42](=O)[CH2:41][CH2:40]2)[CH:36]=[CH:37][CH:38]=1>>[CH3:31][N:32]([CH3:47])[C:33]1[CH:34]=[C:35]([C:39]2([OH:46])[CH2:44][CH2:43][CH:42]([N:8]3[CH2:9][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]4[C:24]5[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:27])([F:26])[F:28])[CH:23]=5)[N:18]([CH3:29])[N:17]=4)[CH2:11]3)[CH2:41][CH2:40]2)[CH:36]=[CH:37][CH:38]=1
Reactant: CN(C)c1cccc(C2(O)CCC(=O)CC2)c1
Reactant: Cn1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1cccc(C2(O)CCC(N3CC(NC(=O)CNc4nn(C)c5ccc(C(F)(F)F)cc45)C3)CC2)c1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(1-methyl-5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide TFA salt (as prepared in Example 18, Step D) and 4-(3-dimethylamino-phenyl)-4-hydroxy-cyclohexanone using the procedure described in Step E of Example 1.