Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@:2]([NH:26]C(=O)OC(C)(C)C)([C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]([O:14][C:15]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:16]=2[CH:17]([CH3:25])[CH2:18][CH2:19][O:20]3)=[N:12][CH:13]=1)=[O:6])[CH2:3][CH3:4].C(O)(C(F)(F)F)=O>ClCCl>[CH3:25][CH:17]1[C:16]2[C:21](=[CH:22][CH:23]=[CH:24][C:15]=2[O:14][C:11]2[N:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[C@:2]([CH3:1])([CH2:3][CH3:4])[NH2:26])=[CH:9][N:10]=2)[O:20][CH2:19][CH2:18]1
Reactant: CC[C@@](C)(NC(=O)OC(C)(C)C)C(=O)Nc1cnc(Oc2cccc3c2C(C)CCO3)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@](C)(N)C(=O)Nc1cnc(Oc2cccc3c2C(C)CCO3)nc1
Reaction time: 3 h
Yield: 99.9 %

Procedure:
To a solution of 1,1-dimethylethyl {(1R)-1-methyl-1-[({2-[(4-methyl-3,4-dihydro-2H-chromen-5-yl)oxy]-5-pyrimidinyl}amino)carbonyl]propyl}carbamate (Intermediate 218, 100 mg, 0.219 mmol) in dry Dichloromethane (5 mL), cooled to 0° C., TFA (1 mL, 12.98 mmol) was added dropwise. The reaction mixture was stirred at that temperature for 3 hours, then it was allowed to reach the room temperature and stirred at that temperature for 2 hours. Volatiles were evaporated and the residue was diluted with DCM (10 mL) and washed with an aqueous saturated solution of NaHCO3 (10 mL). The organic layer was separated, dried (Na2SO4), filtered and evaporated to afford the title compound (78 mg) as white solid that was used in the next step without further purification.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH2:15][CH2:16]O>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH2:15][CH2:16][Cl:3]
Reactant: O=[N+]([O-])c1cccc(Cl)c1CCO
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(Cl)c1CCCl
Yield: 93.2 %

Procedure:
15.60 9 g thionyl chloride (130 mmol) in 10 ml toluene (abs.) is added quickly in a drop-wise manner to 8.8 g 2-(2-chloro-6-nitrophenyl) ethanol (44 mmol) in 100 ml abs. toluene. The reaction solution is heated under reflux 1 h. After cooling, this is poured onto ice, diluted with 50 ml CH2Cl2 and the H2O phase is extracted 2× each with 50 ml CH2Cl2. The combined organic phases are dried over Na2SO4 and rotary evaporated. 9.08 g (41 mmol, 94%) 2-(2-chloro-6-nitrophenyl)ethyl chloride are obtained as a brown oil which crystallizes after storage for several days in a refrigerator.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([S:35]([CH:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)(=[O:37])=[O:36])[CH:30]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH:38]1([S:35]([C:31]2[CH:30]=[C:29]([CH2:28][CH2:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][NH:1][CH2:2][C@@H:3]([C:5]3[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=3)[OH:4])[CH:34]=[CH:33][CH:32]=2)(=[O:37])=[O:36])[CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: O=S(=O)(c1cccc(CCCCOCCCCCCBr)c1)C1CCCC1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNCCCCCCOCCCCc2cccc(S(=O)(=O)C3CCCC3)c2)ccc1O
Temperature: 25 °C
Reaction time: 113 h

Procedure:
N-{5-[(1R)-2-Amino-1-hydroxyethyl]-2-hydroxyphenyl}methanesulfonamide (33.2 mg) was added to a solution of 1-{4-[(6-bromohexyl)oxy]butyl}-3-(cyclopentylsulfonyl)benzene (Example 1v.) (50 mg) in DMF (5 ml). The reaction mixture was treated with N,N-diisopropylethylamine (29.3 μl) and stirred at room temperature for 113 h. The reaction mixture was partitioned between EtOAc and water and the organic extracts were washed with ammonium chloride, dried (MgSO4) and concentrated in vacuo. The residue was purified by column DCM) to afford the title compound. LCMS RT=2.73 min 610(M+H)+
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(OO)(=[O:17])C>ClCCl.C(=O)(O)[O-].[Na+]>[CH3:14][O:13][C:11]([C:8]1[CH:9]=[C:10]2[C:5]([CH:4]=[CH:3][CH:2]=[N+:1]2[O-:17])=[CH:6][CH:7]=1)=[O:12]
Reactant: COC(=O)c1ccc2cccnc2c1
Reactant: CC(=O)OO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc2ccc[n+]([O-])c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.3 %

Procedure:
To a solution of methyl quinoline-7-carboxylate (17.8 g, 94.87 mmol) in dichloromethane (315 mL) was added peracetic acid (39.9 mL, 190 mmol, 32% in acetic acid). The reaction was stirred at room temperature overnight. Peracetic acid (10 mL, 48 mmol, 32% in acetic acid) was added and the mixture was stirred for 5 h. The reaction mixture was diluted with a saturated solution of aqueous sodium bicarbonate. The aqueous phase was extracted into dichloromethane (2×1 L). The extracts were combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography (2-15% methanol in dichloromethane) gave the title compound (17.4 g, 90%) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d, δ): 9.41 (1H, s), 8.56 (1H, dd, J=6.0, 0.8 Hz), 8.24 (1H, dd, J=8.5, 1.7 Hz), 7.93 (1H, d, J=8.6 Hz), 7.75 (1H, d, J=8.6 Hz), 7.39 (1H, dd, J=8.6, 6.0 Hz), 4.01 (3H, s)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[N:30]1([C:2]2[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=2)[C:5]([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([O:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:10][CH:9]=2)=[O:6])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1
Reactant: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cccc(Br)c1
Reactant: C1COCCN1
Product: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cccc(N2CCOCC2)c1

Procedure:
Compound is formed by reacting 3-bromo-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-benzamide with morpholine under conditions described in general procedure B. Mp: 90-92° C. 1H NMR (300 MHz, DMSO-d6) δ 10.16 (s, 1H), 8.19 (m, 1H), 7.81 (m, 1H), 7.58 (s, 1H), 7.53 (m, 3H), 7.40 (m, 2H), 7.17 (d, 1H, J=8.4), 7.01 (d, 1H, J=8.7), 4.30 (t, 2H, J=4.8), 3.74 (m, 4H), 3.57 (m, 4H), 3.18 (m, 4H), 2.85 (t, 2H, J=5.7), 2.54 (m, 4H). MS: 462.2 (M+1).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([OH:28])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH:36](O)[CH3:37])=[C:32]([C:39]([F:42])([F:41])[F:40])[CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([O:28][CH:36]([C:33]4[CH:34]=[CH:35][C:30]([F:29])=[CH:31][C:32]=4[C:39]([F:42])([F:40])[F:41])[CH3:37])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1O
Reactant: CC(O)c1ccc(F)cc1C(F)(F)F
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1OC(C)c1ccc(F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Under a nitrogen atmosphere, 2.1 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-hydroxythiophene-2-carboxylate are dissolved in 60 ml anhydrous dichloromethane. Consecutively, 1.56 g of 1-[4-fluoro-2-(trifluoromethyl)phenyl]ethanol, 3.3 g triphenylphosphine (polymer bound, ˜3 mmol/g) and 2.3 g of di-tert-butyl azodicarboxylate are added to the solution. The reaction mixture is stirred at room temperature for 15 h and then filtered. The filter cake is washed with 50 ml of a dichloromethane/methanol mixture (95:5). The filtrate is concentrated to dryness under reduced pressure. The crude is purified by flash chromatography [Silica gel, eluent: ethyl acetate/cyclohexane, elution gradient of 5/95 (v/v) to 70/30 (v/v) to yield the title product.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:14]=[C:13]([O:15][CH2:16][CH:17]3[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]3)[C:12](Br)=[CH:11][N:10]=2)[CH2:4][CH2:3]1.[O:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=2)[CH2:31][CH2:30]1>>[CH3:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:14]=[C:13]([O:15][CH2:16][CH:17]3[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]3)[C:12]([C:38]3[CH:37]=[CH:36][C:35]([N:32]4[CH2:31][CH2:30][O:29][CH2:34][CH2:33]4)=[CH:40][CH:39]=3)=[CH:11][N:10]=2)[CH2:4][CH2:3]1
Reactant: OB(O)c1ccc(N2CCOCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CC(COc2nc(N[C@H]3CC[C@@H](C)CC3)ncc2Br)C1
Product: CC(C)(C)OC(=O)N1CC(COc2nc(N[C@H]3CC[C@@H](C)CC3)ncc2-c2ccc(N3CCOCC3)cc2)C1

Procedure:
Using the procedure of Example 1 Step 3, tert-butyl 3-((2-(cis-4-methylcyclohexylamino)-5-bromopyrimidin-4-yloxy)methyl)azetidine-1-carboxylate was reacted with 4-morpholinophenylboronic acid to provide the title compound at 78% yield. 1H NMR (CDCl3, 400 MHz) 8.02 (s, 1H), 7.30 (d, 2H), 6.85 (d, 2H), 5.38 (sb, 1H), 4.41 (d, 2H), 4.07-3.80 (m, 3H), 4.79-3.70 (m, 5H), 3.11-3.09 (m, 4H), 2.95-2.88 (m, 2H), 1.76-1.45 (m, 6H), 1.44 (s, 9H), 1.20-1.16 (m, 3H), 0.87 (d, 3H); MS (ESI) m/z: Calc: 537.3 (M+). Found. 538.3 (M+1).
Reaction SMILES: [CH:1]1([OH:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:9][S:10][CH2:11][CH2:12][CH2:13][C:14](O)=[O:15].C[O-].[Na+]>>[CH:1]1([O:8][C:14](=[O:15])[CH2:13][CH2:12][CH2:11][S:10][CH3:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CSCCCC(=O)O
Reactant: OC1CCCCCC1
Agent: C[O-]
Agent: [Na+]
Product: CSCCCC(=O)OC1CCCCCC1

Procedure:
Into a 250 ml reaction flask equipped with magnetic stirrer, heating mantle, thermometer, nitrogen sparger and reflux condenser are placed 11.4 cycloheptanol; 8.1 grams of the ethyl ester of 4-(methylthio)butyric acid and 0.5 grams of a 25% methanolic solution of sodium methoxide.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:12]=[N:13][C:14](Cl)=[N:15][CH:16]=1.[I-].[Na+].C(N(C(C)C)CC)(C)C>CC(O)C>[Br:10][C:11]1[CH:12]=[N:13][C:14]([NH:1][C:2]2[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=2)=[N:15][CH:16]=1
Reactant: Nc1ccc(CO)cc1
Reactant: Clc1ncc(Br)cn1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: OCc1ccc(Nc2ncc(Br)cn2)cc1
Temperature: 200 °C

Procedure:
To a solution of 4-aminobenzyl alcohol 14 (8.12 mmol) and 5-bromo-2-chloro-pyrimidine 4 (9.74 mmol) in 2-propanol (20 mL) is added sodium iodide (8.12 mmol) and diisopropylethylamine (16.2 mmol). The reaction mixture is heated in the microwave oven at 200° C. for 15 min. Purification by silica gel chromatography with hexane:EtOAc=7:3 affords [4-(5-bromo-pyrimidin-2-ylamino)-phenyl]-methanol 15. 1H NMR (400 MHz, CDCl3) δ 8.36 (s, 2H), 7.49 (d, J=8.8 Hz, 2H), 7.28 (d, J=8.4 Hz, 2H) 7.07 (bs, 1H), 4.60 (s, 2H). MS (m/z) (M+1)+: 280.3, 282.3.
Reaction SMILES: CON(C)[C:4](=[O:24])[C:5]1[CH:10]=[C:9]([NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:8]=[C:7]([S:18]([F:23])([F:22])([F:21])([F:20])[F:19])[CH:6]=1.[CH3:26][Si]([N-][Si](C)(C)C)(C)C.[Li+].C[Mg]Br>C1COCC1>[C:4]([C:5]1[CH:10]=[C:9]([NH:11][C:12](=[O:17])[C:13]([F:15])([F:16])[F:14])[CH:8]=[C:7]([S:18]([F:20])([F:19])([F:22])([F:23])[F:21])[CH:6]=1)(=[O:24])[CH3:26]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CON(C)C(=O)c1cc(NC(=O)C(F)(F)F)cc(S(F)(F)(F)(F)F)c1
Agent: C[Mg]Br
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)c1cc(NC(=O)C(F)(F)F)cc(S(F)(F)(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
N-Methoxy-N-methyl-3-(pentafluorosulfanyl)-5-(2,2,2-trifluoroacetylamino)benzamide (O4.075; 1.65 g) was dissolved in THF (25 ml). At 0° C., lithium bis(trimethylsilyl)amide (0.9 ml) was added while stirring. After 30 min, methylmagnesium bromide (3.5 ml, 3 M in diethyl ether) was added dropwise. After the addition had ended, the ice bath was removed and the mixture was stirred at RT for 2 h. While cooling, 1 N hydrochloric acid, water and EA were then added. After removing the organic phase, the aqueous phase was extracted twice more with EA. The combined EA phases were dried with magnesium sulfate, filtered and concentrated. The crude product is a mixture of N-(3-acetyl-5-pentafluorosulfanyl-phenyl)-2,2,2-trifluoroacetamide and 1-[3-amino-5-(pentafluorosulfanyl)phenyl]ethanone, and so the crude product (1.3 g) was taken up in methylene chloride (60 ml) and admixed with triethylamine (155 μl). Thereafter, trifluoroacetic anhydride (160 μl) was added while stirring. After stirring at RT for 3 h, water and saturated sodium hydrogencarbonate solution were added, the phases were separated and the DCM phase was washed three times more with water. The DCM phase was dried with magnesium sulfate, filtered and concentrated. 1.3 g of the title compound were obtained.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[F:11].C([O-])([O-])=O.[K+].[K+].CC1(C)COB([C:25]2[N:29]([CH3:30])[N:28]=[CH:27][CH:26]=2)OC1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:11][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[C:25]1[N:29]([CH3:30])[N:28]=[CH:27][CH:26]=1)[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1ccc(Br)c(F)c1
Reactant: Cn1nccc1B1OCC(C)(C)CO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1nccc1-c1ccc(C(=O)O)cc1F
Temperature: 80 °C

Procedure:
To a solution of 4-bromo-3-fluorobenzoic acid (110 mg, 0.5 mmol) in dioxane/H2O (5:1, 6 mL) was added K2CO3 (207 mg, 1.5 mmol), tetrakistriphenylphosphine Pd(0) (29 mg, 0.025 mmol) and 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole (107 mg, 0.55 mmol). The reaction mixture was heated to 80° C. in a sealed tube for 12 h and was then partitioned between 6N NaOH and DCM. The pH of the aqueous phase was adjusted to ˜3 with 3M HCl and washed several times with DCM. The combined organic fractions were dried (Na2SO4), concentrated under vacuum and used directly without further purification (98 mg, 89%): LC-MS (ES) m/z=221 (M+H)+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([N:8]1[CH2:16][CH2:15][CH:11]([C:12](Cl)=[O:13])[CH2:10][CH2:9]1)(=[O:7])[CH3:6].[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:5]([N:8]1[CH2:16][CH2:15][CH:11]([C:12](=[O:13])[C:21]2[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)(=[O:7])[CH3:6]
Reactant: Fc1ccccc1
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)N1CCC(C(=O)c2ccc(F)cc2)CC1
Yield: 80 %

Procedure:
A mixture of 93 g (0.7 mole) of aluminum chloride in 150 ml of fluorobenzene was stirred while 70 g (0.37 mole) of 1-acetylisonipecotic acid chloride was added in small portions. After the addition was complete, the mixture was heated at reflux for one hour. The mixture was poured onto ice, and the two resulting layers were separated. The aqueous layer was extracted twice with chloroform and the chloroform extracts were added to the fluorobenzene which was separated previously. The organic solution was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and 73.7 g (80%) of 1-acetyl-4-(p-fluorobenzoyl)piperidine was obtained as a crystalline residue. Recrystallization from ligroin-isopropyl ether gave a white, crystalline product melting at 75°-78° C.
Reaction SMILES: C(OC(N1CC[N:11]([C:14]([C:16]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)=[CH:20][C:19]([CH3:32])=[C:18]([C:33]([N:35]3[CH2:40][CH2:39][CH:38]([N:41]4[CH2:45][CH2:44][CH2:43][CH2:42]4)[CH2:37][CH2:36]3)=[O:34])[N:17]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CO.O1CCOCC1>[NH:11]1[CH2:14][CH2:9][CH:10]([NH:11][C:14]([C:16]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:29])[F:31])[CH:23]=3)=[CH:20][C:19]([CH3:32])=[C:18]([C:33]([N:35]3[CH2:36][CH2:37][CH:38]([N:41]4[CH2:42][CH2:43][CH2:44][CH2:45]4)[CH2:39][CH2:40]3)=[O:34])[N:17]=2)=[O:15])[CH2:9][CH2:10]1
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)nc1C(=O)N1CCC(N2CCCC2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(C(=O)NC2CCNCC2)nc1C(=O)N1CCC(N2CCCC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 150.7 %

Procedure:
A solution of 0.20 g (0.31 mmol) of 4-[5-methyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluoromethyl-phenyl)-pyridine-2-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester (example 59) in 10 ml of MeOH was treated with 0.39 ml (1.56 mmol) of HCl in dioxane (4 molar) and the reaction mixture was then stirred at RT. After 18 hours, it was evaporated, poured into crashed ice, the pH was adjusted to 8-9 with sodium carbonate solution and the mixture was then extracted twice with CH2Cl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 95:5 to 4:1) to give 0.127 g (75%) of the title compound as light yellow solid. MS: 544.3 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([N:12]([CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])[CH2:19][CH2:18]3)[CH2:13][CH2:14][CH3:15])[CH2:9]2)=[CH:4][CH:3]=1.[C:31](Cl)(=[O:35])[CH:32]([CH3:34])[CH3:33]>ClCCl.CCN(C(C)C)C(C)C>[N:25]1([C:23]([N:20]2[CH2:19][CH2:18][CH:17]([CH2:16][N:12]([CH2:13][CH2:14][CH3:15])[CH:8]3[CH2:9][C:10]4[CH:11]=[C:2]([NH:1][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:3]=[CH:4][C:5]=4[CH2:6][CH2:7]3)[CH2:22][CH2:21]2)=[O:24])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: CCCN(CC1CCN(C(=O)N2CCOCC2)CC1)C1CCc2ccc(N)cc2C1
Reactant: CC(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCN(CC1CCN(C(=O)N2CCOCC2)CC1)C1CCc2ccc(NC(=O)C(C)C)cc2C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of (4-{[(7-amino-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-methyl}-piperidin-1-yl)-morpholin-4-yl-methanone (200 μL of 0.25 M in dichloromethane, 50 μmol ) was added 220 μL of a 0.25 M solution of isobutyryl chloride in dichloromethane and 30 μL of DIEA. The solution was allowed to stir for 72 h at 25° C. under N2 and was then concentrated in vacuo. The final product was isolated by preparative RPHPLC (YMC Combiprep ODS-A column, 10-90% acetonitrile: water (0.1% TFA)) to afford N-(7-{[1-(morpholine-4-carbonyl)-piperidin-4-ylmethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-yl)-isobutyramide (8.6 mg) 96, [M+H]+=485.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]([OH:13])=O)=[CH:5][C:4]=1[N+:14]([O-:16])=[O:15].C1N=CN(C(N2C=NC=C2)=O)C=1.O[NH:30][C:31](=[NH:35])[CH2:32][CH2:33][CH3:34]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[O:13][N:35]=[C:31]([CH2:32][CH2:33][CH3:34])[N:30]=2)=[CH:5][C:4]=1[N+:14]([O-:16])=[O:15]
Reactant: CCCC(=N)NO
Reactant: COc1ccc(C=CC(=O)O)cc1[N+](=O)[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CCCc1noc(C=Cc2ccc(OC)c([N+](=O)[O-])c2)n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
3-(4-Methoxy-3-nitro-phenyl)-acrylic acid (compound of Example 6; 0.95 g, 4.25 mmol) was dissolved in DMF (15 mL) to which CDI (0.82 g, 5.10 mmol) was added and the reaction mixture was stirred at room temperature. After 45 min, N-hydroxy-butyramidine (0.52 g, 5.10 mmol) was added. The reaction mixture was stirred at room temperature for about 16-18 h. After completion of the reaction, additional CDI (0.82 g, 5.10 mmol) was added and the reaction mixture was refluxed at 110° C. to 120° C. for 6 h to effect cyclodehydration. DMF was evaporated and the reaction mixture was cooled to room temperature. Water (10 mL) was added to the reaction mixture followed by extraction with ethyl acetate (2×10 mL). The combined organic layers were washed with water (2×10 mL) and brine (10 mL). The organic phase obtained was dried over anhydrous sodium sulfate and concentrated to obtain a crude product, which was purified by column chromatography (silica gel, 0.25% ethyl acetate in petroleum ether) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:20](O)[CH3:21].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([O:17][CH2:20][CH3:21])=[O:16])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: Cn1c(CC(=O)O)ccc1C(=O)c1ccc(Cl)cc1
Reactant: CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)Cc1ccc(C(=O)c2ccc(Cl)cc2)n1C

Procedure:
A suspension of 55.4 g. of 5-(p-chlorobenzoyl)-1-methyl-pyrrole-2-acetic acid, 44 ml. of absolute ethanol, 1g. of p-toluenesulfonic acid and 650 ml. of benzene is heated under reflux with azeotropic removal of water for 7 hours. The reaction mixture is filtered, washed with sodium bicarbonate solution, dried over anhyrous magnesium sulfate and the solvent evaporated in vacuo. The crystalline residue is recrystallized twice from cyclohexane to give ethyl 5-(p-chlorobenzoyl)-1-methyl-pyrrole-2-acetate as a yellow solid, m.p. 74°-76°C.
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]=[CH2:3].[OH:6][C:7]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:8]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].Cl>CCOCC>[Cl:21][C:18]1[CH:19]=[CH:20][C:7]([OH:6])=[C:8]([C:9]([CH2:3][CH:2]=[CH2:1])([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[OH:10])[CH:17]=1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1O
Reactant: C=CC[Mg]Br
Agent: Cl
Solvent: CCOCC
Product: C=CCC(O)(c1ccccc1)c1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
360 ml of an ether solution titrating 1 M/liter of allyl magnesium bromide were added dropwise with stirring to a mixture of 40 g of 2-hydroxy-5-chloro-benzophenone and 400 ml of anhydrous ether and the suspension was iced and stirred at room temperature for 16 hours. 180 ml of 2 N hydrochloric acid were added to the mixture and the decanted organic phase was washed with water, dried over mangesium sulfate and evaporated to dryness under reduced pressure. The oil residue was chromatographed over silica gel and was eluted with methylene chloride to obtain 18.9 g of 5-chloro-2-hydroxy-α-(2-propenyl)-α-phenyl-benzene-methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.O[CH2:31][C@@H:32]1[CH2:36][CH2:35][CH2:34][N:33]1[CH3:37]>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:31][C@@H:32]5[CH2:36][CH2:35][CH2:34][N:33]5[CH3:37])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CN1CCC[C@H]1CO
Product: CN1CCC[C@H]1CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-{[(2S)-1-methylpyrrolidin-2-yl]methyl}-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and (2S)-2-hydroxymethyl-1-methylpyrrolidine following General Procedure J.