Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[C:14]([C:23](=[O:25])[CH3:24])=[N:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:26][CH3:27].C(=O)([O-])[O-].[K+].[K+].[CH2:34]([CH:36]1[O:38][CH2:37]1)Br.O>CN(C)C=O>[CH3:27][O:26][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:34][CH:36]1[CH2:37][O:38]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:12][C:13]1[C:14]([C:23](=[O:25])[CH3:24])=[N:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2
Reactant: BrCC1CO1
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C(C)=O)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3cc4ccccc4nc3C(C)=O)ccnc2cc1OCC1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
1-[3-(7-Hydroxy-6-methoxy-quinolin-4-yloxy)-quinolin-2-yl]-ethanone (compound 390) (200 mg) was dissolved in N,N-dimethylformamide (6 ml) to prepare a solution. Potassium carbonate (230 mg) and epibromohydrin (0.1 ml) were added to the solution, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was 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 the title compound (152 mg, yield 66%).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][CH:14]2[CH2:19][CH2:18][CH:17]([O:20][C:21]3[CH:22]=[CH:23][C:24]4[N:25]([C:27]([N:30]5[C@H:35]([CH3:36])[CH2:34][CH2:33][CH2:32][C@@H:31]5[CH3:37])=[N:28][N:29]=4)[CH:26]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:38]2[CH:39]=[N:40][N:41]([CH2:43][CH2:44][OH:45])[CH:42]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:46][S:47](Cl)(=[O:49])=[O:48].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][CH:14]2[CH2:19][CH2:18][CH:17]([O:20][C:21]3[CH:22]=[CH:23][C:24]4[N:25]([C:27]([N:30]5[C@H:31]([CH3:37])[CH2:32][CH2:33][CH2:34][C@@H:35]5[CH3:36])=[N:28][N:29]=4)[CH:26]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:38]2[CH:39]=[N:40][N:41]([CH2:43][CH2:44][O:45][S:47]([CH3:46])(=[O:49])=[O:48])[CH:42]=2)[N:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(OC3CCC(NC(=O)Nc4cc(C(C)(C)C)nn4-c4cnn(CCO)c4)CC3)cn12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(OC3CCC(NC(=O)Nc4cc(C(C)(C)C)nn4-c4cnn(CCOS(C)(=O)=O)c4)CC3)cn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
A mixture of Intermediate 17b (0.75 g, 1.21 mmol), methanesulfonyl chloride (140 μL, 1.81 mmol) and DIPEA (0.63 mL, 3.62 mmol) in DCM (15 mL) was stirred at RT for 1 h. The reaction mixture was partitioned between DCM and water. The organic layer was washed with brine, separated through a phase separating cartridge and concentrated in vacuo to afford the title compound (0.82 g, 97%). LCMS (Method 3): Rt 3.59 min, m/z 697 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[C:10](=[CH:14][O:15][CH2:16][CH3:17])[C:11](=[O:13])[CH3:12])=[CH:4][CH:3]=1.[CH2:19]([O:21][C:22]([O:25][CH2:26][CH3:27])=[CH:23][CH3:24])[CH3:20].CCCCCC>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:10]2[C@@H:14]([O:15][CH2:16][CH3:17])[C@H:23]([CH3:24])[C:22]([O:25][CH2:26][CH3:27])([O:21][CH2:19][CH3:20])[O:13][C:11]=2[CH3:12])=[O:18])=[CH:6][CH:7]=1
Reactant: CC=C(OCC)OCC
Reactant: CCOC=C(C(C)=O)C(=O)Nc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCO[C@@H]1C(C(=O)Nc2ccc(Cl)cc2)=C(C)OC(OCC)(OCC)[C@H]1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 10.4 %

Procedure:
N-(4'-Chlorophenyl)-2-ethoxymethylene-3-oxobutanamide (1.3 g) and tris (6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedianato)ytterbium (0.26 g) were stirred in toluene (10 ml) whilst 1,1-diethoxyprop-1-ene (2 g) was added dropwise. The mixture was stirred at room temperature for two hours and evaporated to dryness. The residual gum was purified by medium pressure liquid chromatography on K60 silica using ethyl acetate/petroleum ether b.p. 60°-80° C., 15/85 v/v as eluting solvent to give two stereoisomers. The first isomer after trituration with n-hexane gave trans-N-(4'-chlorophenyl)-2,2-diethoxy-3,6-dimethyl-4-ethoxy-3,4-dihydro-2H-pyran-5-carboxamide (0.2 g), m.p. 104°-106° C. The second isomer, again after trituration with n-hexane, gave cis-N-(4'-chlorophenyl)-2,2-diethoxy-3,6-dimethyl-4-ethoxy-3,4-dihydro-2H-pyran-5-carboxamide (1.3 g), m.p. 125°-127° C.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]([CH:18]=[CH:19][C:20]=1[N:21]1[CH2:25][CH2:24][CH2:23][C:22]1=O)[O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=[O:13])(=[O:4])=[O:3].C1CCN2C(=NCCC2)CC1.Cl>C1COCC1>[O:3]=[S:2]1(=[O:4])[C:5]2[CH:6]=[C:7]([O:8][C:9]3[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=3)[C:12]([OH:14])=[O:13])[CH:18]=[CH:19][C:20]=2[N:21]2[CH2:25][CH2:24][CH2:23][C:22]2=[N:1]1
Reactant: NS(=O)(=O)c1cc(Oc2cccc(C(=O)O)c2)ccc1N1CCCC1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cccc(Oc2ccc3c(c2)S(=O)(=O)N=C2CCCN23)c1

Procedure:
A suspension of the product obtained in Step B (850 mg, 2.26 mmol) in 25 ml of THF in the presence of 675 μl (4.52 mmol) of DBU is refluxed for 1 hour. It is allowed to return to ambient temperature and is acidified with 1N HCl, and the white precipitate corresponding to the title product is filtered off. Elemental micro-analysis:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[CH:13][C:14]([OH:17])=[N:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:18][CH:19]([N:21]1[N:25]=[N:24][C:23]([N:26]2[CH2:31][CH2:30][CH:29]([C@H:32](O)[CH3:33])[CH2:28][CH2:27]2)=[N:22]1)[CH3:20]>>[CH3:20][CH:19]([N:21]1[N:25]=[N:24][C:23]([N:26]2[CH2:31][CH2:30][CH:29]([C@@H:32]([O:17][C:14]3[CH:13]=[N:12][C:11]([C:8]4[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=4)=[CH:16][N:15]=3)[CH3:33])[CH2:28][CH2:27]2)=[N:22]1)[CH3:18]
Reactant: CS(=O)(=O)c1ccc(-c2cnc(O)cn2)cc1
Reactant: CC(C)n1nnc(N2CCC([C@@H](C)O)CC2)n1
Product: CC(C)n1nnc(N2CCC([C@H](C)Oc3cnc(-c4ccc(S(C)(=O)=O)cc4)cn3)CC2)n1
Yield: 58 %

Procedure:
The title compound (145 mg, 58%) was prepared from 5-[4-(methylsulfonyl)phenyl]-2-pyrazinol (and tautomers thereof) (prepared as in Example 145, Steps 1-2, 125 mg, 0.5 m mol) and (1R)-1-{1-[2-(1-methylethyl)-2H-tetrazol-5-yl]-4-piperidinyl}ethanol (prepared as in Example 190, Step 3, 120 mg, 0.5 mmol) in a manner similar to Example 190, Step 4. Enantiomeric excess was not determined. 1H NMR (400 MHz, DMSO-d6): 8.91 (d, 1H, J=1.4 Hz), 8.41 (d, 1H, J=1.4 Hz), 8.34-8.26 (m, 2H), 8.07-7.99 (m, 2H), 5.13 (quint, 1H, J=6.2 Hz), 4.87 (septet, 1H, J=6.7 Hz), 4.06-3.91 (m, 2H), 3.26 (s, 3H), 2.95-2.78 (m, 2H), 1.96-1.71 (m, 3H), 1.49 (d, 6H, J=6.7 Hz), 1.45-1.35 (m, 2H), 1.32 (d, 3H, J=6.2 Hz); LRMS (ESI), m/z 472 (M+H).
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[S:12][CH:13]=[CH:14][N:15]=1)([O-:3])=[O:2].[CH3:18][NH2:19]>C(O)C.CCOCC>[N+:1]([CH:4]=[C:5]([NH:19][CH3:18])[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[S:12][CH:13]=[CH:14][N:15]=1)([O-:3])=[O:2]
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1nccs1
Reactant: CN
Solvent: CCOCC
Solvent: CCO
Product: CNC(=C[N+](=O)[O-])NCCSCc1nccs1

Procedure:
Reaction of 1-nitro-2-methylthio-2-[2-(2-thiazolylmethylthio)ethylamino]ethylene with methylamine according to the process of Example 8(ii) yielded the title compound, m.p. 103°-104°, (from ethanol ether).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[C:12]#[C:13][C:14]([CH3:22])([CH3:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C(OCC)(=O)C>CC#N.Cl[Pd]Cl>[F:8][C:6]1[CH:7]=[C:2]2[C:3]([CH:12]=[C:13]([C:14]([CH3:21])([CH3:22])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[NH:1]2)=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: CCOC(=O)CC(C)(C)C#Cc1cc([N+](=O)[O-])c(F)cc1N
Agent: Cl[Pd]Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(C)(C)c1cc2cc([N+](=O)[O-])c(F)cc2[nH]1
Temperature: 25 °C
Yield: 100.3 %

Procedure:
To a mixture of ethyl 5-(2-amino-4-fluoro-5-nitrophenyl)-3,3-dimethylpent-4-ynoate (34.5 g, 0.11 mol) and PdCl2 (10.4 g, 58.6 nmol) in CH3CN (350 mL) was heated to reflux for 1.5 hours. The reaction mixture was cooled down to room temperature. Ethyl acetate (300 mL) was added, the precipitate was filtered off and washed with methanol. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 40:1) to give ethyl 3-(6-fluoro-5-nitro-1H-indol-2-yl)-3-methylbutanoate (34.0 g, 98%) as a deep yellow solid. 1H NMR (300 MHz, CDCl3) δ 10.11 (brs, 1H), 8.30 (d, J=7.2 Hz, 1H), 7.14 (d, J=11.7 Hz, 1H), 6.35 (d, J=1.5 Hz, 1H), 4.17 (q, J=7.2 Hz, 2H), 2.69 (s, 2H), 1.51 (s, 6H), 1.25 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16](O)=[O:17].CCN=C=NCCCN(C)C.Cl.CCN(CC)CC.OC1C2N=NNC=2C=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:6][C:16](=[O:17])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][N:10]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc(N)c1
Reactant: O=C(O)c1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(NC(=O)c2ccccn2)c1
Temperature: 50 °C
Reaction time: 12 h
Yield: 90.1 %

Procedure:
According to Scheme 1 Method B: 3-Methoxyaniline (1.62 mmol, 0.18 mL) was added to a solution of picolinic acid (1.62 mmol, 0.20 g), EDCI.HCl (2.44 mmol, 0.47 g), Et3N (3.25 mmol, 0.45 mL), hydroxybenzotriazole (1.95 mmol, 0.30 g) in DCM (6 mL) at room temperature. The reaction mixture was stirred at 50° C. for 12 hours. The organic phase was washed with a saturated solution of NaHCO3 and with brine, was dried over MgSO4, was filtered and was concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel using cyclohexane/AcOEt (90:10) as eluent to afford N-(3-methoxyphenyl)picolinamide (1.46 mmol, 0.33 g, 90%) as an orange liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[O:6][C:7]3[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=3[CH2:9][N:10]([C:11]([NH:13][NH2:14])=[O:12])[C:4]=2[CH:3]=1.[C:21](Cl)(=[O:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(=O)(O)[O-].[Na+]>>[C:21]([NH:14][NH:13][C:11]([N:10]1[CH2:9][C:8]2[CH:15]=[CH:16][CH:17]=[CH:18][C:7]=2[O:6][C:5]2[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][C:4]1=2)=[O:12])(=[O:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: CCCCCCCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCCCCCCC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21

Procedure:
The reaction of an alkanoyl halide and the hydrazide is illustrated by contacting 8-chloro-10,11-dihydrodibenz-[b,f][1,4]oxazepine-10-carboxylic acid hydrazide with octanoyl chloride in the presence of sodium bicarbonate to give 1-octanoyl-2-(8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine-10-carbonyl)hydrazine.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=1.C([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)(OC(C)(C)C)=O.CCN(CC)CC>CCO>[CH:9]1([C:4]2[CH:5]=[C:6]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:7]=[C:2]([NH2:1])[N:3]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Nc1nc(Cl)cc(C2CCCC2)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1nc(C2CCCC2)cc(N2CCNCC2)n1
Temperature: 25 °C
Yield: 18.1 %

Procedure:
A solution of crude 2-amino-4-chloro-6-cyclopentylpyrimidine (150 mg, 0.76 mmol), N—BOC piperazine (184 mg, 0.99 mmol) and Et3N (210 uL, 1.5 mmol) in EtOH (2 mL) was heated at 70° C. for 16 h. The reaction was cooled to rt and concentrated and the crude residue purified (2 M NH3 in MeOH/CH2Cl2) to yield a white solid (34 mg, 11%). MS (ESI): mass calcd. for C18H29N5O2, 347.2; m/z found, 348.3 [M+H]+. 1H NMR (MeOD): 6.01 (s, 1H), 3.66-3.58 (m, 4H), 3.53-3.43 (m, 4H), 3.33 (td, J=3.3, 1.6, 1H), 2.90-2.75 (m, 1H), 2.05-1.90 (m, 2H), 1.87-1.77 (m, 2H), 1.77-1.62 (m, 4H), 1.53-1.46 (m, 9H).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13](F)[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.O>C(#N)C>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([N:23]2[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]2)[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1NCc1ccccc1
Reactant: CN1CCNCC1
Solvent: CC#N
Solvent: O
Product: CN1CCN(c2ccc([N+](=O)[O-])c(NCc3ccccc3)c2)CC1
Temperature: 160 °C
Reaction time: 0.67 h

Procedure:
Benzyl-(5-fluoro-2-nitro-phenyl)-amine E-1.1″ (2.000 g; 6.579 mmol) is dissolved in acetonitril (10.000 ml). N-Methylpiperazine (1.460 ml; 13.158 mmol) is then added. The reaction mixture is stirred for 40 min at 160° C. in a Biotage XP Sixty microwave. The reaction mixture is poured into water and extracted with 3×50 ml DCM. The combined organic layer is dried over MgSO4 and concentrated under reduced pressure. The residue is used in the next step without further purification.
Reaction SMILES: [ClH:1].[N:2]1([C:9]2[CH:10]=[C:11]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH:28]([F:30])[F:29])[CH:22]=3)(=[O:20])=[O:19])[CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:31]=O>[BH4-].[Na+].C(#N)C>[ClH:1].[F:29][CH:28]([F:30])[O:27][C:23]1[CH:22]=[C:21]([S:18]([NH:17][C:11]2[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:9]([N:2]3[CH2:8][CH2:7][CH2:6][N:5]([CH3:31])[CH2:4][CH2:3]3)[CH:10]=2)(=[O:20])=[O:19])[CH:26]=[CH:25][CH:24]=1
Reactant: C=O
Reactant: COc1ccc(NS(=O)(=O)c2cccc(OC(F)F)c2)cc1N1CCCNCC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(NS(=O)(=O)c2cccc(OC(F)F)c2)cc1N1CCCN(C)CC1

Procedure:
The title compound was prepared from the title compound of Example 1 under reductive amination conditions employing an aqueous solution of formaldehyde and sodium borohydride in acetonitrile as solvent.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:18])[CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[C:4]([O:19][CH3:20])[CH:3]=1.C(N(CC)CC)C.Br[CH2:29][CH2:30][CH3:31]>CN(C=O)C>[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:18])[CH2:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:29][CH2:30][CH3:31])[CH2:16][CH2:17]2)=[C:4]([O:19][CH3:20])[CH:3]=1
Reactant: CCCBr
Reactant: COc1cc(N)c(Cl)cc1C(=O)CCC1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCN1CCC(CCC(=O)c2cc(Cl)c(N)cc2OC)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1-(4-Amino-5-chloro-2-methoxyphenyl)-3-(piperidin-4-yl)propan-1-one (0.2 g, 0.67 mmol), prepared as in Example 3 or Example 7, triethylamine (0.2 mL), and 1-bromopropane (0.065 mL, 0.75 mmol) were dissolved in DMF (4 mL) and the solution was stirred at room temperature for 12 hours. The solution was partitioned between aqueous ammonium hydroxide and ethyl acetate. The ethyl acetate layer was separated, washed with water and then brine, dried over sodium sulfate, and evaporated. Purification of the residue by silica gel chromatography (10% CH3OH--CH2Cl2) gave 1-(4-amino-5-chloro-2-methoxyphenyl)-3-(1-(prop-1-yl) piperidin-4-yl]propan-1-one which was then dissolved in ethanolic hydrochloric acid. Crystallization with ether gave 1-(4-amino-5-chloro-2-methoxyphenyl)-3-[1-(prop-1-yl) piperidin-4-yl]propan-1-one hydrochloride (0.15 g, 0.4 mmol), m.p. 200°-201° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11](Cl)(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH:15]([NH:18][CH2:19][CH2:20][NH:21][CH:22]([CH3:24])[CH3:23])([CH3:17])[CH3:16]>>[CH3:16][CH:15]([NH:18][CH2:19][CH2:20][N:21]([CH:22]([CH3:24])[CH3:23])[S:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:13])=[O:12])[CH3:17]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: CC(C)NCCNC(C)C
Product: COc1ccc(S(=O)(=O)N(CCNC(C)C)C(C)C)cc1OC

Procedure:
Reaction of 3,4-dimethoxybenzene sulfonyl chloride with N,N'-diisopropylethylene diamine following the procedure of Example 1 gave a crude crystalline product which on recrystallization from diethyl ether provided the pure title compound, m.r. 53°-55° C.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:12])=[O:9])=[CH:3][CH:2]=1.[H-].[Na+].C([O-])(=O)CC([O-])=O.[CH3:29][O:30][C:31]([C:33]1[S:45][C:36]2[N:37]=[C:38](S(C)(=O)=O)[N:39]=[CH:40][C:35]=2[CH:34]=1)=[O:32]>C1COCC1.C1COCC1.CN(C=O)C>[CH3:29][O:30][C:31]([C:33]1[S:45][C:36]2[N:37]=[C:38]([CH:10]([C:11](=[O:12])[NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:8](=[O:9])[NH:7][C:4]3[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=3)[N:39]=[CH:40][C:35]=2[CH:34]=1)=[O:32]
Reactant: COC(=O)c1cc2cnc(S(C)(=O)=O)nc2s1
Reactant: O=C(CC(=O)Nc1ccccc1)Nc1ccccc1
Agent: O=C([O-])CC(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)c1cc2cnc(C(C(=O)Nc3ccccc3)C(=O)Nc3ccccc3)nc2s1
Reaction time: 0.17 h

Procedure:
To a solution of malondianilide (102 mg, 0.40 mmol) in THF (2 mL) was added of NaH (16.3 mg, 60% wt. dispersion in mineral oil, 0.41 mmol). After 10 min, the malonate salt solution was added to a solution of 2-methanesulfonyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (100 mg, 0.367 mmol) in THF/DMF (2/0.5 mL). After 1 h, the reaction was quenched with sat. NH4Cl and extracted with EtOAc. The organic layer was washed with brine (1×), dried over MgSO4, filtered, and concentrated. The residue was triturated with EtOAc and H2O, and the solid was filtered.: ESIMS calcd 447 (W+H), found 447 M++H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:41])[CH2:26][C:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:39]=[N:38][CH:37]=[CH:36][N:35]=2)[CH:29]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:35]1[CH:36]=[CH:37][N:38]=[CH:39][C:34]=1[C:30]1[CH:29]=[C:28]([C:27]2[CH2:26][C:25](=[O:41])[NH:24][C:9]3[CH:10]=[C:11]([C:20]([F:22])([F:23])[F:21])[C:12]([O:14][CH2:15][C:16]([F:17])([F:19])[F:18])=[CH:13][C:8]=3[N:7]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2cnccn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3cnccn3)c2)=Nc2cc(OCC(F)(F)F)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from [2-[3-oxo-3-(3-pyrazin-2-yl-phenyl)-propionylamino]-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M103) (0.37 g, 0.62 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (220 mg, 74%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:15])=[C:4]([Cl:14])[C:5]([Cl:13])=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]=12.[CH2:16]([N:18]([CH2:26][CH3:27])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=1)[CH3:17].[Cl-].[Al+3].[Cl-].[Cl-]>ClC1C=CC=CC=1Cl>[CH3:25][C:21]1[CH:20]=[C:19]([N:18]([CH2:16][CH3:17])[CH2:26][CH3:27])[CH:24]=[CH:23][C:22]=1[C:11]([C:6]1[C:5]([Cl:13])=[C:4]([Cl:14])[C:3]([Cl:15])=[C:2]([Cl:1])[C:7]=1[C:8]([OH:10])=[O:9])=[O:12]
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Reactant: CCN(CC)c1cccc(C)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Product: CCN(CC)c1ccc(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)c(C)c1
Temperature: 0 °C
Yield: 77.3 %

Procedure:
A mixture of tetrachlorophthalic anhydride (21.4 g.), N,N-diethyl-m-toluidine (41 g.), aluminum chloride (30 g.) and o-dichlorobenzene (90 ml.) was heated (75°-95° C.) during one to two hours, then diluted with ice-water. The o-dichlorobenzene layer was separated and steam distilled. The residue was heated with dilute sulfuric acid. The mixture was poured onto ice and made alkaline. The resulting oil was heated in concentrated sulfuric acid. Dilution with water and purification of the product with toluene and hexane afforded 2-(2-methyl-4-(diethylamino)benzoyl)-3,4,5,6-tetrachlorobenzoic acid (IV: Y2 = CH3, Y'4 = (CH3CH2)2N, Z4 = Z"5 = Z"6 = Z7 = Cl) (26 g., m.p. 117° C. with sublimation).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]3[CH:15]=[CH:14][CH:13]=[CH:12][C:6]3=[CH:7][CH:8]=2)[N:3]=1.C([Li])CCC.CCCCCC.CN(C)[C:29](=[O:31])[CH3:30].Cl>C1COCC1>[N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]3[CH:12]=[CH:13][CH:14]=[CH:15][C:5]3=2)[CH:10]=[CH:11][C:2]=1[C:29](=[O:31])[CH3:30]
Reactant: Brc1ccc2ccc3ccccc3c2n1
Reactant: CC(=O)N(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(=O)c1ccc2ccc3ccccc3c2n1
Temperature: -78 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
A solution of 2-bromobenzo[h]quinoline (1.52 g, 5.89 mmol) in THF (36 ml) was cooled to −78° C. After 10 minutes a solution of 2.5 M n-butyllithium in n-hexane (2.47 ml, 6.18 mmol) was added. The resulting dark red solution was again stirred at −78° C. for 1 hour after which N,N-dimethylacetamide (0.60 ml, 6.45 mmol) was added drop-wise. The solution was stirred for 1 h at −78° C. and allowed to warm slowly to ambient temperature. A solution of 1 M HCl (7.4 ml, 7.4 mmol) was then added to the organic phase was separated and the aqueous phase was extracted with Et2O (2×15 ml). The organic phases were combined, dried over anhydrous Na2SO4 and the solvent evaporated under reduced pressure. The residue was purified by flash chromatography (petroleum ether/acetate=95/5) to give 1.00 g (77% yield) of 1-(benzo[h]quinolin-2-yl)ethanone in the form of a yellow solid: mp 113-115° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][OH:12].Cl[C@H:14]([CH3:19])[C:15]([O:17][CH3:18])=[O:16].C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C@@H:14]([CH3:19])[C:15]([O:17][CH3:18])=[O:16])=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][OH:12]
Reactant: OCCCc1cc(O)ccc1F
Reactant: COC(=O)[C@@H](C)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](C)Oc1ccc(F)c(CCCO)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 66.8 %

Procedure:
To a mixture of 4-fluoro-3-(3-hydroxypropyl)phenol (1.5 g), methyl (2R)-2-chloropropanoate (1.30 g) in DMSO (7.5 mL) was added Cs2CO3 (3.45 g) at ambient temperature. The mixture was stirred at 60° C. for 3 hours. After cooling to ambient temperature, the reaction mixture was diluted with EtOAc (50 mL) and washed successively with water (30 mL) two times and brine (30 mL). The organic layer was dried over anhydrous MgSO4, filtered and evaporated in vacuo to give crude oil. The crude oil was purified by silica gel column chromatography (n-hexane:EtOAc=4:1-2:1) to give methyl(2S)-2-[4-fluoro-3-(3-hydroxypropyl)phenoxy]propanoate (1.51 g) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:18]#[N:19])[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.BrC1C=CC(C2CCOCC2)=[N:25]C=1>>[NH2:25][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:18]#[N:19])[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: Brc1ccc(C2CCOCC2)nc1
Reactant: N#CC1(c2ccc(Br)cn2)CCC2(CC1)OCCO2
Product: N#CC1(c2ccc(N)cn2)CCC2(CC1)OCCO2

Procedure:
In Reference Example 75(4), 8-(5-bromopyridin-2-yl)-1,4-dioxaspiro[4,5]decane-8-carbonitrile described in Reference Example 82 was used in place of 5-bromo-2-(tetrahydro-2H-pyran-4-yl)pyridine, and reacted and treated in a similar manner to give the titled compound.