Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[NH:2]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18]C4C(C(NC5C=CC(F)=CC=5F)=O)=CN=CC=4)=[CH:14][C:13]=3[F:36])=[C:5]2[CH:4]=[CH:3]1.[Cl:37][C:38]1[N:54]=[C:53]([CH3:55])[CH:52]=[CH:51][C:39]=1[C:40]([NH:42][C:43]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:44]=1[F:50])=[O:41].Cl.CN1C(=O)CCC1>O1CCOCC1>[ClH:37].[ClH:1].[NH:2]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:38]4[N:54]=[C:53]([CH3:55])[CH:52]=[CH:51][C:39]=4[C:40]([NH:42][C:43]4[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:44]=4[F:50])=[O:41])=[CH:14][C:13]=3[F:36])=[C:5]2[CH:4]=[CH:3]1
Reactant: Cc1ccc(C(=O)Nc2ccc(F)cc2F)c(Cl)n1
Reactant: O=C(Nc1ccc(F)cc1F)c1cnccc1Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: Cc1ccc(C(=O)Nc2ccc(F)cc2F)c(Nc2ccc(Oc3ccnc4[nH]ccc34)c(F)c2)n1
Temperature: 25 °C

Procedure:
4-(1H-Pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorobenzenamine (40 mg, 164 μmol, Compound C of Example 1) and 2-chloro-N-(2,4-difluorophenyl)-6-methylnicotinamide (51 mg, 181 μmol) were suspended in 1,4-dioxane (1 mL). 4M HCl in 1,4-dioxane (0.16 mL, 0.333 mmol) was added and the reaction was irradiated (CEM personal microwave, 300 W) to a temperature of 160° C. for 60 min. The reaction was cooled to ambient temperature and NMP (1 mL) was added. The reaction mixture was re-heated to 160° C. (microwave irradiation, 300 W) for an additional two hours. The 1,4-dioxane was removed by rotary evaporation and the residue was partitioned between 10% aq. NaHCO3 solution (10 mL) and EtOAc (10 mL). The organic layer was separated and the aqueous layer was extracted EtOAc (2×10 mL). The combined organic layers were washed with 10% LiCl (20 mL), dried (Na2SO4) and concentrated in vacuo. The crude product was purified by preparative (RP) HPLC Chromatography (YMC S5 ODS, 20×100 mm, 10 minute gradient from 33% to 90% aqueous methanol with 0.1% TFA). The fractions containing the desired product were combined and concentrated. The purified material was dissolved in MeOH (1 mL), acidified with 4 N HCl in 1,4-dioxane (0.10 mL) and concentrated. The resulting salt was triturated with hot EtOAc and collected by filtration to afford a brown solid (4.4 mg, >97% HPLC purity). 1H NMR (DMSO-d6) δ 3.15 (s, 3H), 6.48 (s, 1H), 6.69 (d, 1H, J=6.10 Hz), 6.91 (d, 1H, J=7.63 Hz), 7.06-7.21 (m, 1H), 7.31-7.44 (m, 2H), 7.46-7.64 (m, 3H), 8.12-8.42 (m, 3H), 10.41 (s, 1H), 10.96 (s, 1H), 12.58 (s, 1H); MS(ESI+) m/z 490.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]2[NH:6][C:7]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[C:3]=1[N+:20]([O-])=O.[H][H]>CO.[Pd]>[NH2:20][C:3]1[C:4]2[S:9](=[O:11])(=[O:10])[N:8]=[C:7]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[NH:6][C:5]=2[CH:18]=[CH:19][C:2]=1[OH:1]
Reactant: CCOC(=O)CC1=NS(=O)(=O)c2c(ccc(O)c2[N+](=O)[O-])N1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CC1=NS(=O)(=O)c2c(ccc(O)c2N)N1
Yield: 99.2 %

Procedure:
The product of Example 352D (61 mg, 0.1852 mmol) in methanol (5 mL) was hydrogenated at 1 atmosphere hydrogen pressure (balloon) with 10% palladium on carbon (9 mg, 15 weight %) for 45 minutes. The reaction was filtered through a PTFE membrane filter (0.45 μm) and the catalyst thoroughly washed with warm methanol (50 mL). The filtrate was concentrated under reduced pressure to give the title compound as a beige solid (55 mg, 99%). MS (ESI−) m/z 298 (M−H)−. 1H NMR (300 MHz, DMSO-d6) δ 1.21 (t, J=7.17 Hz, 3 H) 3.61 (s, 2 H) 4.15 (q, J=6.99 Hz, 2 H) 5.22 (s, 2 H) 6.40 (d, J=8.46 Hz, 1 H) 6.93 (d, J=8.46 Hz, 1 H) 9.82 (s, 1 H) 11.86 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8](=[O:18])[NH:9][N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:4]=2[CH:3]=1.I[CH2:20][CH3:21].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([O:18][CH2:20][CH3:21])=[N:9][N:10]([C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[C:4]=2[CH:3]=1
Reactant: CCI
Reactant: CC(C)(C)OC(=O)n1[nH]c(=O)c2cnc(Cl)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1nn(C(=O)OC(C)(C)C)c2cc(Cl)ncc12

Procedure:
tert-Butyl 6-chloro-3-oxo-2,3-dihydro-1H-pyrazolo[4,3-c]pyridine-1-carboxylate (1.19 g, 4.41 mmol), iodoethane (0.715 mL, 8.85 mmol), and cesium carbonate (4.36 g, 13.38 mmol) were stirred in DMF (15 mL) at room temperature for 16 h. Water was added and the products extracted into EtOAc (×2). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the residue by flash chromatography (6-50% EtOAc-hexanes) gave tert-butyl 6-chloro-3-ethoxy-1H-pyrazolo[4,3-c]pyridine-1-carboxylate. MS ESI calc'd. For C13H16ClN3O3 [M+1]+ 298. found 298.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]2[CH2:17][CH:16]=[CH:15][O:14]2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH2:18]([O:20][C:21](=[O:29])[C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=1)[CH3:19].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(#N)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:18]([O:20][C:21](=[O:29])[C:22]1[CH:27]=[CH:26][C:25]([CH:15]2[CH:16]=[CH:17][CH:13]([C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[O:14]2)=[CH:24][CH:23]=1)[CH3:19]
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: COc1cc(C2CC=CO2)cc(OC)c1OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CCOC(=O)c1ccc(C2C=CC(c3cc(OC)c(OC)c(OC)c3)O2)cc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 86.1 %

Procedure:
To a solution of 287 (200 mg, 0.846 mmol) and 4-Iodo-benzoic acid ethyl ester (468 mg, 1.69 mmol) in dry acetonitrile (4 mL) were added PPh3 (20 mg, 0.076 mmol), Ag2CO3 (467 mg, 1.69 mmol) and Pd(OAc)2 (7 mg, 0.03 mmol). The reaction mixture was stirred 18 h at 80° C. The reaction mixture was filtered through celite and washed with AcOEt. Water was added and the phases were separated. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (AcOEt/Hexane: 30/70) to afford the title compound 288 (280 mg, 0.728 mmol, 86% yield). 1H NMR (300 MHz, CDCl3) δ (ppm): 8.05 (d, J=7.5 Hz, 2H), 7.45 (d, J=7.5 Hz, 2H), 6.61 (s, 2H), 6.18-5.95 (m, 4H), 4.38 (q, J=7.0 Hz, 2H), 3.88 (s, 6H), 3.84 (s, 3H), 1.39 (t, J=7.0 Hz).
Reaction SMILES: [CH3:1][SH:2].[N:3]1[C:10]([Cl:11])=[N:9][C:7]([Cl:8])=[N:6][C:4]=1Cl.N1C(C)=CC(C)=CC=1C.Cl.N1C(C)=CC(C)=CC=1C>CC(C)=O>[CH3:1][S:2][C:4]1[N:6]=[C:7]([Cl:8])[N:9]=[C:10]([Cl:11])[N:3]=1
Reactant: CS
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: Cl
Solvent: Cc1cc(C)nc(C)c1
Solvent: CC(C)=O
Product: CSc1nc(Cl)nc(Cl)n1
Reaction time: 1 h

Procedure:
Methanethiol is passed into a solution of 18.5 g of cyanuric chloride in 200 ml of acetone at a temperature of -25° to -30° C. 13.5 ml of collidine are then added slowly at the same temperature, whereupon collidine hydrochloride precipitates. The mixture is left to stand for 1 hour at 0° C. and is then poured onto ice, whereupon a white crystalline substance precipitates. After filtering the mixture, washing the product with water and drying it in a desiccator, 17.5 g of 2-methylthio-4,6-dichloro-1,3,5-triazine with a melting point of 57° to 59° C. are obtained.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].CC1(C)C(C)(C)OB([C:21]2[CH:26]=[CH:25]C=[CH:23][C:22]=2O)O1.C([O-])([O-])=O.[K+].[K+]>C(Cl)(Cl)Cl.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>[CH3:12][C:10]1[CH:9]=[CH:8][C:3]2[C:4](=[O:5])[O:6][C:7]3[C:25]([C:2]=2[CH:11]=1)=[CH:26][CH:21]=[CH:22][CH:23]=3
Reactant: COC(=O)c1ccc(C)cc1Br
Reactant: CC1(C)OB(c2ccccc2O)OC1(C)C
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: ClC(Cl)Cl
Product: Cc1ccc2c(=O)oc3ccccc3c2c1
Temperature: 130 °C

Procedure:
A sealed tube containing methyl 2-bromo-4-methylbenzoate (650 mg, 2.84 mmol), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (781 mg, 3.55 mmol) and TETRAKIS(TRIPHENYLPHOSPHINE)PALLADIUM(0) (164 mg, 0.142 mmol) was evacuated and backfilled with nitrogen before Toluene (1.29E+04 μl) and Ethanol (1290 μl) were added, followed by K2CO3 (2838 μl, 5.68 mmol). The tube was heated in the microwave for 25 minutes at 130° C. The mixture was cooled, diluted with chloroform (15 mL), washed with aqueous ammonium chloride (saturated, 10 mL), dried (Na2 SO4), filtered and the solvent was evaporated under reduced pressure. The crude product was then purified by column chromatography on silica gel Isolute Flash Si; eluting with 5-10% EtOAc/isohexane to give 9-methyl-6H-benzo[c]chromen-6-one. 1H NMR (500 MHz; CDCl3): 8.32 (d, J=8.3 Hz, 1H), 8.09 (d, J=8.0 Hz, 1H), 7.94 (s, 1H), 7.51 (m, 1H), 7.37 (m, 3H), 2.59 (s, 3H); LC-MS (IE, m/z): 211 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][CH:10]=[C:4]2[N:3]=1.[Br:11]N1C(=O)CCC1=O.O>ClCCl>[Br:11][C:10]1[CH:9]=[N:8][N:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[N:3][C:4]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: Clc1ccn2nccc2n1
Solvent: O
Solvent: ClCCl
Product: Clc1ccn2ncc(Br)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
To a solution of 5-chloropyrazolo[1,5-a]pyrimidine (2.30 g, 15.0 mmol) in dichloromethane (100 mL) was added N-bromosuccinimide (2.67 g, 15.0 mmol) and the mixture allowed to stir at ambient temperature for 1 hour. The reaction mixture was poured into water, extracted with dichloromethane, and dried over sodium sulfate. The crude product was purified by column chromatography, eluting with 1% MeOH/dichloromethane and afforded 1.50 g (45%) of 3-bromo-5-chloropyrazolo[1,5-a]pyrimidine as a light yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Cl[CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:16]1[CH2:17][CH2:18][N:13]([CH2:12][CH2:11][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:14][CH2:15]1
Reactant: ClCCN1CCOCC1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCN2CCOCC2)cc1
Temperature: 0 °C
Yield: 73.8 %

Procedure:
92.8 g of 4-hydroxybenzaldehyde are dissolved in 820 ml of dimethylformamide. After the addition of 228 g of 4-(2-chloroethyl)morpholine and 415 g of finely powdered potassium carbonate the reaction mixture is heated to 100° overnight under argon and while stirring vigorously. The cooled solution is poured into 3 l of ice-water, extracted with ethyl acetate, washed with water, dried and evaporated. The residual dark oil is distilled in a high vacuum and gives 132 g of 4-(2-morpholinoethoxy)benzaldehyde as a yellowish oil, boiling point 145°-150°/33 Pa.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([Cl:7])[N:6]=1.CCN(CC)CC.C1(P([N:32]=[N+:33]=[N-:34])(C2C=CC=CC=2)=O)C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[S:3][C:4]([C:8]([N:32]=[N+:33]=[N-:34])=[O:10])=[C:5]([Cl:7])[N:6]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1sc(Cl)nc1Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NC(=O)c1sc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 81.6 %

Procedure:
To a solution of 2,4-dichloro-thiazole-5-carboxylic acid (1.98 g, 10 mmol) in toluene (50 mL) was added Et3N (1.01 g, 10 mmol) followed by diphenyl phosphoryl azide (2.75 g, 10 mmol). The reaction mixture was stirred at room temperature for 20 h. The reaction mixture was concentrated in vacuo and purified by silica gel chromatography (0 to 100% ethyl acetate/hexanes) to afford product as a brown solid (1.82 g, 82%): 13C NMR (75 MHz, CDCl3) δ 163.33, 156.83, 143.94, 124.02.
Reaction SMILES: B.[C:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][CH:16]=1)[C:8]([NH:10][CH2:11]OC)=[O:9])#[N:3].[O:17]1[CH2:21]CC[CH2:18]1>>[NH2:3][CH2:2][CH2:4][C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][CH:16]=1)[C:8]([NH:10][CH2:11][CH2:18][O:17][CH3:21])=[O:9]
Reactant: C1CCOC1
Reactant: COCNC(=O)c1cccc(CC#N)c1
Agent: B
Product: COCCNC(=O)c1cccc(CCN)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Borane (1N in tetrahydrofuran, 467 ml, 0.467 mol) was added dropwise to a solution of 3-(cyanomethyl)N-(methoxymethyl)benzamide (14.57 g, 0.067 mol) [see preparation 40] in tetrahydrofuran (30 ml) over 20 minutes. The reaction mixture was then stirred at room temperature for 18 hrs and then heated to reflux for 2 hrs, after which time the solvent was evaporated under reduced pressure and the residue acidified with hydrochloric acid (2N). The resultant mixture was heated to reflux for 10 minutes after which time it was basified with sodium hydroxide. The product was extracted with dichloromethane (3×30 ml), the combined organic layers were dried over MgSO4 and the solvent evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol:0.88 ammonia (95:5:0.5) changing to (92.5:7.5:0.25) changing to (90:10:1) to afford the title compound, 6.15 g, (44%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[N:9]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([NH:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[O:17])=[CH:12][CH:11]=2)[N:8]=[N:7][C:6]=1[C:24]([NH:26][CH:27]1[CH2:29][CH2:28]1)=[O:25].O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C>[CH:27]1([NH:26][C:24]([C:6]2[N:7]=[N:8][N:9]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([NH:18][CH2:19][C:20]([F:21])([F:22])[F:23])=[O:17])=[CH:12][CH:11]=3)[C:5]=2/[CH:4]=[CH:3]/[CH3:2])=[O:25])[CH2:29][CH2:28]1
Reactant: O=C(NCC(F)(F)F)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCBr)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC#N
Solvent: O
Product: C/C=C/c1c(C(=O)NC2CC2)nnn1-c1ccc(C(=O)NCC(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 15.6 %

Procedure:
5-(3-Bromopropyl)-N-cyclopropyl-1-(4-{[(2,2,2-trifluoroethyl)amino]carbonyl}phenyl)-1H-1,2,3-triazole-4-carboxamide (212 mg, 0.45 mmol) obtained in Example 399a) was dissolved in acetonitrile (5.0 ml), tetrabutylammonium fluoride monohydrate (140 mg, 0.54 mmol) was added, and the mixture was stirred at 80° C. for 16 hr. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column (ethyl acetate/hexane=1/9 to 7/3) and recrystallized from ethyl acetate-hexane to give the title compound as a colorless powder (27.7 mg, 16%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[OH:15].F[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1
Reactant: COc1cc2nccc(O)c2cc1OC
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC

Procedure:
L1 was prepared from 6,7-dimethoxyquinolin-4-ol and 4-fluoro-nitrobenzene following the general procedure reported in Preparative Example 1 Step 1-2. 1H NMR (400 MHz, d6-DMSO, 300K) δ 3.91 (s, 3H), 3.92 (s, 3H), 5.16 (br s, 2H), 6.36 (d, J=5.3 Hz, 1H), 6.65 (d, J=8.8 Hz, 2H), 6.91 (d, J=8.8 Hz, 2H), 7.34 (s, 1H), 7.49 (s, 1H), 8.41 (d, J=5.3 Hz, 1H). MS (ES) C17H16N2O3 requires: 296. Found: 297 (M+H)+.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].[F:31][CH:32]1[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][CH2:39][O:40][C:41]2[CH:46]=[CH:45][C:44]([NH2:47])=[CH:43][CH:42]=2)[CH2:33]1>C1COCC1>[F:31][CH:32]1[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][CH2:39][O:40][C:41]2[CH:42]=[CH:43][C:44]([NH:47][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=6)=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:30])=[CH:45][CH:46]=2)[CH2:33]1
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Reactant: Nc1ccc(OCCCN2CCC(F)C2)cc1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(OCCCN4CCC(F)C4)cc3)c2)n(C)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 39 %

Procedure:
A small screw cap test tube was charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 60, 100 mg, 0.249 mmol) and THF (2 mL). To the resulting solution was added 4-[3-(3-Fluoro-pyrrolidin-1-yl)-propoxy]-phenylamine (prepared below, 59.3 mg, 0.249 mmol), and the mixture was stirred for 24 h at 65° C. The reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture causing a black precipitate to form. The precipitate was vacuum filtered and the filtrate was then concentrated in vacuo and redissolved into ˜3 mL of EtOAc. Hexanes were added causing a yellow precipitate to form. The precipitate was then filtered and washed with ˜1 mL of i-prOH yielding 39% (0.060 g, 0.097 mmol) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][C:4](=[O:20])[CH:3]=1.C1C(=O)N([Br:28])C(=O)C1>>[Br:28][C:3]1[C:4](=[O:20])[O:5][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:7][C:2]=1[OH:1]
Reactant: O=C1C=C(O)CC(c2ccccc2)(c2ccccc2)O1
Reactant: O=C1CCC(=O)N1Br
Product: O=C1OC(c2ccccc2)(c2ccccc2)CC(O)=C1Br

Procedure:
The title compound was prepared as described in General Method 3 using 4.0 mmol of 5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (prepared in Example W) and 4.0 mmol of NBS. The product was obtained as a solid. 1H NMR (DMSO-d6) δ 3.68 (s, 2 H), 7.27-7.40 (m, 10 H).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[S:3]([C:6]1[S:10][C:9]([N:11]([CH3:15])[C:12](Cl)=[O:13])=[N:8][C:7]=1[CH3:16])(=[O:5])=[O:4].C(N(CC)CC)C.[O:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1>O1CCOCC1>[CH3:1][N:2]([CH3:17])[S:3]([C:6]1[S:10][C:9]([N:11]([CH3:15])[C:12]([NH:35][C:34]2[CH:33]=[CH:32][C:31]([N:28]3[CH2:29][CH2:30][O:25][CH2:26][CH2:27]3)=[CH:37][CH:36]=2)=[O:13])=[N:8][C:7]=1[CH3:16])(=[O:5])=[O:4]
Reactant: Cc1nc(N(C)C(=O)Cl)sc1S(=O)(=O)N(C)C
Reactant: Nc1ccc(N2CCOCC2)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1nc(N(C)C(=O)Nc2ccc(N3CCOCC3)cc2)sc1S(=O)(=O)N(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
12.0 g (40.3 mmol) of 5-[(dimethylamino)sulphonyl]-4-methyl-1,3-thiazol-2-yl(methyl)carbamoyl chloride and 4.08 g (40.3 mmol) of triethylamine were dissolved in 150 ml of dioxane, and 7.18 g (40.3 mmol) of 4-morpholinoaniline, dissolved in 60 ml of dioxane, were added dropwise. The mixture was stirred at room temperature for 12 h, and the resulting precipitate was filtered off and dissolved in a dichloromethane/water (1:1) solvent mixture. The organic phase was separated off, dried over sodium sulphate and concentrated in vacuo.
Reaction SMILES: N#N.[N+:3]([C:6]1[CH:7]=[N:8][N:9]([CH2:11][C:12]2[O:16][C:15]([CH:17]=[O:18])=[CH:14][CH:13]=2)[CH:10]=1)([O-:5])=[O:4].[CH3:19][Mg]Br.[NH4+].[Cl-]>C1COCC1>[N+:3]([C:6]1[CH:7]=[N:8][N:9]([CH2:11][C:12]2[O:16][C:15]([CH:17]([OH:18])[CH3:19])=[CH:14][CH:13]=2)[CH:10]=1)([O-:5])=[O:4]
Reactant: O=Cc1ccc(Cn2cc([N+](=O)[O-])cn2)o1
Reactant: C[Mg]Br
Agent: N#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1ccc(Cn2cc([N+](=O)[O-])cn2)o1
Temperature: -78 °C
Reaction time: 4 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-(4-nitro-pyrazol-1-ylmethyl)-furan-2-carbaldehyde (3.79 g, 17.14 mmol) in THF (173.0 mL) was treated at −78° C. with methylmagnesium bromide (17.1 mL of a 1M solution in THF, 17.14 mmol). The reaction mixture was stirred at −78° C. for 4 h then poured on sat. aq. NH4Cl (150 mL) and extracted with EA (2×300 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (50:50 hept-EA) gave the title compound as a yellow oil. TLC: rf (50:50 hept-EA)=0.24. LC-MS-conditions 02: tR=0.79 min. 1H NMR (400 MHz, CDCl3) δ 1.55 (d, J=6.5 Hz, 3H), 2.09 (d, J=5.0 Hz, 1H), 4.83-4.95 (m, 1H), 5.31 (s, 2H), 6.28 (d, J=3.0 Hz, 1H), 6.46 (d, J=3.0 Hz, 1H), 8.09 (s, 1H), 8.13 (s, 1H).
Reaction SMILES: O=[C:2]1[CH2:16][CH:5]2[CH2:6][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH:4]2[CH2:3]1.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:17]([NH:24][CH:2]1[CH2:16][CH:5]2[CH2:6][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH:4]2[CH2:3]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CC2CC(=O)CC2C1
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CC2CC(NCc3ccccc3)CC2C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
To a solution of tert-butyl 5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (9.57 g, 42.5 mmol) in DCM (170 mL) were added BnNH2 (4.56 g, 42.5 mmol) and AcOH (2.55 g, 42.5 mmol) at 0° C. and the reaction mixture was stirred at 0° C. for 0.5 h. Then NaBH(OAc)3 (18.00 g, 85.0 mmol) was added to the above mixture and the resulting mixture was stirred at rt for another 20 h, then quenched with saturated NaHCO3 solution (142 mL), and extracted with DCM (250 mL×3). The combined organic phases were washed with brine (250 mL×3), dried over anhydrous Na2SO4, concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc) to give the title compound as a yellow solid (7.44 g, 55.3%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:8](Cl)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[OH-].[Na+]>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH3:8])[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: CCCCCCCCCCCCCl
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCCCN1CCN(C)CC1
Yield: 65.9 %

Procedure:
100 g (1 mole) of 1-methyl-piperazine were heated to 100° C and a total of 204.5 g (1 mole) of dodecyl chloride was added in 3 portions. After a reaction time of 15 minutes, 40 g (1 mole) of solid sodium hydroxide was added in several portions and the mixture was allowed to react for 2 hours at 140°-150° C. The reaction product was then separated from the solid inorganic residue by filtering the reaction mixture whilst hot. The inorganic residue was extracted twice with 200 ml of benzene, the benzene phase was separated off and concentrated and the residue was added to the main filtrate. The product was subjected to a fractional distillation. 177 g (66% of theory) of 1-methyl-4-dodecyl-piperazine of boiling point 90°-115° C/0.01 mm Hg were thus obtained.