Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][O:14][CH2:15][CH3:16])[CH:9]=[CH:8][C:7]=1[O:17][CH3:18])[CH3:2].[Li][CH2:20]CCC.CI>C1COCC1>[CH2:15]([O:14][CH2:13][O:12][C:10]1[CH:9]=[CH:8][C:7]([O:17][CH3:18])=[C:6]([O:5][CH2:4][O:3][CH2:1][CH3:2])[C:11]=1[CH3:20])[CH3:16]
Reactant: CCOCOc1ccc(OC)c(OCOCC)c1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CCOCOc1ccc(OC)c(OCOCC)c1C
Temperature: -78 °C
Reaction time: 1 h
Yield: 57.5 %

Procedure:
A solution of 4a (632 mg, 2.27 mmol) in anhydrous THF (1.94 mL) was added dropwise to a solution of nBuLi (2.5 M in hexanes, 1.48 mL, 3.70 mmol) in anhydrous THF (1.62 mL) at room temperature. After one hour, the solution was cooled to −78° C. and methyl iodide (620 μL, 9.87 mmol) was added. The resulting solution was warmed to room temperature over 12 hours, and the reaction was quenched by the addition of saturated aqueous NH4Cl. Water (5 mL) was added and the solution was extracted with CH2Cl2 (3×10 mL). Combined organic fractions were dried (Na2SO4), filtered, and concentrated. The residue was purified via column chromatography (SiO2, 8:1→5:1 Hexane:EtOAc) to afford 5a as a yellow oil (353 mg, 53%): 1H NMR (CDCl3, 500 MHz) 6.74 (d, J=9.0 Hz, 1H), 6.60 (d, J=9.0 Hz, 1H) 5.10 (s, 2H), 5.05 (s, 2H), 3.78 (q, J=7.1 Hz, 2H), 3.72 (s, 3H), 3.67 (q, J=7.1 Hz, 2H), 2.14 (s, 3H), 1.18-1.15 (m, 6H); 13C NMR (CDCl3, 125 MHz) δ 149.1, 146.5, 121.7, 109.0, 108.4, 96.2, 93.0, 64.3, 63.1, 55.1, 28.7, 14.2, 14.1, 8.8; IR (film) νmax 2918, 2359, 1487, 1260, 1248, 1082, 1055, 945, 798 cm−1; HRMS (ESI+) m/z: [M+Na]+ calcd for Cl4H22O5, 293.1365; found, 293.1357.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:18]1([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:17])[O:24][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: OC1CCCCC1
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Product: N=C(OC1CCCCC1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile and cyclohexanol there is obtained cyclohexyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a syrup, 1H-NMR(CDCl3): 1.5-2.1 (8H), 4.2 (s, 4H), 4.67 (broad s, NH), 5.1 (m, OCH), 7.3-7.7 (8H).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18](=[O:39])[NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][NH:27][C:28]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][CH:32]=4)=[O:29])[CH:21]=3)[CH:14]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[C:37]([C:34]1[CH:35]=[CH:36][C:31]([NH:30][C:28](=[O:29])[NH:27][CH2:26][C:22]2[CH:21]=[C:20]([NH:19][C:18]([C:13]3[CH:14]=[C:15]4[C:10](=[CH:11][CH:12]=3)[CH2:9][NH:8][CH2:17][CH2:16]4)=[O:39])[CH:25]=[CH:24][CH:23]=2)=[CH:32][CH:33]=1)#[N:38]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(C(=O)Nc3cccc(CNC(=O)Nc4ccc(C#N)cc4)c3)ccc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(NC(=O)NCc2cccc(NC(=O)c3ccc4c(c3)CCNC4)c2)cc1
Reaction time: 2 h
Yield: 48 %

Procedure:
3,4-Dihydro-1H-isoquinoline-2,6-dicarboxylic acid 2-tert-butyl ester (50 mg, 0.18 mmol), EDC (38.3 mg, 0.2 mmol) and HOBt (24.3 mg, 0.18 mmol) were combined in a reaction vial, and DMF (1 mL) was added. To the solution thus formed, N-methylmorpholine (0.22 mL, 0.2 mmol) was added and the reaction mixture was agitated for 1 hour. The urea, 1-(3-amino-benzyl)-3-(4-cyano-phenyl)-urea (40 mg, 0.15 mmol), prepared as described above, was then added as a solution in DMF (0.3 mL), and the reaction mixture was agitated for 48 h. The reaction mixture was diluted to 6 mL with dichloromethane, washed with 1N HCl (3×2 mL), NaHCO3 (satd. aq., 3×2 mL, and brine (1×2 mL), dried and evaporated to 59 mg of an oil (95% yield). This intermediate (6-{3-[3-(4-cyano-phenyl)-ureidomethyl]-phenylcarbamoyl}-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester) was dissolved in dichloromethane (1 mL) and TFA (0.4 mL) was added. The reaction mixture was stirred for 2 h, then the solvents were evaporated and the resulting residue was purified directly by preparative HPLC using an acetonitrile/water/formic acid gradient providing the title compound (20 mg, 48% yield), MS analysis electrospray, 426 (M+H).
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:17]([OH:19])=O)[C:13]([CH3:16])([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[CH2:48]([NH:55][NH2:56])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1.CCN(CC)CC>>[CH2:4]([O:3][C:1](=[O:2])[NH:11][C@H:12]([C:17]([NH:56][NH:55][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:19])[C:13]([CH3:14])([CH3:15])[CH3:16])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: NNCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CCN(CC)CC
Product: CC(C)(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NNCc1ccccc1
Yield: 67 %

Procedure:
The general procedure for the preparation of hydrazides described above was followed using Cbz-(L)-tert-leucine (2.00 g, 4.48 mmol), EDAC (0.969 g, 5.05 mmol), HOBT (0.669 g, 4.95 mmol), NMM (0.542 mL, 4.93 mmol), benzylhydrazine×2HCl (0.962 g, 4.93 mmol) and Et3N (1.38 mL, 9.85 mmol) which gave the title compound (1.11 g, 67%) as a low melting solid.
Reaction SMILES: [NH:1]([C:23]([O:25][CH2:26][CH:27]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:24])[C@H:2]([C:20](O)=[O:21])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:5]=1.[CH2:40]([NH2:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[NH:1]([C:23]([O:25][CH2:26][CH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:34]2[C:39]1=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:24])[C@H:2]([C:20]([NH:47][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:21])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([C:13]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:14])[CH:5]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)n1cc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)c2ccccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1cc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)NCc2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.9 %

Procedure:
To the mixture of Fmoc-Trp(Boc)-OH (205 mg, 0.39 mmol) and benzylamine (165 μL, 1.51 mmol) in DMF (5 mL) was added TBTU (249 mg, 0.77 mmol) and N,N-diisopropylethylamine (340 μL, 1.95 mmol). The reaction was stirred for 2 hours at room temperature. The solvent was removed in vacuo and the residue was purified by flash column silica gel chromatography (2:1, hexane:ethyl acetate) to yield the Fmoc-Trp(Boc)-NHBn (151 mg, 63%). The solution of Fmoc-Trp(Boc)-NHBn (151 mg, 0.25 mmol) and piperidine (0.5 mL) in DMF (2 mL) was stirred for 1 hour at room temperature. The solvent was removed in vacuo and the crude product was purified by flash column silica gel chromatography (from ethyl acetate to 5% methanol in ethyl acetate) to afford the NH2-Trp(Boc)-NHBn (81 mg, 80%). Compound 16 (23 mg, 0.04 mmol) was dissolved in DMF (2 mL) and NH2-Trp(Boc)-NHBn (72 mg, 0.18 mmol), TBTU (33 mg, 0.10 mmol), and N,N-diisopropylethylamine (37 μL, 0.21 mmol). The mixture was stirred for 4 hours at room temperature before removing the solvent under reduced pressure. The crude product was purified by flash chromatography using ethyl acetate as eluent to afford 17 (24 mg, 63%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([I:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12]1[C:21]2[C:20](=[O:22])[NH:19][CH:18]=[N:17][C:16]=2[N:15]([CH3:23])[C:14](=[O:24])[C:13]=1C.Cl[CH2:27][C@H:28]1[CH2:32][O:31][C:30]([CH3:34])([CH3:33])[O:29]1>CN(C=O)C>[CH3:33][C:30]1([CH3:34])[O:29][C@@H:28]([CH2:27][N:19]2[C:20](=[O:22])[C:21]3[C:12]([NH:11][C:5]4[CH:6]=[CH:7][C:8]([I:10])=[CH:9][C:4]=4[F:3])=[CH:13][C:14](=[O:24])[N:15]([CH3:23])[C:16]=3[N:17]=[CH:18]2)[CH2:32][O:31]1
Reactant: Cc1c(Nc2ccc(I)cc2F)c2c(=O)[nH]cnc2n(C)c1=O
Reactant: CC1(C)OC[C@H](CCl)O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)cc(Nc2ccc(I)cc2F)c2c(=O)n(C[C@H]3COC(C)(C)O3)cnc21
Reaction time: 0.17 h

Procedure:
Sodium hydride (89 mg, 4.7 mmol, 5 eq) was stirred in anhydrous DMF (1 mL) for 10 minutes. 5-(2-Fluoro-4-iodophenylamino)-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (400 mg, 0.94 mmol, 1 eq) in anhydrous DMF (400 μL) was added and the mixture stirred for 10 minutes. (R)-4-(Chloromethyl)-2,2-dimethyl-1,3-dioxolane (260 μl, 1.88 mmol, 2 eq) was added and the mixture subjected to microwave irradiation at 150° C. for 35 minutes. The solvent was removed in vacuo and the residue purified by HPLC. 1H NMR (400 MHz, MeOD) δ ppm 1.37 (s, 3H) 1.47 (s, 3H) 3.70 (s, 3H) 3.85 (dd, J=8.97, 5.68 Hz, 1H) 4.13 (dd, J=13.89, 7.07 Hz, 1H) 4.20 (dd, J=8.72, 6.69 Hz, 1H) 4.38 (dd, J=13.89, 3.03 Hz, 1H) 4.50-4.59 (m, 1H) 5.81 (s, 1H) 7.36 (t, J=8.21 Hz, 1H) 7.62-7.74 (m, 2H) 8.49 (s, 1H). [M+H] calc'd for C20H20FIN4O4, 527. found, 527.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[BH4-].[Na+]>CN(C)C=O.C(O)C>[CH2:9]([N:6]1[CH2:7][CH:8]=[C:3]([CH2:2][OH:1])[CH2:4][CH2:5]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCc1ccccc1
Reactant: OCc1ccncc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: OCC1=CCN(Cc2ccccc2)CC1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A solution of 4-hydroxymethylpyridine (20 g, 0.183 mol) in anhydrous dimethylformamide (70 ml) was treated with benzyl bromide (24 ml, 0.202 mol) and the mixture was stirred at 100° C. for two hours. The reaction was cooled to room temperature and diluted with absolute ethanol (250 ml). Sodium borohydride (8.7 g, 0.229 mol) was added portionwise and the mixture stirred at reflux for 3 hours. The solvent was evaporated in vacuo and the residue partitioned between dichloromethane and water. The organic phase was separated, dried (MgSO4) and evaporated in vacuo. The residue was chromatographed with 1:1 hexane/ethyl acetate as eluant to the title compound (13 g, 35%) as a lemon yellow solid; δH (CDCl3) 2.12-2.20 (2H, m, tetrahydropyridinyl CH2), 2.60 (2H, t, J 7.5 Hz, tetrahydropyridinyl CH2), 2.96-3.04 (2H, m, tetrahydropyridyl CH2), 3.60 (2H, s, PhCH2N), 4.00-4.04 (2H, m, CH2OH), 5.60-5.66 (1H, m, tetrahydropyridinyl 5-H), and 7.20-7.40 (5H, m, ArH). m/z (CI+, NH3) 204 (M+1)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[F:14][C:15]1[CH:16]=[CH:17][C:18]([NH2:24])=[N:19][C:20]=1[CH:21]([CH3:23])[CH3:22]>C(#N)C>[Cl:8][C:6]1[N:5]=[N:4][C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:2]([NH:24][C:18]2[CH:17]=[CH:16][C:15]([F:14])=[C:20]([CH:21]([CH3:23])[CH3:22])[N:19]=2)[CH:7]=1
Reactant: CCOC(=O)c1nnc(Cl)cc1Cl
Reactant: CC(C)c1nc(N)ccc1F
Solvent: CC#N
Product: CCOC(=O)c1nnc(Cl)cc1Nc1ccc(F)c(C(C)C)n1
Temperature: 130 °C

Procedure:
To a solution of ethyl 4,6-dichloropyridazine-3-carboxylate (674 mg, 3.05 mmol) in acetonitrile (10 mL) was added 5-fluoro-6-isopropylpyridin-2-amine (470 mg, 3.05 mmol) and heated at 130° C. in a sealed tube for 18 h. Upon completion, the mixture was concentrated on to silica gel and purified by chromatography (silica. 10% to 33% EtOAc in hexanes) to give recovered aniline (300 mg) and ethyl 6-chloro-4-(5-fluoro-6-isopropylpyridin-2-ylamino)pyridazine-3-carboxylate (150 mg, 22%). 1H NMR (400 MHz, CHLOROFORM-d6) δ ppm 10.72 (s, 1H), 9.23 (s, 1H), 7.38 (t, J=8.4 Hz, 1H), 6.79 (dd, J=8.5, 2.8 Hz, 1H), 4.57 (m, 2H), 3.45 (m, 1H), 1.53 (m, 3H), 1.36 (d, J=6.9 Hz, 6H).
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:25]=[CH:24][C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13](/[C:17](=[N:19]/[N:20]=[C:21]([NH2:23])[NH2:22])/[CH3:18])[CH:12]=2)=[O:9])=[CH:6][CH:5]=1.CCO.[Cl:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=[CH:32][CH:31]=1.Cl>O>[ClH:29].[ClH:1].[NH2:22][C:21](=[N:20]/[N:19]=[C:17](/[C:13]1[CH:12]=[C:11]([NH:10][C:8](=[O:9])[C:7]2[CH:6]=[CH:5][C:4]([NH:3][C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:33]=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)[CH:16]=[CH:15][CH:14]=1)\[CH3:18])[NH2:23]
Reactant: C/C(=N\N=C(N)N)c1cccc(NC(=O)c2ccc(N)cc2)c1
Reactant: Clc1ccnc2ccccc12
Agent: Cl
Solvent: O
Solvent: CCO
Product: C/C(=N\N=C(N)N)c1cccc(NC(=O)c2ccc(Nc3ccnc4ccccc34)cc2)c1

Procedure:
To a solution of triamine F5 (0.35 g, 0.91 mmol) in 1:2 EtOH:H2O (30 mL) were sequentially added 4-chloroquinoline (0.64 g, 3.90 mmol) and c.HCl (0.25 mL, 8.24 mmol), and the resulting solution was refluxed for 20 h (reaction progress followed by TLC, eluting with the top phase of a 5:4:1 mixture of n-BuOH:H2O:acetic acid; product Rf=0.51, yellow spot after staining with KMnO4). After this time, solvent was removed under reduced pressure, and the residue dried via two MeOH-azeotrope cycles. The residue was re-precipitated from MeOH:EtOAc to give Cpd. JJ2 (91 mg, 20%) as a pale yellow amorphous solid; mp 240-244° C. (powder-glue), 264-268° C. (glue-liquid); 1H NMR (400 MHz, DMSO): δ 14.67 (br s, 1H, quinolinyl-N+—H), 11.19 (s, 1H, hydrazonyl-N+—H), 11.07 (s, 1H, ArC(O)NHAr), 10.48 (s, 1H, ArNHAr), 8.72 (d, J=8.52 Hz, 1H, ArH), 8.61 (d, J=6.90 Hz, 1H, ArH), 8.24 (m, 3H, ArH), 8.08 (m, 2H, ArH), 7.95 (d, J=8.10 Hz, 1H, ArH), 7.82 (m, 6H, ArH & ═C(NH2)2), 7.68 (d, J=8.38 Hz, 2H, ArH), 7.43 (t, J=7.97 Hz, 1H, ArH), 7.01 (d, J=6.90 Hz, 1H, ArH), 2.37 (s, 3H, Ar(CH3)2═N—); LCMS (APCI+): 438 (100%); HPLC: 96.4%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:17])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[C:6](Cl)[CH:7]=1.BrC1C=CC([F:25])=C(Cl)C=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:17])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[F:25]
Reactant: Fc1ccc(Br)cc1Cl
Reactant: O=C(Cc1ccccc1)c1cc(Cl)cc(Cl)c1
Product: O=C(Cc1ccccc1)c1ccc(F)c(Cl)c1
Yield: 20 %

Procedure:
Prepared following the procedure described in Intermediate 13, starting from 4-bromo-2-chloro-1-fluorobenzene, where the crude product was purified by column chromatography (PE: EtOAc=100:1) to afford Intermediate 17 (110 mg, yield 20.0%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][C:5]=1OC1C=CC=CC=1)([O-:3])=[O:2].[CH2:24]([NH2:27])[CH:25]=[CH2:26]>O1CCCC1>[O:10]([C:7]1[CH:6]=[C:5]([C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[NH:27][CH2:24][CH:25]=[CH2:26])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccccc2)cc1Oc1ccccc1
Reactant: C=CCN
Solvent: C1CCOC1
Product: C=CCNc1cc(Oc2ccccc2)ccc1[N+](=O)[O-]

Procedure:
A mixture of 10 gm of 4-nitro-1,3-diphenoxy-benzene, 30 ml of tetrahydrofuran and 10 l ml of allylamine was refluxed for 8 hours. Thereafter, the reaction mixture was worked up as in Example 3, and the reaction product was recrystallized from ethanol, yielding 6.1 gm (69% of theory) of the thin-layer chromatographically (cyclohexane/toluene=1:1) uniform title compound, m.p. 67°-68° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=O)[CH2:10][CH:9]1[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:21]([CH:23]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:22]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=[CH:23][CH:21]=[O:22])[CH2:10][CH:9]1[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1CC(C=O)CCN1C(=O)OC(C)(C)C
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CC(C=CC=O)CCN1C(=O)OC(C)(C)C

Procedure:
A solution of 1 g of 1-(tert-butoxycarbonyl)-2-ethoxycarbonylpiperidine-4-carboxaldehyde and 2g of formylmethylene-triphenylphosphoran in 16 ml of toluene is heated to 100° (bath) for 2 hours. The solution is cooled and purified by flash chromatography using ethyl acetate/hexane (25:75) to yield 1-(tert-butoxycarbonyl)-2-ethoxycarbonyl-piperidine-4-acrylaldehyde.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=2[C:18]([F:21])([F:20])[F:19])[CH2:4][CH2:3]1.[H][H]>CO.[Pd]>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=2[C:18]([F:19])([F:20])[F:21])[CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: CN1CCC(Oc2ccc([N+](=O)[O-])cc2C(F)(F)F)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCC(Oc2ccc(N)cc2C(F)(F)F)CC1

Procedure:
4-(N-methylpiperidin-4-yl)oxy-3-trifluoromethyl-1-nitrobenzene was dissolved in methanol in the presence of Pd/C. The solution was hydrogenated at 50 psi for 1 hour until hydrogen intake was completed. The catalyst was filtered off and the filtrate was concentrated to afford 4-(N-methylpiperidin-4-yl)oxy-3-trifluoromethylbenzenamine, >95%.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[N:10]([CH2:31][CH3:32])[CH2:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1B1OC(C)(C)C(C)(C)O1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:34]([O:36][C:37](=[O:54])[CH2:38][C:39]1[CH:44]=[C:43](OS(C(F)(F)F)(=O)=O)[CH:42]=[C:41]([Cl:53])[CH:40]=1)[CH3:35]>>[CH2:34]([O:36][C:37](=[O:54])[CH2:38][C:39]1[CH:44]=[C:43]([C:13]2[CH:14]=[CH:15][C:16]([C:18]([F:20])([F:19])[F:21])=[CH:17][C:12]=2[CH2:11][N:10]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:33])[CH2:31][CH3:32])[CH:42]=[C:41]([Cl:53])[CH:40]=1)[CH3:35]
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)OCc1ccccc1
Reactant: CCOC(=O)Cc1cc(Cl)cc(OS(=O)(=O)C(F)(F)F)c1
Product: CCOC(=O)Cc1cc(Cl)cc(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)OCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: ethyl-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-carbamic acid benzyl ester and (3-chloro-5-trifluoromethanesulfonyloxy-phenyl)-acetic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:10][S:11]([C:14]2[S:15][C:16]([Cl:19])=[CH:17][CH:18]=2)(=[O:13])=[O:12])=[O:9])=[CH:4][CH:3]=1.[N:20]([C:23]1[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=1[C:25](OC)=[O:26])=[C:21]=[O:22].C1CCN2C(=NCCC2)CC1>C1COCC1>[O:22]=[C:21]1[N:1]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([NH:10][S:11]([C:14]3[S:15][C:16]([Cl:19])=[CH:17][CH:18]=3)(=[O:13])=[O:12])=[O:9])=[CH:4][CH:3]=2)[C:25](=[O:26])[C:24]2[C:23](=[CH:32][CH:31]=[CH:30][CH:29]=2)[NH:20]1
Reactant: COC(=O)c1ccccc1N=C=O
Reactant: Nc1ccc(C(=O)NS(=O)(=O)c2ccc(Cl)s2)cc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(NS(=O)(=O)c1ccc(Cl)s1)c1ccc(-n2c(=O)[nH]c3ccccc3c2=O)cc1
Reaction time: 18 h
Yield: 34 %

Procedure:
A 44 mg portion (0.14) of (4-aminophenyl)-N-[(5-chloro(2-thienyl))sulfonyl]carboxamide was combined with 25 mg (0.14 mmol) of methyl 2 isocyanatobenzoate in 500 uL of THF followed by the addition of 1 equivalent of TEA (24 μL) and 1 equivalent of DBU. After 18 h, the mixture was purified by RP-HPLC, to give 21 mg (34%) of the desired compound. ES-MS (M+H)+=462 (Cl).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][CH:23]([C:26](=[O:31])C(Cl)(Cl)Cl)[C:22](=O)[C:21]2=[O:33])=[CH:16][CH:15]=1)([O-:13])=[O:12]>CO.C(O)(=O)C>[OH:31][C:26]1[C:23]2[CH2:24][CH2:25][N:20]([C:17]3[CH:18]=[CH:19][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=3)[C:21](=[O:33])[C:22]=2[N:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1
Reactant: COc1ccc(NN)cc1
Reactant: O=C1C(=O)N(c2ccc([N+](=O)[O-])cc2)CCC1C(=O)C(Cl)(Cl)Cl
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(-n2nc(O)c3c2C(=O)N(c2ccc([N+](=O)[O-])cc2)CC3)cc1

Procedure:
Condensation of 4-methoxyphenylhydrazine with 1-(4-nitro-phenyl)-4-(2,2,2-trichloro-acetyl)-piperidine-2,3-dione in refluxing methanol-acetic acid media afforded 3-hydroxy-1-(4-methoxy-phenyl)-6-(4-nitro-phenyl)-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one. Treatment of this intermediate with NaH and isopropyliodide afforded the corresponding 3-isopropoxy pyrazolo intermediate which was subjected to the same experimental protocol as described for Example 3 to afford the title compound. ESI mass spectrum 460 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][NH2:20])[O:16][C:15]2=[O:21])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:35])[CH2:30][CH2:31][C:32](O)=[O:33])=[CH:25][CH:24]=1.C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][NH:20][C:32](=[O:33])[CH2:31][CH2:30][C:29]([C:26]3[CH:25]=[CH:24][C:23]([Cl:22])=[CH:28][CH:27]=3)=[O:35])[O:16][C:15]2=[O:21])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1
Reactant: O=C(O)CCC(=O)c1ccc(Cl)cc1
Reactant: NC[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: O=C(CCC(=O)c1ccc(Cl)cc1)NC[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Temperature: 0 °C
Reaction time: 24 h
Yield: 42 %

Procedure:
(S)-N-[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl amine (0.100 gm, 0.00034 moles) was taken up in 1:1 THF-water mixture (20 ml). To this was added 4-(4-chlorophenyl)-4-oxobutanoic acid (0.072 g, 0.00034 moles and HOBt (0.046 g, 0.00034 moles). The resulting mixture was cooled to 0° C., and then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.071 gm, 0.00037 moles) was added. The resulting mixture was allowed to warm to room temperature and then stirred for 24 hr. The reaction mixture was concentrated and 2 ml of saturated aqueous sodium bicarbonate solution was added, stirred for 15 min and then extracted with dichloromethane. The organic layer was separated and evaporated off. The residue was chromatographed over silica gel (100-200 mesh, 20 g) and eluted with mixture of ethyl acetate:hexane, and finally with ethyl acetate. The combined fractions were concentrated to give (0.070 gm, 42%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([N:4]([CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([CH3:20])=[C:14]2[CH3:21])[CH3:5])[CH:2]=[CH2:3].F[C:23]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=1>>[CH2:1]([N:4]([CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([C:23]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=1)[C:15]([CH3:20])=[C:14]2[CH3:21])[CH3:5])[CH:2]=[CH2:3]
Reactant: Fc1ccc(Br)cc1
Reactant: C=CCN(C)CCCCOc1ccc2[nH]c(C)c(C)c2c1
Product: C=CCN(C)CCCCOc1ccc2c(c1)c(C)c(C)n2-c1ccc(Br)cc1

Procedure:
In analogy to example 9.1, Allyl-[4-(2,3-dimethyl-1H-indol-5-yloxy)-butyl]-methyl-amine and 1-fluoro-4-bromobenzene were converted to yield Allyl-{4-[1-(4-bromo-phenyl)-2,3-dimethyl-1H-indol-5-yloxy]-butyl}-methyl-amine as orange oil, MS: 441 (MH+,1 Br).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[F:26][C:27]1[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:28]=1B(O)O>O1CCOCC1.O>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:28]3[CH:29]=[C:30]([F:34])[C:31]([F:33])=[CH:32][C:27]=3[F:26])=[CH:14][CH:13]=2)[CH:5]=1
Reactant: OB(O)c1cc(F)c(F)cc1F
Reactant: COC(=O)c1cccc(COc2ccc(I)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cccc(COc2ccc(-c3cc(F)c(F)cc3F)cc2)c1
Yield: 77.9 %

Procedure:
Bis(tricyclohexylphosphine)palladium (200 mg, 0.3 mmol) was added to a stirred solution of 3-(4-iodo-phenoxymethyl)-benzoic acid methyl ester (3.68 g, 10 mmol), potassium carbonate (2.76 g, 20 mmol) and 2,4,5-trifluorophenylboronic acid (3.5 g, 20 mmol) in 100 mL dioxane and 10 mL H2O were reacted as above and purified by flash chromatography with a gradient of 0-5% ethyl acetate in hexanes to give 2.9 g (77.9%) of 3-(2′,4′,5′-trifluoro-biphenyl-4-yloxymethyl)-benzoic acid methyl ester.