Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[CH3:41][O:42][C:43]1[CH:44]=[C:45]([CH:49]=[C:50]([O:54][CH3:55])[C:51]=1[O:52][CH3:53])[C:46](O)=[O:47]>C(Cl)Cl>[C:1]1([CH:7]2[CH2:8][CH2:9][N:10]([C:46]([C:45]3[CH:49]=[C:50]([O:54][CH3:55])[C:51]([O:52][CH3:53])=[C:43]([O:42][CH3:41])[CH:44]=3)=[O:47])[CH2:11][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: COc1cc(C(=O)O)cc(OC)c1OC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCC(c3ccccc3)CC2)cc(OC)c1OC
Reaction time: 8 h

Procedure:
To a mixture of 4-phenylpiperidine 41g (5 mmol), EDCI (6 mmol), HOBt (5.5 mmol) and NMM (6 mmol) in CH2Cl2 (50 mL) was added 3,4,5-trimethoxybenzoic acid (5.3 mmol) and stirring continued at RT for overnight. The reaction mixture was diluted with CH2Cl2 (100 mL) and sequentially washed with water, satd. NaHCO3, brine and dried over MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography to obtain pure compound 1g. (57.9%). 1H NMR (CDCl3) δ 7.35-7.21 (m, 5H), 6.66 (s, 2H), 4.84 (br, 1H), 3.95 (br, 1H), 3.88 (s, 6H), 3.86 (s, 3H), 3.20-2.87 (br, 2H), 2.85-2.74 (tt, 1H, J=3.6 Hz, J=15.6 Hz) 1.92 (br, 2H), 1.70 (br, 2H); MS (ESI) m/z 378.1 (M+Na)+.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][NH:5][C:6]([C:8]1([NH:11][C:12](=[O:76])[C@H:13]([NH:35][C:36](=[O:75])[C@H:37]([NH:45][C:46](=[O:74])[CH2:47][C@H:48](O)/[CH:49]=[CH:50]/[CH2:51][CH2:52][S:53][C:54]([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:14][S:15][C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=[O:7].[Li+].[OH-:79].CC1C=CC=C([N+]([O-])=O)C=1C(OC(C1C([N+]([O-])=O)=CC=CC=1C)=O)=O>C1COCC1.O.CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:38]([C@H:37]1[NH:45][C:46](=[O:74])[CH2:47][C@@H:48](/[CH:49]=[CH:50]/[CH2:51][CH2:52][S:53][C:54]([C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)([C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=2)[C:67]2[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=2)[O:79][C:3](=[O:2])[CH2:4][NH:5][C:6](=[O:7])[C:8]2([CH2:10][CH2:9]2)[NH:11][C:12](=[O:76])[C@@H:13]([CH2:14][S:15][C:16]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:35][C:36]1=[O:75])[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: [OH-]
Reactant: COC(=O)CNC(=O)C1(NC(=O)[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(=O)[C@@H](Cc2ccccc2)NC(=O)C[C@H](O)/C=C/CCSC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Agent: CN(C)c1ccncc1
Agent: Cc1cccc([N+](=O)[O-])c1C(=O)OC(=O)c1c(C)cccc1[N+](=O)[O-]
Agent: [Li+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C1C[C@@H](/C=C/CCSC(c2ccccc2)(c2ccccc2)c2ccccc2)OC(=O)CNC(=O)C2(CC2)NC(=O)[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(=O)[C@@H](Cc2ccccc2)N1
Reaction time: 2 h
Yield: 57.1 %

Procedure:
To a solution of 4 (305 mg, 0.29 mmol, 1 eq) in THF (10 mL) at 0° C. was added a solution of LiOH (10.3 mg, 0.43 mmol, 1.5 eq) in H2O (2 mL) dropwise. The mixture was stirred for 2 h, then quenched with 1N HCl (3 mL) and brine (10 mL). The organic layer was separated and the resulting aqueous layer was further extracted with EtOAc (2×15 mL) and (15 mL). The combined organic extracts were dried over MgSO4 and the solvent was removed in vacuo. The resulting carboxylic acid was then dried on the high-vacuum pump for 2 h. To a solution of MNBA (118 mg, 0.34 mmol, 1.2 eq) and DMAP (84 mg, 0.69 mmol, 2.4 eq) in CH2CL2 (200 mL) was added a solution of the crude carboxylic acid in CH2Cl2 (130 mL) and THF (20 mL) dropwise over 3 h. The reaction mixture was then left to stir up at rt overnight. The solvent was then removed in vacuo and the residue was further purified by silica gel column chromatography with hexane/EtOAc (1:9→0:1) to yield 5 as a white solid (171 mg, 58%).
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[C:24]([O:25][CH3:26])=[C:23]([S:27][CH3:28])[CH:22]=[CH:21][C:10]=1[C:11]([C:13]1[CH:14]=[N:15][O:16][C:17]=1[CH:18]1[CH2:20][CH2:19]1)=[O:12]>ClCCl>[Br:8][C:9]1[C:24]([O:25][CH3:26])=[C:23]([S:27][CH3:28])[CH:22]=[CH:21][C:10]=1[C:11](=[O:12])[CH:13]([C:14]#[N:15])[C:17]([CH:18]1[CH2:20][CH2:19]1)=[O:16]
Reactant: COc1c(SC)ccc(C(=O)c2cnoc2C2CC2)c1Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(SC)ccc(C(=O)C(C#N)C(=O)C2CC2)c1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.5 %

Procedure:
Triethylamine (0.58 g) was added to a stirred solution of 4(2-bromo-3-methoxy-4-methylsulphenylbenzoyl)-5-cyclopropylisoxazole (2.0 g) in dichloromethane and the mixture was stirred at room temperature for 3 hours. The mixture was evaporated to dryness and the residue triturated with ether and filtered. The solid was re-dissolved in dichloromethane and washed with hydrochloric acid (2M). The organic layer was washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue triturated with ether and filtered to give 1-(2-bromo-3-methoxy-4-methylsulphenylphenyl)-2-cyano-3-cyclopropylpropan-1,3-dione (COMPOUND 661, 1.33 g) as a white solid, m.p. 128°-129° C.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][OH:10])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[Cl:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15]Cl.[H-].[Na+].[Cl-].[NH4+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[CH2:1]([O:3][P:4]([CH2:9][O:10][CH2:15]/[CH:14]=[CH:13]\[CH2:12][Cl:11])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(CO)OCC
Reactant: ClC/C=C\CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CCOP(=O)(COC/C=C\CCl)OCC

Procedure:
To a mixture of hydroxymethyl phosphonic acid diethylester (1.68 g, 10 mmol), Z-1,4-dichloro-2-butene (1.9 g, 15 mmol) and tetra-n-butylammonium iodide (0.36 g, 1 mmol) in anhydrous tetrahydrofuran (15 ml), sodium hydride (0.48 g, 12 mmol, 60% in oil) is added at 0° C. The resulting mixture is stirred overnight at 20° C., hydrolyzed with a saturated solution of ammonium chloride and extracted with diethylether. The title product is obtained by flash chromatography on silica gel (1.2 g, 45%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[NH2:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1[CH:21]=[CH:22][NH:23]2.Cl.N1C=CC=CC=1.C(OC(O)C)C.C(=O)([O-])[O-].[Na+].[Na+].Cl>O>[NH:23]1[C:24]2[C:20](=[C:19]([NH:18][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][C:3]=3[C:16]#[N:17])[CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:22]1
Reactant: Nc1cccc2[nH]ccc12
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: CCOC(C)O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: c1ccncc1
Solvent: O
Product: COc1cc2ncc(C#N)c(Nc3cccc4[nH]ccc34)c2cc1OC
Yield: 72.4 %

Procedure:
A mixture of 0.249 g of 4-chloro-6,7-dimethoxy-quinolin-3-carbonitrile, 0.132 g of 4-aminoindole, 0.020 g of pyridine hydrochloride, and 10 ml of ethoxyethanol was stirred under nitrogen, at reflux temperature for 2 hours. The mixture was cooled and added to 40 ml of water. To this mixture was added sodium carbonate and concentrated hydrochloric acid to adjust pH to 7. The product was collected, washed with water, and dried to give 0.249 g of 4-(1H-indol-4-ylamino)-6,7-dimethoxy-quinoline-3-carbonitrile as a solid, mp 260° C. (decomposed); mass spectrum (EI, m/e): M 344.1282.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20](=O)[CH3:21])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:4]=2[N:3]=1.[CH2:28]([CH2:30][NH2:31])[OH:29].C(O)(C(F)(F)F)=O>>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]([NH:31][CH2:30][CH2:28][OH:29])[CH3:21])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:4]=2[N:3]=1
Reactant: NCCO
Reactant: CC(=O)c1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(C)NCCO)cc3)cc12

Procedure:
2-(1-(4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenyl)ethylamino)ethanol (from Example 171) was prepared from 1-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenyl)ethanone and ethanol amine (commercially available) following the procedures described for Example 176. 1H NMR (Acetone-d6) of TFA Salt: δ 8.78 (d, 1H), 8.29 (d, 1H), 7.83 (s, 1H), 7.45 (m, 3H), 7.28 (m, 3H), 4.22 (m, 1H), 3.52 (m, 2H), 3.23 (t, 2H), 3.09 (t, 2H), 2.85 (m, 1H), 2.65 (m, 1H), 2.41 (s, 3H), 1.61 (d, 3H). LRMS [M+H]=401.2
Reaction SMILES: [CH2:1]([O:8][N:9]([C@H:22]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:25]([C:35](=[NH:38])[NH:36][OH:37])[CH2:24][CH2:23]1)[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:39]C1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>COC(OC)OC>[CH2:1]([O:8][N:9]([C@H:22]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:25]([C:35]2[N:38]=[CH:39][O:37][N:36]=2)[CH2:24][CH2:23]1)[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1C[C@H](N(OCc2ccccc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])CC[C@H]1C(=N)NO
Agent: c1cc[nH+]cc1
Solvent: COC(OC)OC
Product: CC(C)(C)OC(=O)N1C[C@H](N(OCc2ccccc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])CC[C@H]1c1ncon1
Temperature: 70 °C
Reaction time: 4 h
Yield: 1178.8 %

Procedure:
A mixture of (2S,5R)-tert-butyl 5-(N-(benzyloxy)-2-nitrophenylsulfonamido)-2-(N-hydroxycarbamimidoyl)piperidine-1-carboxylate (3.0 g, 5.46 mmol), trimethoxymethane (60 mL), and PPTS (0.08 g) was stirred at 70° C. for 4 hrs. The solvent was then removed under vacuum. The residue was purified by silica gel column chromatography (gradient elution 0˜35% petroleum ether/EtOAc) to give (2S,5R)-tert-butyl 5-(N-(benzyloxy)-2-nitrophenylsulfonamido)-2-(1,2,4-oxadiazol-3-yl)piperidine-1-carboxylate (2.1 g, 69%) as a yellow solid. ESI-MS (EI+, m/z): 582 [M+Na]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:11]([CH2:45][CH:46]([CH3:48])[CH3:47])=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)=[CH:17][C:16]([NH:27]C(=O)OCC1C3C=CC=CC=3C3C1=CC=CC=3)=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1CCCCC1.O>CN(C)C=O>[NH2:27][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([CH2:45][CH:46]([CH3:48])[CH3:47])[C:10]([CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[C:19]2[C:20]1[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=1
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(NC(=O)OCC4c5ccccc5-c5ccccc54)cc23)cc1
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(N)cc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
To a solution of 9H-fluoren-9-ylmethyl 3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-4-(4-methylphenyl)-6-quinolinylcarbamate (1.28 g, 2.0 mmol) in N,N-dimethylformamide (20 ml) was added piperidine (1 ml), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium-sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give tert-butyl [6-amino-2-isobutyl-4-(4-methylphenyl)-3-quinolinyl]methylcarbamate (0.81 g, yield 96.4%).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[CH2:9][C:10]([F:17])([F:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])C1C=CC=CC=1.[C:25]([OH:31])([C:27]([F:30])([F:29])[F:28])=[O:26]>CCO>[OH:31][C:25]([C:27]([F:30])([F:29])[F:28])=[O:26].[NH2:8][CH2:9][C:10]([F:17])([F:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(F)(F)CN(Cc1ccccc1)Cc1ccccc1
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(F)(F)CN
Reaction time: 8 h
Yield: 94 %

Procedure:
In a round bottom flask, Ethyl 3-(dibenzylamino)-2,2-difluoropropanoate (1.72 g, 5.2 mmol) was solubilized in EtOH (25 mL) and TFA added (0.4 mL, 5.5 mmol). Under an atmosphere of nitrogen Pd(OH)2/C (170 mg of 20% Pd by wt. wet) was added. The reaction mixture was repeatedly purged with nitrogen and then left under hydrogen overnight. At this point the reaction was deemed complete by LCMS, filtered through a pad of Celite, the pad washed with EtOH and the filtrate concentrated without heating to yield a foggy syrup which starts to crystallize upon standing (1.31 g, 94% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.29 (t, J=7.20 Hz, 3 H) 3.72 (t, J=16.17 Hz, 2 H) 4.34 (q, J=7.24 Hz, 2 H). [M+H] calc'd for C5H9F2NO2, 154; found 154.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]2[N:7]([CH3:26])[C:8](=[O:25])[N:9]([CH2:10][C@H:11]3[CH2:16][CH2:15][C@H:14]([C:17]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[O:18])[CH2:13][CH2:12]3)[C:5]=2[CH:4]=1.C(N(CC)CC)C.[C:36](Cl)(=[O:38])[CH3:37]>C(Cl)Cl>[C:36]([N:22]1[CH2:21][CH2:20][N:19]([C:17]([C@H:14]2[CH2:15][CH2:16][C@H:11]([CH2:10][N:9]3[C:5]4[CH:4]=[C:3]([O:2][CH3:1])[CH:28]=[CH:27][C:6]=4[N:7]([CH3:26])[C:8]3=[O:25])[CH2:12][CH2:13]2)=[O:18])[CH2:24][CH2:23]1)(=[O:38])[CH3:37]
Reactant: COc1ccc2c(c1)n(C[C@H]1CC[C@H](C(=O)N3CCNCC3)CC1)c(=O)n2C
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2c(c1)n(C[C@H]1CC[C@H](C(=O)N3CCN(C(C)=O)CC3)CC1)c(=O)n2C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Methoxy-1-methyl-3-[trans-4-(piperazine-1-carbonyl)-cyclohexylmethyl]-1,3-dihydro-benzoimidazol-2-one (85 mg, 0.22 mmol) was dissolved in anhydrous DCM (4 ml). Triethyl amine (0.12 ml, 0.66 mmol) and acetyl chloride (0.02 ml, 0.26 mmol) were added and the mixture was stirred at room temperature overnight. The solution was washed with saturated NaHCO3 the organic phase was concentrated and the crude product purified on silica column using EtOAc as eluent to give the titled compound (60 mg, 64%).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:16][C:15]=1[N+:30]([O-:32])=[O:31])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][CH:7]=1.[BH4-].[Li+]>C(COC)OC>[CH2:23]([O:22][C:17]1[C:18]([O:20][CH3:21])=[CH:19][C:14]([CH:4]([NH:5][C:6]2[CH:7]=[CH:8][C:9]([C:12]#[N:13])=[CH:10][CH:11]=2)[CH2:3][OH:2])=[C:15]([N+:30]([O-:32])=[O:31])[CH:16]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)C(Nc1ccc(C#N)cc1)c1cc(OC)c(OCc2ccccc2)cc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Li+]
Solvent: COCCOC
Product: COc1cc(C(CO)Nc2ccc(C#N)cc2)c([N+](=O)[O-])cc1OCc1ccccc1
Temperature: 25 °C
Yield: 73.9 %

Procedure:
(4-Benzyloxy-5-methoxy-2-nitro-phenyl)-(4-cyano-phenylamino)-acetic acid methyl ester (4.5 g, 10 mmole) was dissolved in dimethoxyethane and lithium borohydride (0.210 g, 10 mmole) added. The reaction was heated to reflux for three hours and cooled to room temperature. The reaction was quenched with water containing acetic acid and diluted with ethyl acetate. After transferring to a separatory funnel, the organic layer was washed with water several times. The organic layer was dried over anhydrous sodium sulfate, filtered and the solvent removed. The crude material was then submitted to flash chromatography to yield 3.1 g of 4-[1-(4-Benzyloxy-5-methoxy-2-nitro-phenyl)-2-hydroxy-ethylamino]-benzonitrile (74%). 1HNMR(CDCl3):7.77 (s, 1H), 7.3-7.5 (m, 7H), 7.15 (s, 1H), 6.42 (d, 2H), 5.4 (bs, 1H), 5.18 (dd AB syst., 2H), 4.15 (dd, 1H), 3.83 (s, 3H), 3.79-3.86 (dd, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]([CH2:15][CH:16]2[CH2:18][CH2:17]2)[CH2:11][C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH2:19]([NH2:21])[CH3:20]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]([CH2:15][CH:16]2[CH2:18][CH2:17]2)[CH2:11][C:12]([NH:21][CH2:19][CH3:20])=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CCN
Reactant: N#Cc1ccc(N(CC(=O)O)CC2CC2)cc1Cl
Product: CCNC(=O)CN(CC1CC1)c1ccc(C#N)c(Cl)c1

Procedure:
Synthesized in a manner similar to example 3 using N-(3-chloro-4-cyanophenyl)-N-(cyclopropylmethyl)glycine and ethylamine: MS (ES) m/z 292 (M+1).
Reaction SMILES: [ClH:1].Cl.[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:27][CH:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=1)[CH2:4][CH2:5][CH3:6].[C:35]([Cl:38])(=[O:37])[CH3:36].CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOCC>[ClH:38].[ClH:1].[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:27][CH:28]2[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]2)=[CH:11][C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24]([C:35](=[O:37])[CH3:36])[CH2:23][CH2:22]2)=[CH:17][CH:18]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CC(=O)Cl
Reactant: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OCC2CCNCC2)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OCC2CCN(C(C)=O)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-butyl-6-(1-methyl-piperidin-4-yloxy)-4-[4-(piperidin-4-ylmethoxy)-phenyl]-pyridazine dihydrochloride (0.2 mmol, 103 mg) in DCM (1 mL) at 0° C. was added acetyl chloride (0.4 mmol, 29 μL), DIEA (0.4 mmol, 70 μL) and DMAP (5 mg). The mixture was stirred at room temperature for 1 hour. The mixture was then condensed in vacuo and the residue was purified by silica gel chromatography (DCM to DCM+10% 2N NH3 in MeOH) to give a colorless sticky solid, which was dissolved in DCM (1.0 mL), 2N HCl in ether (1.0 mL) was added, kept at room temperature for 10 min, condensed, triturated with hexanes to provide the title compound. LCMS: m/z 482 [M+1]. 1H NMR (400 MHz, CD3OD): δ 7.63 and 7.75 (1H, s), 7.44-7.50 (2H, m), 7.12-7.17 (2H, m), 5.37-5.54 (1H, m), 4.37 (2H, d), 3.36-3.69 (3H, m), 3.08-3.30 (4H, m), 2.92 (3H, s), 2.11-2.74 (5H, m), 2.10 (3H, s), 1.86-2.08 (4H, m), 1.25-1.54 (7H, m), 0.82 (3H, t).
Reaction SMILES: [NH:1]([CH:19]1[CH2:24][C:23]([CH3:26])([CH3:25])[NH:22][C:21]([CH3:28])([CH3:27])[CH2:20]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]1.[CH2:29]([N:32]([CH2:49][CH:50]=[CH2:51])[C:33]1[N:38]=[C:37](Cl)[N:36]=[C:35]([NH:40][C:41]([CH2:44][C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:43])[CH3:42])[N:34]=1)[CH:30]=[CH2:31].[OH-].[Na+]>C1(C)C(C)=CC=CC=1>[CH3:25][C:23]1([CH3:26])[CH2:24][CH:19]([N:1]([C:37]2[N:38]=[C:33]([N:32]([CH2:49][CH:50]=[CH2:51])[CH2:29][CH:30]=[CH2:31])[N:34]=[C:35]([NH:40][C:41]([CH2:44][C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:43])[CH3:42])[N:36]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([C:37]2[N:38]=[C:33]([N:32]([CH2:49][CH:50]=[CH2:51])[CH2:29][CH:30]=[CH2:31])[N:34]=[C:35]([NH:40][C:41]([CH2:44][C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:43])[CH3:42])[N:36]=2)[CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:17])([CH3:18])[CH2:10]2)[CH2:20][C:21]([CH3:28])([CH3:27])[NH:22]1
Reactant: CC1(C)CC(NCCCCCCNC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Reactant: C=CCN(CC=C)c1nc(Cl)nc(NC(C)(C)CC(C)(C)C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: C=CCN(CC=C)c1nc(NC(C)(C)CC(C)(C)C)nc(N(CCCCCCN(c2nc(NC(C)(C)CC(C)(C)C)nc(N(CC=C)CC=C)n2)C2CC(C)(C)NC(C)(C)C2)C2CC(C)(C)NC(C)(C)C2)n1
Yield: 19.2 %

Procedure:
A stirred solution of 4,4'(hexamethylenediimino)bis(2,2,6,6-tetramethylpiperidine) (9.5 grams; 0.024 mole), 2-diallylamino-4-chloro-6-t-octylamino-1,3,5-triazine (16.0 grams; 0.048 mole), and powdered sodium hydroxide (2.0 grams; 0.05 mole) in xylene (150 mls) is heated at reflux for 24 hours while removing by-product water by means of a trap. The resulting mixture is then filtered and the filtrate is heated to evaporate the solvent and obtain a light tan oil which solidifies on triturating with petroleum ether. The solid is then recovered and dried to obtain 4.6 grams of the desired product, mp 113-115° C.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][C:32]=2[C:34](O)=[O:35])[CH:27]=[CH:26][CH:25]=1>>[Cl:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:34]([C:32]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:33]=2[N:24]=[CH:25][CH:26]=[CH:27]3)=[O:35])=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1cccc2cccnc12
Reactant: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c(-c2cccc(Cl)c2)s1
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc3cccnc23)c(-c2cccc(Cl)c2)s1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-[5-(3-chloro-phenyl)-2-methyl-thiazol-4-yl]-methanone with Quinoline-8-carboxylic acid. LC-MS (basic): tR=0.90 min; [M+H]+=503.3.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3].Cl.[N:24]1([CH2:30][C:31]2[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C(N1C2C(=CC(C#C[Si](C)(C)C)=CC=2)[C@H](NC(=O)OC(C)(C)C)C[C@@H]1C)(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)C.C1(C)C=CC=CC=1.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>[C:18]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:34]3[CH:33]=[CH:32][C:31]([CH2:30][N:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)=[CH:36][CH:35]=3)=[CH:13][CH:12]=2)[C@H:7]([NH:6][C:5](=[O:22])[O:4][CH:2]([CH3:3])[CH3:1])[CH2:8][C@@H:9]1[CH3:21])(=[O:20])[CH3:19]
Reactant: OB(O)c1ccc(CN2CCCCC2)cc1
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)N1c2ccc(C#C[Si](C)(C)C)cc2[C@H](NC(=O)OC(C)(C)C)C[C@@H]1C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(=O)N1c2ccc(-c3ccc(CN4CCCCC4)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 100 °C

Procedure:
1-Methylethyl[(2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Example 4) (50 mg, 0.135 mmol), [4-(1-piperidinylmethyl)phenyl]boronic acid hydrochloride (for a preparation see Intermediate 1) (45.0 mg, 0.176 mmol), potassium carbonate (43.0 mg, 0.311 mmol) and tetrakis(triphenylphosphine)palladium(0) (7.82 mg, 6.77 μmol) were suspended in a mixture of Ethanol (0.5 ml) and Toluene (0.5 ml) and heated under microwave conditions in an Emrys Optimiser at 100° C. for 3 hours. Further tetrakis(triphenylphosphine)palladium(0) (7.82 mg, 6.77 μmol) added and the mixture heated at 90° C. thermally for 23 hours. The mixture was cooled to room temperature, loaded on to a 2 g SCX cartridge, eluted with MeOH (25 ml), 2M methanolic ammonia (25 ml) and the basic fractions evaporated to dryness. The residue was loaded on to a 12+M Biotage silica column and eluted with a gradient of 0 to 4% methanloic ammonia in DCM. The clean, product containing fractions were evaporated to a white solid (10 mg).