Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][O:8][CH:9]([C:15]2[C:24]([CH3:25])=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]=2[OH:26])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1.C([O-])(O)=O.[Na+].[Br:34]Br.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][CH:9]([C:15]2[C:24]([CH3:25])=[C:23]([Br:34])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]=2[OH:26])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:27][CH:28]=1
Reactant: CCOC(=O)C(OCc1ccc(OC)cc1)c1c(C)cc2ccccc2c1O
Reactant: BrBr
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(OCc1ccc(OC)cc1)c1c(C)c(Br)c2ccccc2c1O
Reaction time: 0.25 h
Yield: 67.4 %

Procedure:
A solution of ethyl 2-(4-methoxybenzyloxy)-2-(1-hydroxy-3-methylnaphthalen-2-yl)acetate (102 mg, 0.268 mmol) in CHCl3 (5.0 mL) was treated with solid NaHCO3 (46 mg, 0.281 mmol). Br2 (45 mg) in CHCl3 (1.0 mL) was added dropwise over 5 min at 23° C. After 15 min, 10% Na2S2O3 (10 mL) was added. The reaction was extracted two times with CHCl3. Combined organic phases were dried (Na2SO4), filtered, and concentrated. The residue was dissolved in DCM. The solution was wet-loaded onto a 12 g “gold” ISCO silica gel column and purified by flash chromatography (ethyl acetate/hexanes) giving the desired product (83 mg, 67%). 1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.29 (d, J=8.2 Hz, 1H), 8.22 (d, J=8.6 Hz, 1H), 7.59 (dd, J=7.4, 7.4 Hz, 1H), 7.47 (dd, J=7.8, 7.8 Hz, 1H), 7.26 (d, J=8.2 Hz, 2H), 6.91 (d, J=8.6 Hz, 2H), 5.47 (s, 1H), 4.67-4.56 (m, 2H), 4.26-4.08 (m, 2H), 3.81 (s, 3H), 2.60 (s, 3H), 1.20 (t, J=7.1 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C:10]([C@@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH2:17][CH3:18])=O)N)=[N:6][CH:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC[N:40](CC)CC.ClC(Cl)(Cl)C(Cl)(Cl)Cl.N>C1COCC1.CO.C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:8]([C:10]([C@@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3[CH2:17][CH3:18])=[N:40][N:6]=2)[CH:7]=1
Reactant: CCN(CC)CC
Reactant: CCN1CCC[C@H]1C(=O)N(N)c1ccc(F)cn1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCN1CCC[C@H]1c1nnc2ccc(F)cn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.4 %

Procedure:
To a solution of Intermediate 61a (190 mg, 0.75 mmol), Ph3P (395 mg, 1.51 mmol) and Et3N (419 μL, 3.01 mmol) in THF (6.00 mL) at 0° C. was added hexachloroethane (357 mg, 1.51 mmol). The reaction was stirred at RT overnight then partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was dissolved in MeOH and loaded onto an SCX-2 cartridge, which was washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 0-10% [2M NH3 in MeOH] in DCM, gave the title compound (157 mg, 89%). LCMS (Method 2): Rt 0.28 min, m/z 235.2 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([F:16])[C:13]([F:15])=[CH:14][C:9]=2[N:8]=[C:7]1[C:17]1[C:18]([OH:23])=[N:19][CH:20]=[CH:21][CH:22]=1.[CH3:27][O:28][C:29](=[O:40])[CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38]Br)=[CH:34][CH:33]=1>>[CH3:27][O:28][C:29](=[O:40])[CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][O:23][C:18]2[C:17]([C:7]3[N:6]([CH2:5][C:4]4[CH:24]=[CH:25][CH:26]=[C:2]([Cl:1])[CH:3]=4)[C:10]4[CH:11]=[C:12]([F:16])[C:13]([F:15])=[CH:14][C:9]=4[N:8]=3)=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:34][CH:33]=1
Reactant: COC(=O)COc1ccc(CBr)cc1
Reactant: Oc1ncccc1-c1nc2cc(F)c(F)cc2n1Cc1cccc(Cl)c1
Product: COC(=O)COc1ccc(COc2ncccc2-c2nc3cc(F)c(F)cc3n2Cc2cccc(Cl)c2)cc1

Procedure:
The title compound was prepared in analogy to Example 5, intermediate a, from 3-[1-(3-chloro-benzyl)-5,6-difluoro-1H-benzoimidazol-2-yl]-pyridin-2-ol and (4-bromomethyl-phenoxy)-acetic acid methyl ester (CAS Reg. No. 104508-23-8). Colorless powder (67%). MS (Turbo Spray): m/z=550.1 (M+H).
Reaction SMILES: O.[C:2]1([CH:8]([N:10]2[CH2:15][CH2:14][CH2:13][C@H:12]([CH2:16][N:17]3[CH2:22][CH2:21][N:20](C(OCC4C=CC=CC=4)=O)[CH2:19][CH2:18]3)[CH2:11]2)[CH3:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].C(O)C>[C:2]1([CH:8]([N:10]2[CH2:15][CH2:14][CH2:13][C@H:12]([CH2:16][N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH2:11]2)[CH3:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(c1ccccc1)N1CCC[C@H](CN2CCN(C(=O)OCc3ccccc3)CC2)C1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: CC(c1ccccc1)N1CCC[C@H](CN2CCNCC2)C1
Reaction time: 8 h
Yield: 100.3 %

Procedure:
Water (5 ml), 10% palladium on carbon (900 mg) and ethanol (50 ml) were added to benzyl 4-{[(3R)-1-phenylethylpiperidin-3-yl]methyl}piperazine-1-carboxylate (950 mg) under an argon atmosphere. The mixture was stirred overnight under a hydrogen filled balloon. The catalyst was remove by filtration through celite and the filtrate concentrated in vacuo and azeotroped once with toluene to give 1-{[(3R)-1-phenylethylpiperidin-3-yl]methyl}piperazine as a yellow oil (650 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]1[N:11]2[CH:12]=[C:13]([O:16][C@H:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C@@H:20]([NH2:27])[CH2:19][CH2:18]3)[CH:14]=[CH:15][C:10]2=[N:9][N:8]=1.ClC(Cl)(Cl)C[O:31][C:32](=O)[NH:33][C:34]1[N:35]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([O:49][CH2:50][CH2:51][O:52][CH:53]3[CH2:58][CH2:57][CH2:56][CH2:55][O:54]3)[CH:44]=2)[N:36]=[C:37]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:38]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:39]([C:37]1[CH:38]=[C:34]([NH:33][C:32]([NH:27][C@@H:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:17]([O:16][C:13]3[CH:14]=[CH:15][C:10]4[N:11]([C:7]([C@@H:3]5[CH2:4][CH2:5][CH2:6][N:2]5[CH3:1])=[N:8][N:9]=4)[CH:12]=3)[CH2:18][CH2:19]2)=[O:31])[N:35]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([O:49][CH2:50][CH2:51][O:52][CH:53]3[CH2:58][CH2:57][CH2:56][CH2:55][O:54]3)[CH:44]=2)[N:36]=1)([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(OCCOC3CCCCO3)c2)n1
Reactant: CN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCOC5CCCCO5)c4)c4ccccc43)cn12
Temperature: 90 °C
Reaction time: 4.5 h
Yield: 76.2 %

Procedure:
A mixture of Intermediate 5c (150 mg, 0.410 mmol) and Intermediate 39b (230 mg, 0.430 mmol) in 1,4-dioxane (4 mL) and DIPEA (113 μL, 0.65 mmol) was stirred at 90° C. for 4.5 h. The mixture was concentrated in vacuo. The residue was purified by FCC twice, using 0-10% MeOH in DCM, to give the title compound as a pale yellow foam (234 mg, 76%). LCMS (Method 3): Rt 3.03 min, m/z 749.2 [MH+].
Reaction SMILES: [O:1]1[CH2:7][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH2:17])=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:5][O:4][CH2:3][CH2:2]1.[Cl:20][CH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1.O1CC(C2C3SC(NC(C4SC(C)=CC=4)=O)=NC=3C(OC)=CC=2)COCC1>>[Cl:20][CH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:17][C:14]2[S:15][C:16]3[C:8]([CH:6]4[CH2:5][O:4][CH2:3][CH2:2][O:1][CH2:7]4)=[CH:9][CH:10]=[C:11]([O:18][CH3:19])[C:12]=3[N:13]=2)=[O:27])=[CH:24][CH:23]=1
Reactant: O=C(O)c1ccc(CCl)cc1
Reactant: COc1ccc(C2COCCOC2)c2sc(N)nc12
Agent: COc1ccc(C2COCCOC2)c2sc(NC(=O)c3ccc(C)s3)nc12
Product: COc1ccc(C2COCCOC2)c2sc(NC(=O)c3ccc(CCl)cc3)nc12

Procedure:
Using 7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-ylamine and 4-chloromethyl-benzoic acid, the title compound was prepared in the same manner as described for 5-methyl-thiophene-2-carboxylic acid (7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-yl)-amide and obtained as light brown powder. MS: m/e=434(M+H+).
Reaction SMILES: [CH:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[O:9]=[CH:10][C:11]([Cl:14])([Cl:13])[Cl:12].[Cl-].[Al+3].[Cl-].[Cl-]>Cl>[CH:1]1([CH:10]([OH:9])[C:11]([Cl:14])([Cl:13])[Cl:12])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: C1=CCCCCCC1
Reactant: O=CC(Cl)(Cl)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: OC(C1C=CCCCCC1)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
A solution of cyclooctene (28 g; 254 m. moles) and chloral (36 g; 244 m. moles) in light petroleum (b.p. 80°-100° C.; 200 ml) was stirred and cooled and aluminum chloride (4 g; 30 m. moles) was added. The reaction was allowed to proceed for a period of 1 hour and was then stirred at room temperature for a further 31/2 hours. Ice (150 g) and concentrated hydrochloric acid (50 ml) was added, the mixture extracted with light petroleum (b.p. 40°-60° C.; 2×400 ml) and the combined extracts washed with saturated aqueous sodium carbonate (2×100 ml) and water (100 ml). The dried (Na2SO4) extract was evaporated to give crude 1-(2-cycloocten-1-yl)-2,2,2-trichloroethanol (61.4 g) as a brown oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.[NH:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[CH2:24][C@H:13]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[N:12]1([C:5]([C:4]2[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([OH:1])[CH:3]=2)=[O:7])[CH2:17][CH2:16][CH2:15][C@@H:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[CH2:24][C@H:13]12
Reactant: Cc1ccc(C(=O)O)cc1O
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1ccc(C(=O)N2CCC[C@@H]3c4ccccc4C[C@@H]32)cc1O
Yield: 45 %

Procedure:
The title compound is prepared from 3-hydroxy-4-methyl-benzoic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 45% of theory; LC (method 4): tR=1.98 min; Mass spectrum (ESI+): m/z=308 [M+H]+.
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]1[CH2:10][N:9]([C:11]([O:13]C(C)(C)C)=O)[C@H:8]([C:18]([OH:20])=O)[CH2:7]1)[CH:2]=[CH2:3].[CH3:21][N:22]([CH3:29])[CH2:23][CH2:24][CH2:25]C(Cl)=O.[C:30]1([CH2:40][NH2:41])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1>>[CH2:1]([O:4][N:5]=[C:6]1[CH2:10][N:9]([C:11](=[O:13])[CH2:25][CH2:24][CH2:23][N:22]([CH3:29])[CH3:21])[C@H:8]([C:18]([NH:41][CH2:40][C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=[CH:32][CH:31]=2)=[O:20])[CH2:7]1)[CH:2]=[CH2:3]
Reactant: NCc1cccc2ccccc12
Reactant: CN(C)CCCC(=O)Cl
Reactant: C=CCON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: C=CCON=C1C[C@@H](C(=O)NCc2cccc3ccccc23)N(C(=O)CCCN(C)C)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(allyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, 4-(dimethylamino)butanoyl chloride, and 1-naphthylmethylamine the title compound was obtained in 85% purity by LC/MS. MS(ESI+): m/z=437.2.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:24][C:25]4[C:26]([CH3:35])=[C:27]([CH:32]=[CH:33][CH:34]=4)[C:28]([O:30][CH3:31])=[O:29])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CCOC(C)=O.CO.[Pd]>[C:1]1([C:7]2[N:8]=[C:9]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]3[CH2:24][C:25]3[C:26]([CH3:35])=[C:27]([CH:32]=[CH:33][CH:34]=3)[C:28]([O:30][CH3:31])=[O:29])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1C
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(CC2CCCCC2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.5 %

Procedure:
To a solution of methyl 3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}-2-methylbenzoate (119 mg) in EtOAc (8 m1) and MeOH (10 ml) was added 10% Pd/C (wet) (60 mg) and the mixture was stirred under hydrogen atmosphere at 3 atm at room temperature for 18 hours. The catalyst was removed by filtration and the filtrate was evaporated to give methyl 3-{[2-(4,5-diphenyloxazol-2-yl)-1-cyclohexyl]methyl}-2-methyl-benzoate (115.3 mg) as an amorphous solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=3)=[CH:13][C:12]2=[O:26])=[CH:5][CH:4]=1.[NH:27]1[CH2:32][CH2:31][CH:30]([NH:33][C:34](=[O:36])[CH3:35])[CH2:29][CH2:28]1>>[CH3:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][O:17][C:14]2[CH:15]=[CH:16][N:11]([CH2:10][CH2:9][C:6]3[CH:7]=[CH:8][C:3]([CH2:2][N:27]4[CH2:32][CH2:31][CH:30]([NH:33][C:34](=[O:36])[CH3:35])[CH2:29][CH2:28]4)=[CH:4][CH:5]=3)[C:12](=[O:26])[CH:13]=2)=[N:20][CH:21]=1
Reactant: CC(=O)NC1CCNCC1
Reactant: Cc1ccc(COc2ccn(CCc3ccc(CBr)cc3)c(=O)c2)nc1
Product: CC(=O)NC1CCN(Cc2ccc(CCn3ccc(OCc4ccc(C)cn4)cc3=O)cc2)CC1

Procedure:
N-[1-(4-{2-[4-(5-Methyl-pyridin-2-ylmethoxy)-2-oxo-2H-pyridin-1-yl]-ethyl}-benzyl)-piperidin-4-yl]-acetamide is prepared as example 13.1c from 55 mg (0.13 mmol) 1-[2-(4-bromomethyl-phenyl)-ethyl]-4-(5-methyl-pyridin-2-ylmethoxy)-1H-pyridin-2-one (example 13.1b) and 76 mg (0.53 mmol) N-piperidin-4-yl-acetamide.
Reaction SMILES: [OH-:1].[K+].C([O:5][C:6]([N:8]1[CH2:17][CH:16]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])C.[CH2:29]([OH:32])[CH2:30][CH3:31]>O>[C:6]([OH:7])(=[O:5])/[CH:31]=[CH:30]\[C:29]([OH:1])=[O:32].[F:28][C:25]([F:26])([F:27])[C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[O:18][CH:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][NH:8][CH2:17]1
Reactant: CCOC(=O)N1Cc2ccccc2C(Oc2cccc(C(F)(F)F)c2)C1
Reactant: CCCO
Reactant: [OH-]
Agent: [K+]
Solvent: O
Product: FC(F)(F)c1cccc(OC2CNCc3ccccc32)c1
Product: O=C(O)/C=C\C(=O)O

Procedure:
To a solution of potassium hydroxide (14.0 g, 0.25 mole) in 14 ml water, is added a solution of 2-ethoxycarbonyl-1,2,3,4-tetrahydro-4-(m-trifluoromethylphenoxy) isoquinoline of Example 13 (11.5 g, 0.0315 mole) in 170 ml n-propanol, and the mixture is stirred at reflux for four hours. After cooling, the solvent is evaporated to a semi-solid, which is stirred with 500 ml water for fifteen minutes, then extracted with ether. The ether extract is washed twice with water, then dried (saturated NaCl, anhydrous MgSO4).
Reaction SMILES: Br[O:2][CH2:3][CH:4]([O:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:5][O:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[CH3:42][NH:43][CH3:44].C(OCC)(=O)C>C(Cl)(Cl)Cl.CCCCCC>[CH2:8]([O:7][O:6][CH2:5][CH:4]([CH2:3][O:2][N:43]([CH3:44])[CH3:42])[O:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CNC
Reactant: CCCCCCCCCCCCCCCCOOCC(COBr)OOCCCCCCCCCCCCCCCC
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCOOCC(CON(C)C)OOCCCCCCCCCCCCCCCC
Reaction time: 8 h

Procedure:
900 mg of 3-bromo-1,2-dihexadecyloxy glycerol was dissolved in 30 ml chloroform in a 100 ml round bottom flask. 720 mg dimethylamine was added to yield an approximately 10 fold molar excess, and the reaction mixture stirred at room-temperature overnight. The progress of the reaction was measured by thin-layer-chromatography (30% ethyl acetate in hexane).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:14]=[CH:15][CH:16]=3)[C:11]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[N:10][N:9]=2)[CH:5]=[N:6][CH:7]=1.N1C=CC=CC=1.[C:38](Cl)(=[O:40])[CH3:39]>ClCCl>[C:18]1([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:12]=2[C:11]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)=[N:10][N:9]=[C:8]3[C:4]2[CH:3]=[C:2]([NH:1][C:38](=[O:40])[CH3:39])[CH:7]=[N:6][CH:5]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1cncc(-c2nnc(NCc3ccccn3)c3c(-c4ccccc4)cccc23)c1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1cncc(-c2nnc(NCc3ccccn3)c3c(-c4ccccc4)cccc23)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 45.2 %

Procedure:
To a solution of 4-(5-aminopyridin-3-yl)-8-phenyl-N-(pyridin-2-ylmethyl) phthalazin-1-amine (50.0 mg, 0.124 mmol) in dichloromethane (5 mL) at ambient temperature was added pyridine (0.0200 mL, 0.247 mmol) followed by acetyl chloride (0.0132 mL, 0.185 mmol). After stirring for 5 h at room temperature, the reaction mixture was diluted with dichloromethane (50 mL) and the organic portion washed with water (10 mL) followed by brine (10 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (Condition 31 as described in general methods) to obtain N-(5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)phthalazin-1-yl)pyridin-3-yl)acetamide (25.0 mg, 45.3%) as a white solid. LCMS (Condition 4): retention time 2.08 min, [M+1]=447.2. HPLC (Condition 28): retention time=5.63 min, purity 94.65%. 1H NMR (400 MHz, CD3OD) δ 2.21 (s, 3 H), 4.65 (s, 2 H), 7.21-7.26 (m, 2 H), 7.49 (br s, 5 H), 7.69-7.73 (m, 2 H), 7.88-7.94 (m, 2 H), 8.28-8.30 (m, 1 H), 8.42 (dd, J=2.0 Hz, J=2.4 Hz, 1 H), 8.55 (d, J=2.0 Hz, 1 H), 8.90 (d, J=2.4 Hz, 1 H).
Reaction SMILES: C([C:3]1[CH:18]=[C:17]([C:19](=[NH:22])[NH:20][OH:21])[CH:16]=[C:15](C)[C:4]=1[O:5][CH2:6][C@@H:7]([OH:14])[CH2:8][NH:9][C:10](=[O:13])[CH2:11][OH:12])C.O[C:25]1C=CC(C#N)=C(C)C=1>>[OH:12][CH2:11][C:10]([NH:9][CH2:8][C@H:7]([OH:14])[CH2:6][O:5][C:4]1[CH:3]=[CH:18][C:17]([C:19](=[NH:22])[NH:20][OH:21])=[C:16]([CH3:25])[CH:15]=1)=[O:13]
Reactant: Cc1cc(O)ccc1C#N
Reactant: CCc1cc(C(=N)NO)cc(C)c1OC[C@@H](O)CNC(=O)CO
Product: Cc1cc(OC[C@@H](O)CNC(=O)CO)ccc1C(=N)NO

Procedure:
The title compound is obtained as a beige oil (1.0 g) in analogy to N—((S)-3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenoxy]-2-hydroxy-propyl)-2-hydroxy-acetamide starting from 4-hydroxy-2-methyl-benzonitrile; LC-MS: tR=0.35 min, [M+H]+=297.99.
Reaction SMILES: Br[C:2]1[N:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15](B2OC(C)(C)C(C)(C)O2)[N:14]=1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:12][C:13]1[N:14]=[C:15]([C:2]2[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][CH:9]=[CH:10][N:11]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: CC1(C)OB(c2cccc(Cl)n2)OC1(C)C
Reactant: COC(=O)c1cccnc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cccnc1-c1cccc(Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.49 g (0.70 mmol) of (Ph3P)2PdCl2 is added under argan to a solution of 3.0 g (13.9 mmol) of methyl 2-bromonicotinate in 10 ml of dioxane and the mixture is stirred for 30 min at room temperature. Thereafter, 3.33 g (13.78 mmol) of 2-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, 5.76 g (41.68 mmol) of K2CO3 and 11 ml of H2O are added in succession to the mixture, and the mixture is stirred for 6 hours under reflux and subsequently allowed to stand overnight at room temperature (RT). For work-up, the reaction mixture is poured into 150 ml of H2O and extracted repeatedly with CH2Cl2. The combined organic phases are dried over Na2SO4 and subsequently concentrated. The crude product thus obtained is purified by chromatography on silica gel using heptane/ethyl acetate (7:3) as the mobile phase. This gives 2.50 g (72%) of product as a colorless oil; 1H NMR (CDCl3) δ 8.70 (dd, 1H), 8.15 (dd, 1H), 7.95 (dd, 1H), 7.80 (dd, 1H), 7.40 (dd, 1H), 7.37 (dd, 1H), 3.90 (s, 3H, COOMe).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([OH:14])=O)[CH:7]=2)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.ClC(OC)=O.[N:32]1([CH2:37][C:38]2[CH:39]=[C:40]([CH:42]=[CH:43][CH:44]=2)[NH2:41])[CH:36]=[CH:35][N:34]=[CH:33]1>C(Cl)Cl>[CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:41][C:40]3[CH:42]=[CH:43][CH:44]=[C:38]([CH2:37][N:32]4[CH:36]=[CH:35][N:34]=[CH:33]4)[CH:39]=3)=[O:14])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Nc1cccc(Cn2ccnc2)c1
Reactant: CCCN(CC1CC1)c1cc(C(=O)O)ncn1
Agent: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2cccc(Cn3ccnc3)c2)ncn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A cooled (0° C.) solution of 6-(cyclopropylmethyl(propyl)amino)pyrimidine-4-carboxylic acid (Intermediate 21, 112 mg; 0.45 mmol) in DCM was treated with diisopropylethylamine (78.4 mL; 0.52 mmol) and methyl chloroformate (36.2 mL; 0.47 mmol). After stirring at 0° C. for 15 minutes, 3-(1H-imidazol-1-ylmethyl)aniline (Maybridge, 117 mg; 0.67 mmol) was added and the mixture stirred for 72 hours. The solvent was evaporated and the compound purified by preparative HPLC to give the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][C:14](=[O:18])[NH:15]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:19][N:20]([CH3:33])[CH2:21][CH2:22][CH2:23][C:24]1[C:25]([CH3:32])=[C:26]([CH:30]=O)[NH:27][C:28]=1[CH3:29]>>[CH3:33][N:20]([CH3:19])[CH2:21][CH2:22][CH2:23][C:24]1[C:25]([CH3:32])=[C:26]([CH:30]=[C:13]2[C:12]3[C:16](=[CH:17][C:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)=[CH:10][CH:11]=3)[NH:15][C:14]2=[O:18])[NH:27][C:28]=1[CH3:29]
Reactant: COc1ccc(-c2ccc3c(c2)NC(=O)C3)cc1
Reactant: Cc1[nH]c(C=O)c(C)c1CCCN(C)C
Product: COc1ccc(-c2ccc3c(c2)NC(=O)C3=Cc2[nH]c(C)c(CCCN(C)C)c2C)cc1
Yield: 77.5 %

Procedure:
6-(4-Methoxyphenyl)-1,3-dihydroindol-2-one (239 mg, 1.0 mmol) was condensed with 4-(3-dimethylaminopropyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (208 mg, 1.0 mmol) using method B to give 333 mg (83%) of 3-[4-(3-dimethylaminopropyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-6-(4-methoxyphenyl)-1,3-dihydroindol-2-one as a brown solid.