Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:2]1.[C:10]1([CH:16]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:17]2[CH2:20][C:19](=O)[CH2:18]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CO>C(O)(=O)C>[C:10]1([CH:16]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:17]2[CH2:20][CH:19]([N:1]3[CH2:6][CH2:5][CH:4]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:2]3)[CH2:18]2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: NC(=O)C1CCNCC1
Solvent: CO
Solvent: CC(=O)O
Product: NC(=O)C1CCN(C2CN(C(c3ccccc3)c3ccccc3)C2)CC1
Temperature: 120 °C
Yield: 99.5 %

Procedure:
To a mixture of piperidine-4-carboxamide (1.05 g, 8.2 mmol), 1-(diphenylmethyl)azetidin-3-one (see Bioorg. Med. Chem. Lett.; 13; 2003; 2191-2194, 1.94 g, 8.2 mmol), methanol (30 mL) and acetic acid (3 mL) was added (polystyrylmethyl)trimethylammonium cyanoborohydride (4.1 mmol/g, 1.9 g). The reaction mixture was heated for 5 min at 120° C. using microwave single node heating. The resin was filtered off and the solvent was removed by evaporation. There was obtained 2.85 g (99%) of 1-[1-(diphenylmethyl)azetidin-3-yl]piperidine-4-carboxamide. 1H NMR (500 MHz, CDCl3): 1.6-1.9 (m, 6H), 2.1-2.2 (m, 1H), 2.7-2.8 (d, 2H), 2.9-3.0 (m, 3H), 3.4 (t, 2H), 4.4 (s, 1H), 5.7-5.8 (b, 1H), 6.2 (b, 1H), 7.2 (t, 2H), 7.2-7.3 (t, 4H), 7.4 (d, 4H); LCMS: m/z 350 (M+1)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[CH:8]2)#[CH:2].[CH3:13][N:14]([CH2:16][C:17]1[N:18]([C:22]2[CH:23]=[C:24]([NH:32][C:33](=[O:42])[C:34]3[CH:39]=[CH:38][C:37]([CH3:40])=[C:36](I)[CH:35]=3)[CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=2)[CH:19]=[CH:20][N:21]=1)[CH3:15]>>[CH3:15][N:14]([CH2:16][C:17]1[N:18]([C:22]2[CH:23]=[C:24]([NH:32][C:33](=[O:42])[C:34]3[CH:35]=[CH:36][C:37]([CH3:40])=[C:38]([CH2:2][CH2:1][C:3]4[CH:4]=[N:5][CH:6]=[C:7]5[C:12]=4[N:11]=[CH:10][CH:9]=[CH:8]5)[CH:39]=3)[CH:25]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:27]=2)[CH:19]=[CH:20][N:21]=1)[CH3:13]
Reactant: C#Cc1cncc2cccnc12
Reactant: Cc1ccc(C(=O)Nc2cc(-n3ccnc3CN(C)C)cc(C(F)(F)F)c2)cc1I
Product: Cc1ccc(C(=O)Nc2cc(-n3ccnc3CN(C)C)cc(C(F)(F)F)c2)cc1CCc1cncc2cccnc12

Procedure:
The title compound can be synthesized from 8-ethynyl-1,6-naphthyridine and N-(3-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-iodo-4-methylbenzamide in a manner similar to that described for Example 1. 8-ethynyl-1,6-naphthyridine is prepared from 8-bromo-1,6-naphthyridine and ethynyltrimethylsilane according to the 2 steps procedure described in Example 1.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:18][NH2:19])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[N:6][CH:7]=1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH:25]=O.Cl>CCOCC.CCO>[F:1][C:2]1[C:3]([NH:18]/[N:19]=[CH:25]/[C:21]2[S:20][CH:24]=[CH:23][CH:22]=2)=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[N:6][CH:7]=1
Reactant: COc1cccc(COc2ncc(F)c(NN)n2)c1
Reactant: O=Cc1cccs1
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: COc1cccc(COc2ncc(F)c(N/N=C/c3cccs3)n2)c1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 76.7 %

Procedure:
A 20 mL vial was charged with 5-fluoro-4-hydrazinyl-2-(3-methoxybenzyloxy)-pyrimidine (74.7 mg, 0.283 mmol), EtOH (2 mL), thiophene-2-carbaldehyde (26 μL, 0.284 mmol) and 1 M HCl in Et2O (14 μL, 0.014 mmol) and heated at 50° C. on shaker. After 90 minutes, the reaction was cooled to room temperature concentrated on high vacuum to provide the title compound (77.8 mg, 77%) as a yellow solid: mp 136-139° C.; 1H NMR (300 MHz, DMSO-d6) δ 11.46 (bs, 1H), 8.50 (bs, 1H), 8.16 (d, J=3.6 Hz, 1H), 7.64 (d, J=5.0 Hz, 1H), 7.41 (d, J=3.4 Hz, 1H), 7.28 (t, J=8.0 Hz, 1H), 7.12 (dd, J=3.8, 4.8 Hz, 1H), 7.04 (m, 2H), 6.88 (dd, J=2.4, 8.3 Hz, 1H), 5.27 (s, 2H), 3.73 (s, 3H); MS (ESI) m/z 359.2 (M+H)+, 357.2 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[NH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2ccc(Br)cc2)nc2cccnc21
Reactant: NCCN1CCCCC1
Solvent: C1CCOC1
Product: O=C(Cn1c(-c2ccc(Br)cc2)nc2cccnc21)NCCN1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.8 %

Procedure:
A suspension of 2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (6.0 g, 0.018 mole), 1,1'-carbondiimidazole (2.9 g, 0.018 mole) and anhydrous tetrahydrofuran (100 ml) was stirred at room temperature with a stream of nitrogen bubbling through for 3 hours. The nitrogen flow was stopped and a solution of 1-(2-aminoethyl)piperdine (2.3 g, 0.018 mole) in dry tetrahydrofuran (25 ml) was added. The solution was stirred at room temperature under nitrogen for 2 hours. The reaction mixture was concentrated in vacuo and the residue triturated in potassium bicarbonate solution (100 ml) and filtered. The filter cake was washed with water and recrystallized from isopropyl alcohol-isopropyl ether to give 5.8 g (73%) of off-white needles, mp 178°-179° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:14][C:15]([NH2:17])=[S:16])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]1.Br[CH:19]1[C:24](=O)[CH:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])[CH2:22][CH2:21][CH2:20]1>>[Cl:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH:23]1[C:22]2[N:17]=[C:15]([NH:14][C:4]3[CH:5]=[CH:6][C:7]([N:8]4[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]4)=[C:2]([F:1])[CH:3]=3)[S:16][C:21]=2[CH2:20][CH2:19][CH2:24]1
Reactant: O=C1C(Br)CCCC1c1ccccc1Cl
Reactant: Cc1cn(-c2ccc(NC(N)=S)cc2F)cn1
Product: Cc1cn(-c2ccc(Nc3nc4c(s3)CCCC4c3ccccc3Cl)cc2F)cn1

Procedure:
The title compound was prepared from [3-fluoro-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (45 mg, 0.18 mmol) and 6-bromo-2-(2-chloro-phenyl)-cyclohexanone (145 mg, ca. 0.5 mmol) using in analogous manner the procedure described in example 1b). Obtained as a light-brown solid (68 mg, 76%). MS ISP (m/e): 439.1 [(M+H)+]. mp 204-206° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH2:34][OH:35])([CH2:32][OH:33])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[C:13]([C:28]([F:31])([F:30])[F:29])[CH:12]=1)(C)(C)C.[ClH:37].O1CCOCC1>C(Cl)Cl>[ClH:37].[NH2:7][C:8]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[C:13]([C:28]([F:29])([F:30])[F:31])[CH:12]=1)([CH2:32][OH:33])[CH2:34][OH:35]
Reactant: CC(C)(C)OC(=O)NC(CO)(CO)CCc1ccc(OCCCCC2CCCCC2)c(C(F)(F)F)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC(CO)(CO)CCc1ccc(OCCCCC2CCCCC2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Compound 3-8 (520 mg) was dissolved in methylene chloride (5 ml), hydrogen chloride-containing dioxane (4 mol/l 5 ml) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (410 mg) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[C:11]1(=O)[O:17][C:15](=[O:16])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]2[CH2:12]1>O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:8]2[C:11](=[O:17])[CH2:12][C:13]3[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:15]2=[O:16])=[CH:5][CH:4]=1
Reactant: O=C1Cc2ccccc2C(=O)O1
Reactant: COc1ccc(CN)cc1
Solvent: O
Product: COc1ccc(CN2C(=O)Cc3ccccc3C2=O)cc1
Temperature: 180 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
4-Methoxybenzylamine (8.3 g) was added to homophthalic anhydride (8.1 g). The mixture was stirred at 180° C. overnight. Water was added to the reaction solution. The mixture was then extracted with ethyl acetate. The organic layer was then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=8:2) to give 2-(4-methoxybenzyl)-4H-isoquinoline-1,3-dione (11.8 g).
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:13]([O:17][C:18](=[O:32])[C:19]1[CH:24]=[CH:23][C:22]([NH:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:21][CH:20]=1)([CH3:16])([CH3:15])[CH3:14]>C(O)CCCC>[C:13]([O:17][C:18](=[O:32])[C:19]1[CH:24]=[CH:23][C:22]([NH:25][CH:26]2[CH2:31][CH2:30][N:29]([C:2]3[NH:6][C:5]4[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:4]=4[N:3]=3)[CH2:28][CH2:27]2)=[CH:21][CH:20]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: COc1ccc2nc(Cl)[nH]c2c1
Reactant: CC(C)(C)OC(=O)c1ccc(NC2CCNCC2)cc1
Solvent: CCCCCO
Product: COc1ccc2[nH]c(N3CCC(Nc4ccc(C(=O)OC(C)(C)C)cc4)CC3)nc2c1
Temperature: 120 °C
Yield: 82.1 %

Procedure:
2-Chloro-5-methoxybenzimidazole (0.089 g, 0.49 mmol) was added to a solution of (49) (0.14 g, 0.5 mmol) in n-pentanol (3 mL) at 25° C. The mixture was heated to 120° C. and was maintained at that temperature for 12 h. The reaction mixture was cooled to room temperature and the desired product was filtered and rinsed with acetone to give 0.17 g (83.3%) of the title compound: TLC (Rf =0.30; 5% MeOH/CH2Cl2); 1H NMR (DMSO) δ 13.40 (br s, 1H), 7.63 (d, 2H, J=8.3), 7.29 (d, 1H, J=8.7), 6.91 (s, 1H), 6.83 (d, 1H, J=8.4), 6.65 (d, 2H, J=8.3), 6.50 (s, 1H), 4.13 (d, 2H, J=12.7), 3.77 (s, 3H), 3.73 (m, 1H), 3.47 (m, 4H), 2.06 (d, 2H, J=11.0), 1.48 (s, 9H); 13C NMR (DMSO) δ 165.2, 156.1, 151.3, 149.8, 131.0, 130.9, 124.0, 117.8, 111.8, 111.3, 110.2, 96.4, 79.0, 55.7, 47.3, 45.6, 30.2, 30.0; HRMS (FAB) m/z 423.2388 (M+H)+ (C24H30N4O3 requires 423.2389); Anal. (C24H30N4O3 ·1HCl·1/2H2O) C, H, N.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:8][CH:9]=1)(=O)[CH3:2].Cl.[NH2:19][O:20][CH2:21][CH2:22][O:23][C:24]1[CH:37]=[CH:36][C:27]([CH2:28][CH:29]2[S:33][C:32](=[O:34])[NH:31][C:30]2=[O:35])=[CH:26][CH:25]=1>>[CH2:11]([O:10][C:7]1[CH:6]=[CH:5][C:4]([C:1](=[N:19][O:20][CH2:21][CH2:22][O:23][C:24]2[CH:25]=[CH:26][C:27]([CH2:28][CH:29]3[S:33][C:32](=[O:34])[NH:31][C:30]3=[O:35])=[CH:36][CH:37]=2)[CH3:2])=[CH:9][N:8]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)nc1
Reactant: NOCCOc1ccc(CC2SC(=O)NC2=O)cc1
Agent: Cl
Product: CC(=NOCCOc1ccc(CC2SC(=O)NC2=O)cc1)c1ccc(OCc2ccccc2)nc1
Yield: 78 %

Procedure:
Following a procedure similar to that described in Example 40(f), 130 mg of 5-acetyl-2-benzyloxypyridine were reacted with 182 mg of 5-[4-(2-aminooxyethoxy)-benzyl]thiazolidine-2,4-dione hydrochloride [prepared as described in Example 40(e)]. The reaction mixture was concentrated by evaporation under reduced pressure, and the resulting residue was extracted with ethyl acetate. The extract was washed with water and the solvent was removed by distillation under reduced pressure, to give 219 mg of the title compound, melting at 160°-161° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:42])[C@@H:4]([NH:32][C@H:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:34][CH3:35])[CH2:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@H:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)=[CH:16][CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1.C=O.F[C:46](F)(F)C(O)=O>O1CCOCC1.CCOC(C)=O>[CH3:1][O:2][C:3]([C@@H:4]1[CH2:5][C:6]2[CH:7]=[C:8]3[O:13][CH2:12][C@@H:11]([C:14]4[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]5[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=5)=[CH:18][CH:19]=4)[O:10][C:9]3=[CH:30][C:31]=2[CH2:46][N:32]1[C@H:33]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[CH2:34][CH3:35])=[O:42]
Reactant: O=C(O)C(F)(F)F
Reactant: CC[C@H](N[C@@H](Cc1ccc2c(c1)OC[C@@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2)C(=O)OC)c1ccccc1
Agent: C=O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)OC)OC[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Temperature: 25 °C
Reaction time: 20 h

Procedure:
(S)-3-{(R)-2-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-2-((S)-1-phenyl-propylamino)-propionic acid methyl ester (1.0 g) was dissolved in 37 mL dry dioxane and 149 mg paraformaldehyde added. 30 mL dry dioxane and 17 mL trifluoroacetic acid were mixed, cooled on ice and added to the reaction mixture. The reaction was stirred for 20 hours at room temperature and diluted with EtOAc. The oranic layer was washed with 10% sodium, dried over Na2SO4 and evaporated. The residue was purified by silica gel flash chromatography (DCM+0.2% TEA) to give 934 mg of product after drying. 1H NMR (400 MHz, acetone-d6): 7.71 (d, 1H), 7.61 (d, 1H), 7.50-7.41 (m, 3H), 7.38-7.26 (m, 5H), 7.09 (m, 2H), 6.67 (s, 1H), 6.60 (s, 1H), 5.19 (s, 2H), 5.10 (m, 1H), 4.32 (m, 1H), 4.12 (m, 2H), 4.01 (m, 1H), 3.92 (m, 1H), 3.59 (m, 1H), 3.51 (s, 3H), 2.97-2.78 (m, 2H), 2.16 (m, 1H), 1.68 (m, 1H), 0.66 (t, 3H).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13].C(N(C(C)C)C(C)C)C>ClCCl>[C:12]([NH:16][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([CH2:2][Cl:1])[CH:4]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)N
Reactant: O=C(Cl)c1cccc(CCl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)NC(=O)c1cccc(CCl)c1
Temperature: -15 °C
Reaction time: 0.17 h

Procedure:
3-(Chloromethyl)benzoyl chloride (2.26 ml, 15.9 mmol) was added to a stirred solution of dichloromethane (50 mL) at −30° C. (cold-bath temperature) under argon. After 10 minutes stirring, a solution of tert-butylamine (1.66 mL, 15.9 mmol) and N-ethyl-N-isopropylpropan-2-amine (5.53 mL, 31.7 mmol) in dichloromethane (5 mL) was added dropwise. Stirring was continued while allowing the cold-bath temperature to slowly increase to −15° C. over 45 minutes. The reaction mixture was concentrated under vacuum to give the intermediate N-tert-butyl-3-(chloromethyl)benzamide as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:34]2[CH:39]=[CH:38][C:37]([O:40]CC3C=CC=CC=3)=[CH:36][CH:35]=2)=[C:4]([O:22][C:23]2[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32])=[CH:25][CH:24]=2)[C:5]2[C:10]([C:11]=1[O:12][CH3:13])=[CH:9][C:8]([O:14]CC1C=CC=CC=1)=[CH:7][CH:6]=2>C(Cl)(Cl)Cl.CO>[OH:14][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[C:4]([O:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:27][CH:28]=1)=[C:3]([C:34]1[CH:35]=[CH:36][C:37]([OH:40])=[CH:38][CH:39]=1)[C:2]([CH3:1])=[C:11]2[O:12][CH3:13]
Reactant: COc1c(C)c(-c2ccc(OCc3ccccc3)cc2)c(Oc2ccc(/C=C/C(=O)O)cc2)c2ccc(OCc3ccccc3)cc12
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1c(C)c(-c2ccc(O)cc2)c(Oc2ccc(CCC(=O)O)cc2)c2ccc(O)cc12

Procedure:
Synthesized in manner similar to that employed for Example 46 (Step 8) using (2E)-3-{4-[(3-methyl-4-(methyloxy)-6-[(phenylmethyl)oxy]-2-{4-[(phenylmethyl)oxy]phenyl}-1-naphthalenyl)oxy]phenyl}-2-propenoic acid (258). 1H NMR (CD3OD, 400 MHz) δ 7.61 (d, J=9.1 Hz, 1H), 7.35 (d, J=2.4 Hz, 1H), 6.94-6.89 (m, 5H), 6.66 (d, J=8.4 Hz, 2H), 6.42 (d, J=8.4 Hz, 2H), 3.88 (s, 3H), 2.77-2.73 (m, 2H), 2.38 (bs, 2H), 2.12 (s, 3H). LRMS (ES−) m/z 443 (M−1)−. TLC (90:10; CHCl3/MeOH): Rf=0.07.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:19]2[N:23]=[C:22]([C:24](OCC)=[O:25])[O:21][N:20]=2)[CH:5]=[C:6]([Cl:18])[C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1.[OH:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH2:35])=[CH:32][CH:31]=1>CCO>[Cl:18][C:6]1[CH:5]=[C:4]([C:19]2[N:23]=[C:22]([C:24]([NH:35][CH2:34][C:33]3[CH:36]=[CH:37][C:30]([OH:29])=[CH:31][CH:32]=3)=[O:25])[O:21][N:20]=2)[CH:3]=[C:2]([Cl:1])[C:7]=1[O:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=1
Reactant: NCc1ccc(O)cc1
Reactant: CCOC(=O)c1nc(-c2cc(Cl)c(OCc3ccc(OC)cc3)c(Cl)c2)no1
Solvent: CCO
Product: COc1ccc(COc2c(Cl)cc(-c3noc(C(=O)NCc4ccc(O)cc4)n3)cc2Cl)cc1
Temperature: 25 °C
Yield: 87.9 %

Procedure:
Ethyl 3-(3,5-dichloro-4-(4-methoxybenzyloxy)phenyl)-1,2,4-oxadiazole-5-carboxylate (4 g, 9.46 mmol) and 4-hydroxybenzylamine (2.33 g, 18.91 mmol) were heated in EtOH (150 mL) at 80° C. forming a yellow solution. After 1 h a colourless precipitate formed and the mixture was cooled to room temperature. The solid was filtered off, washed with EtOH and dried in a vacuum oven giving the title compound (4.16 g, 8.32 mmol, 88%) as a colourless solid. 1H NMR δ (ppm) (DMSO-d6): 3.81 (2H, s), 4.41 (2H, d, J=6.08 Hz), 5.12 (2H, s), 6.76 (2H, d, J=8.08 Hz), 7.00 (2H, d, J=8.20 Hz), 7.20 (2H, d, J=8.06 Hz), 7.49 (2H, d, J=8.18 Hz), 8.13 (2H, s), 9.38 (1H, s), 9.95 (1H, t, J=6.15 Hz). LCMS (10 cm_esci_AmmBicarb_MeCN) tR 4.18 min; m/z 498 [M]−.
Reaction SMILES: [OH:1][N:2]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][C:12]3[C:13]2=[C:4]([CH:5]=[C:6]2[C:11]=3[CH2:10][O:9]C[O:7]2)[C:3]1=[O:20].BrBr.O>O1CCOCC1>[OH:1][N:2]1[C:3](=[O:20])[C:4]2[CH:5]=[C:6]([OH:7])[C:11]([CH:10]=[O:9])=[C:12]3[C:13]=2[C:14](=[CH:17][CH:18]=[CH:19]3)[C:15]1=[O:16]
Reactant: O=C1c2cccc3c4c(cc(c23)C(=O)N1O)OCOC4
Agent: BrBr
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1c(O)cc2c3c(cccc13)C(=O)N(O)C2=O
Yield: 84.8 %

Procedure:
To a suspension of 360 mg (1.33 mmol) of 5-hydroxy-11H-8,10-dioxa-5-aza-benzo[de]anthracene-4,6-dione (from Example 45) in 20 mL dioxane was added 0.36 mL (6.98 mmol) of bromine. The reaction mixture was refluxed for 1 hour and poured into 150 mL water. The precipitate was isolated and dried to yield 290 mg of the title compound, mp 237-253° C. (dec.)
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH2:8])[CH:2]=1.C([O-])(O)=O.[Na+].[C:20](Cl)(=[O:22])[CH3:21]>C(Cl)Cl>[C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:20](=[O:22])[CH3:21])[CH:2]=1
Reactant: CC(=O)Cl
Reactant: NCc1cccc(-c2ccccc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)NCc1cccc(-c2ccccc2)c1
Reaction time: 0.75 h
Yield: 128.5 %

Procedure:
C-Biphenyl-3-yl-methylamine (700 mg, 3.8 mmol) was dissolved in 38 mL of CH2Cl2. To this was added 38 mL of satd NaHCO3 (aq) followed by acetyl chloride (1.41 mL 19,8 mmol). The resulting mixture was stirred 45 min. The organic layer was separated, washed with satd NaCl, dried over Na2SO4, filtered and solvent removed under vacuum to yield 1.1 grams of N-biphenyl-3-ylmethyl-acetamide.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21][NH2:22])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24]>C(#N)C>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:15]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:21][NH:22][C:23]2=[O:24])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NCc1ccccc1NC1CCN(Cc2ccccc2)CC1
Solvent: CC#N
Product: O=C1NCc2ccccc2N1C1CCN(Cc2ccccc2)CC1
Yield: 48.7 %

Procedure:
In this reference example, to the mixture of 23.0 g of 1-benzyl-4-[N-(o-aminomethylphenyl)-amino]-piperidine and 200 ml of acetonitrile, 17.4 g of 1,1'-carbonyldiimidazole is added over a period of 3 hours with stirring at 40° to 60° C. Then, the resultant mixture is refluxed with heating for one hour, brought back to room temperature and stirred at room temperature for 2 hours. The crystals deposited are separated by filtration, successively washed with water and methanol and dried to obtain 16.8 g of a crude product. The crude product is recrystallized from methanol to obtain 12.18 g of the desired product.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:19](=[O:21])[CH3:20])=[C:6]([CH3:18])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=2[CH3:17])[C:8]=1[CH3:9])(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:29][CH2:30][F:31]>>[C:1]([C:4]1[C:5]([C:19](=[O:21])[CH3:20])=[C:6]([CH3:18])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:29][CH2:30][F:31])=[CH:12][C:11]=2[CH3:17])[C:8]=1[CH3:9])(=[O:3])[CH3:2]
Reactant: FCCBr
Reactant: CC(=O)c1c(C(C)=O)c(C)n(-c2ccc(O)cc2C)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)c1c(C(C)=O)c(C)n(-c2ccc(OCCF)cc2C)c1C

Procedure:
As outlined in Example 65, 1-[4-acetyl-1-(4-hydroxy-2-methyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone (20 mg) reacted with 1-bromo-2-fluoro ethane (50 μL), in the presence of K2CO3 powder (50 mg), to afford 1-{4-acetyl-1-[4-(2-fluoro-ethoxy)-2-methyl-phenyl]-2,5-dimethyl-1H-pyrrol-3-yl}-ethanone: MS (ESI) 332 (M+H)+. Utilizing the general procedure outlined in Example 48, 1-[4-acetyl-1-(4-ethoxy-2-methyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone and hydrazine reacted to give 6-[4-(2-fluoro-ethoxy)-2-methyl-phenyl]-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine as light yellow solid: 1H NMR (CDCl3, 500 MHz) δ 7.06 (d, 1H), 6.94 (s, 1H), 6.90 (m, 1H), 4.12 (q, 2H), 2.81 (s, 6H), 2.38 (s, 6H), 1.80 (s, 3H), 1.50 (t, 3H); MS (ESI) 310 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15](F)[C:14]=2[N+:20]([O-:22])=[O:21])[CH:3]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)[NH2:32])=[CH:27][CH:26]=1.C(N(C(C)C)C(C)C)C>CN1CCCC1=O>[CH3:40][O:39][C:36]1[CH:35]=[CH:34][C:33]([CH:31]([NH:32][C:15]2[C:14]([N+:20]([O-:22])=[O:21])=[C:13]([CH:18]=[CH:17][CH:16]=2)[O:12][C:4]2[CH:3]=[C:2]([F:1])[CH:11]=[CH:10][C:5]=2[C:6]([O:8][CH3:9])=[O:7])[C:28]2[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)=[CH:38][CH:37]=1
Reactant: COc1ccc(C(N)c2ccc(OC)cc2)cc1
Reactant: COC(=O)c1ccc(F)cc1Oc1cccc(F)c1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(F)cc1Oc1cccc(NC(c2ccc(OC)cc2)c2ccc(OC)cc2)c1[N+](=O)[O-]

Procedure:
A solution of EXAMPLE 368A (1.33 g), bis(4-methoxyphenyl)methanamine (1.046 g) and N-ethyl-N-isopropylpropan-2-amine (1.127 ml) in anhydrous 1-methyl-2-pyrrolidinone (20 mL) was stirred at 120° C. overnight. The mixture was concentrated and the residue was taken up in water (100 mL) and extracted with dichloromethane. The residue was absorbed on silica and purified by chromatography on a silica gel column, eluting with 25% ethyl acetate in hexane to provide the title compound.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:12]3[C@@H:21]4[C@@H:16]([C:17]5[CH:25]=[CH:24][C:23]([C:26]([OH:28])=O)=[CH:22][C:18]=5[CH2:19][CH2:20]4)[CH2:15][CH2:14][CH2:13]3)=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH3:29]>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:12]3[C@@H:21]4[C@@H:16]([C:17]5[CH:25]=[CH:24][C:23]([C:26]([NH2:29])=[O:28])=[CH:22][C:18]=5[CH2:19][CH2:20]4)[CH2:15][CH2:14][CH2:13]3)=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: N
Reactant: O=C(O)c1ccc2c(c1)CC[C@H]1[C@@H]2CCCN1C(=O)c1ccc2[nH]cnc2c1
Product: NC(=O)c1ccc2c(c1)CC[C@H]1[C@@H]2CCCN1C(=O)c1ccc2[nH]cnc2c1
Yield: 58 %

Procedure:
The title compound is prepared from cis-4-(1H-benzoimidazole-5-carbonyl)-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline-8-carboxylic acid and ammonia (28% in water) following a procedure analogous to that described in Example 1. Yield: 58% of theory; LC (method 1): tR=1.78 min; Mass spectrum (ESI+): m/z=375 [M+H]+.