Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([CH3:11])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[N:33]=[C:32]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:30][CH:29]=2)[CH2:24][CH2:23]1>>[C:35]([NH:34][C:32]1[N:33]=[C:28]([CH:25]2[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][CH2:19][NH:18][C:8](=[O:10])[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH3:11])[CH2:23][CH2:24]2)[CH:29]=[CH:30][CH:31]=1)(=[O:39])[CH:36]([CH3:38])[CH3:37]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)n1
Reactant: CC(C(=O)O)(c1ccccc1)c1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C(C)(c3ccccc3)c3ccccc3)CC2)n1

Procedure:
Example 83 was prepared from 2,2-diphenylpropanoic acid and N-{6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 8.05 (d, 1H, J=8.0 Hz), 7.80 (s, 1H), 7.63 (t, 1H, J=7.6 Hz), 7.35–7.24 (m, 10H), 6.85 (d, 1H, J=8.0 Hz), 6.26 (t, 1H, J=4.8 Hz), 3.38 (dd, 2H, J=6.4,12.4 Hz), 2.92–2.89 (m, 2H), 2.55–2.48 (m, 2H), 2.32 (t, 2H, J=6.8 Hz), 2.00 (s, 3H), 1.96 (t, 2H, J=11.2 Hz), 1.79 (d, 2H, J=11.6 Hz), 1.72–1.61 (m, 4H), 1.27 (d, 6H, 6.8 Hz); ESMS m/e: 513.3 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([O:13][CH3:14])[CH2:10][C@H:9]1[CH2:15][O:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:14][O:13][C@@H:11]1[CH2:12][NH:8][C@H:9]([CH2:15][O:16][C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=2)[CH2:10]1
Reactant: COC(=O)c1ccc(OC[C@@H]2C[C@H](OC)CN2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(OC[C@@H]2C[C@H](OC)CN2)cc1
Reaction time: 14 h
Yield: 99.2 %

Procedure:
To a stirred solution of methyl 4-[(2S,4S)-1-tert-butoxycarbonyl-4-methoxy-2-pyrrolidinyl]methoxybenzoate (2.38 g, 3.61 mmol) in CH2Cl2 (46 ml) was added TFA (23 ml) at room temperature. After 14 h stirring, the mixture was concentrated in vacuo. The residue was diluted by the addition of CH2Cl2 and 1 N NaOH, and extracted with CH2Cl2. The combined extracts were washed with brine, dried over Na2SO4, which was concentrated in vacuo. The residue was chromatographed on silica gel [50 g, CHCl3/MeOH (20/1)], to give methyl 4-[(2S,4S)-4-methoxy-2-pyrrolidinyl]methoxybenzoate (950 mg, 99%) as a yellow oil. 1H-NMR (CDCl3) δ 2.16 (t, J=5.3 Hz, 1H), 2.72 (s, 1H), 2.95 (d, J=6.8 Hz, 1H), 3.11 (d, J=11.0 Hz, 1H), 3.26 (t, J=1.9 Hz, 3H), 3.52 (br, 1H), 3.84 (d, J=1.7 Hz, 3H), 3.92 (s, 1H), 4.00 (d, J=4.1 Hz, 2H), 6.88 (m, 2H), 7.94 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:25](=[O:37])[NH:26][CH2:27][C:28]2[C:29](=[O:36])[NH:30][C:31]([CH3:35])=[CH:32][C:33]=2[CH3:34])[C:5]([CH3:24])=[C:6]([N:8]([CH2:22][CH3:23])[CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH:7]=1.Cl.O.C(Cl)Cl>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:22][CH3:23])[CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[C:5]([CH3:24])=[C:4]([CH:3]=1)[C:25]([NH:26][CH2:27][C:28]1[C:29](=[O:36])[NH:30][C:31]([CH3:35])=[CH:32][C:33]=1[CH3:34])=[O:37]
Reactant: CCN(c1cc(Cl)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CCN(c1cc(Cl)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCNCC1
Yield: 93.7 %

Procedure:
To a solution of tert-butyl 4-[(5-chloro-3-{[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]carbamoyl}-2-methylphenyl)(ethyl)amino]piperidine-1-carboxylate (140 mg, 0.26 mmol) in 1,4-dioxane (5 ml) at room temperature was added HCl (4M in dioxane) (1.32 ml). A gum formed after stirring for a short time which then dissolved upon the addition of deionized water (2 ml). The reaction was stirred for 21 h before being concentrated under reduced pressure to give a thick oil. DCM (3 ml) was added and a solid formed. This mixture was concentrated to give 105 mg of a yellow solid which was stirred in DCM (10 ml) for 1 hour before being filtered and dried under high vacuum in a vacuum oven for 24 hours. The sample was then dissolved in deionized water (0.2 ml) and lyophilized to give 86 mg (70%) of the title compound as a beige solid. LC-MS 100%, m/z=431.2/433.2, 1H NMR (500 MHz, Chloroform-d) δ ppm 7.44 (bs, 1H), 7.26 (bs, 1H), 6.69 (bs, 1H), 4.55 (s, 2H), 3.53-3.34 (m, 3H), 3.28-3.08 (m, 2H), 3.01 (t, J=11.8 Hz, 2H), 2.51 (s, 3H), 2.43 (s, 3H), 2.33 (s, 3H), 2.16-1.96 (m, 2H), 1.91-1.76 (m, 2H), 0.92 (t, J=6.9 Hz, 3H).
Reaction SMILES: C([N:8]1[C:11]2([CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H].[C:24]([OH:29])(=[O:28])[C:25]([OH:27])=[O:26]>CO.C(OCC)C.C(O)C.[Pd]>[C:24]([O-:29])(=[O:28])[C:25]([O-:27])=[O:26].[C:18]([O:17][C:15]([N:13]1[CH2:12][C:11]2([NH2+:8][CH2:9][CH2:10]2)[CH2:14]1)=[O:16])([CH3:21])([CH3:19])[CH3:20].[C:18]([O:17][C:15]([N:13]1[CH2:12][C:11]2([NH2+:8][CH2:9][CH2:10]2)[CH2:14]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CC2(CCN2Cc2ccccc2)C1
Reactant: O=C(O)C(=O)O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOCC
Solvent: CCO
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC2(CC[NH2+]2)C1
Product: O=C([O-])C(=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.2 %

Procedure:
tert-Butyl 1-benzyl-1,6-diazaspiro[3.3]heptane-6-carboxylate (1.79 g, 6.21 mmol) was dissolved in methanol (33 mL), and Pd (10% on charcoal; 628 mg, 590 μmol) was added. A hydrogen atmosphere (balloon) was built up, and the mixture was stirred at ambient temperature for 24 h. Further Pd (10% on charcoal; 100 mg, 94 μmol, 0.015 equiv) was added and stirring under an hydrogen atmosphere was continued for another 24 h. The crude suspension was filtered over celite and the filter cake thoroughly washed with methanol, and the filtrate was concentrated under reduced pressure. To a solution of the residue in diethylether (140 mL) was added a solution of anhydrous oxalic acid (279 mg, 3.1 mmol) in ethanol (0.6 mL), upon which a precipitate formed immediately. The solid was filtered and dried under reduced pressure to give the title compound (1.18 g, 78%) as an amorphous colorless solid. MS (EI) m/e: 199.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:8]([CH:9]=[C:10]3[C:15]=1[N:14]=[C:13]([C:16]1[N:17]([C:25]4[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][N:26]=4)[N:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[O:12][C:11]3=[O:32])=[N:7][C:6]([CH3:33])=[C:5]([CH3:34])[N:4]=2.[CH3:35][NH2:36]>>[CH3:35][NH:36][C:11]([C:10]1[CH:9]=[C:8]2[C:3](=[C:2]([Cl:1])[C:15]=1[NH:14][C:13]([C:16]1[N:17]([C:25]3[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][N:26]=3)[N:18]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:20]=1)=[O:12])[N:4]=[C:5]([CH3:34])[C:6]([CH3:33])=[N:7]2)=[O:32]
Reactant: CN
Reactant: Cc1nc2cc3c(=O)oc(-c4cc(C(F)(F)F)nn4-c4ncccc4Cl)nc3c(Cl)c2nc1C
Product: CNC(=O)c1cc2nc(C)c(C)nc2c(Cl)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Yield: 68 %

Procedure:
See example H3 for the reaction conditions using 9-chloro-2-[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-6,7-dimethyl-3-oxa-1,5,8-triaza-anthracen-4-one as starting material and 2 equivalents of methylamine (40% in H2O). After 10 hours reaction time and purification by flash chromatography on silica gel, a white solid is obtained in 68% yield. m.p.: 221-224° C.
Reaction SMILES: C(N(C1C=CC=CC=1C1CCC2C(=CC=C(OC)C=2)C1)CCC1C=CC(O)=CC=1)C.Cl.ClCCN1CCCCC1.[CH2:41]([N:43]([C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=1[CH:67]1[CH2:76][CH2:75][C:74]2[C:69](=[CH:70][CH:71]=[C:72]([O:77]C)[CH:73]=2)[CH2:68]1)[CH2:44][CH2:45][C:46]1[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH2:54][N:55]2[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]2)=[CH:48][CH:47]=1)[CH3:42]>>[CH2:41]([N:43]([CH2:44][CH2:45][C:46]1[CH:47]=[CH:48][C:49]([O:52][CH2:53][CH2:54][N:55]2[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]2)=[CH:50][CH:51]=1)[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=1[CH:67]1[CH2:76][CH2:75][C:74]2[CH:73]=[C:72]([OH:77])[CH:71]=[CH:70][C:69]=2[CH2:68]1)[CH3:42]
Reactant: CCN(CCc1ccc(OCCN2CCCCC2)cc1)c1ccccc1C1CCc2cc(OC)ccc2C1
Agent: CCN(CCc1ccc(O)cc1)c1ccccc1C1CCc2cc(OC)ccc2C1
Agent: Cl
Agent: ClCCN1CCCCC1
Product: CCN(CCc1ccc(OCCN2CCCCC2)cc1)c1ccccc1C1CCc2cc(O)ccc2C1
Yield: 86.8 %

Procedure:
Synthesized from 4-{2-{ethyl[2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amino}ethyl}phenol and 1-(2-chloroethyl)piperidine hydrochloride according to an analogous synthetic method to Preparation Example 40, ethyl[2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]{2-[4-(2-piperidin-1-ylethoxy)phenyl]ethyl}amine (308 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (260 mg).
Reaction SMILES: [Li]CCCC.[S:6]1[C:10]2[C:11]3[S:16][CH:15]=[CH:14][C:12]=3[S:13][C:9]=2[CH:8]=[CH:7]1.[Sn:17](Cl)([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21]>>[CH2:26]([Sn:17]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH3:25])[C:15]1[S:16][C:11]2[C:10]3[S:6][CH:7]=[CH:8][C:9]=3[S:13][C:12]=2[CH:14]=1)[CH2:27][CH2:28][CH3:29]
Reactant: c1cc2sc3ccsc3c2s1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Product: CCCC[Sn](CCCC)(CCCC)c1cc2sc3ccsc3c2s1

Procedure:
2.5 M of n-BuLi (2.04 mL/hexane, 5.09 mmol) was added to dithieno[3,2-b;2′,3′-d]thiophene 20 (1 g, 5.09 mmol/THF (20 mL)) and reacted at 0° C. for 1 hour under a dry and anaerobic operation condition to form a solution. SnBu3Cl (1.58 mL, 5.6 mmol) was then added to the solution and reacted at 0° C. for 30 minutes. After returning to room temperature, the solution was continuously reacted for 8 hours. After the reaction was completed, the solution was extracted by ether (30 mL) and deionized water (50 mL). An organic phase was collected. After removal of ether by a rotary concentrator, the organic phase was purified by reduced-pressure distillation to form a transparent pale yellow oily product (25, 2.1 g, 85%).
Reaction SMILES: [C:1]([C:5]1[C:6]([O:32][CH3:33])=[C:7]([CH:21]=[C:22]([N:24]2[CH:29]=[CH:28][C:27](=[O:30])[NH:26][C:25]2=[O:31])[CH:23]=1)/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)[F:35].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C.CO.O>[C:1]([C:5]1[C:6]([O:32][CH3:33])=[C:7]([CH:21]=[C:22]([N:24]2[CH:29]=[C:28]([F:35])[C:27](=[O:30])[NH:26][C:25]2=[O:31])[CH:23]=1)/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH3:20])(=[O:18])=[O:19])=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: F[B-](F)(F)F
Reactant: COc1c(/C=C/c2ccc(NS(C)(=O)=O)cc2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: O
Solvent: CO
Solvent: CC#N
Product: COc1c(/C=C/c2ccc(NS(C)(=O)=O)cc2)cc(-n2cc(F)c(=O)[nH]c2=O)cc1C(C)(C)C
Temperature: 90 °C
Yield: 29 %

Procedure:
The fluorination procedure was performed as described in Lal, G S, et al. J. Org Chem., 60:7340-7342 (1995). The product from Example 13A, Part B (0.42 g, 1.26 mmol) and Selectfluor™ (0.672 g, 1.9 mmol) were combined in a mixture of acetonitrile (8 mL) and methanol (1 mL) and heated at 90° C. under N2 for 5 h. The solution was diluted with water, extracted into ethyl acetate, washed with sodium bicarbonate solution, concentrated and purified by column chromatography on silica gel to give the title compound (0.138 g, 29%).
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][C:8]2[C:11]([F:15])=[CH:12][CH:13]=[CH:14][C:7]=2[NH:6][C:5]1=[O:16])=[N+:2]=[N-:3].C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:29][C:30]([F:33])([F:32])[F:31])(=O)=O>CN(C=O)C.O.CCOC(C)=O>[N:1]([CH:4]1[CH2:10][CH2:9][C:8]2[C:11]([F:15])=[CH:12][CH:13]=[CH:14][C:7]=2[N:6]([CH2:29][C:30]([F:33])([F:32])[F:31])[C:5]1=[O:16])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NC1CCc2c(F)cccc2NC1=O
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NC1CCc2c(F)cccc2N(CC(F)(F)F)C1=O
Yield: 82 %

Procedure:
3-Azido-6-fluoro-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (2.25 g, 10.22 mmol), cesium carbonate (4.65 g, 14.30 mmol), and 2,2,2-trifluoroethyl trifluoromethanesulfonate (2.67 mL, 18.39 mmol) in DMF (34.1 mL) heated to 40° C. for 1 hour. The reaction mixture was diluted with water before EtOAc was added to extract the product. The organic phase was separated and washed with water (2×) and brine (1×) before being dried with Na2SO4 and evaporated to yield the crude product. This material was chromatographed on silica gel (0-80% EtOAc in hexanes) to yield 2.534 g of 3-azido-6-fluoro-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one as an orange/brown solid.
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]([CH:6]=O)=[CH:4][C:3]=2[O:2]1.[C:15](#[N:19])[CH2:16][C:17]#[N:18].NCCC(O)=O.O>C(O)C>[CH2:1]1[O:11][C:10]2[CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]([CH:6]=[C:16]([C:15]#[N:19])[C:17]#[N:18])=[CH:4][C:3]=2[O:2]1
Reactant: N#CCC#N
Reactant: O=Cc1cc2c(cc1[N+](=O)[O-])OCO2
Agent: NCCC(=O)O
Solvent: CCO
Solvent: O
Product: N#CC(C#N)=Cc1cc2c(cc1[N+](=O)[O-])OCO2
Yield: 80.6 %

Procedure:
1 g (5.1 mmol) 3,4-Methylenedioxy-6-nitrobenzaldehyde, 0.4 g (6 mmol) malononitrile and 0.2 g β-alanine in 30 ml ethanol were stirred 16 hours at room temperature, 50 ml H2O was added and the reaction mixture was filtered, giving 1 g (80% yield) of a bright yellow solid, m.p. 104° C.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([C:12]([OH:14])=[O:13])[C:6]2[CH:7]=[N:8][NH:9][C:10]=2[CH:11]=1.[CH3:15]O>>[Br:2][C:3]1[CH:4]=[C:5]([C:12]([O:14][CH3:15])=[O:13])[C:6]2[CH:7]=[N:8][NH:9][C:10]=2[CH:11]=1
Reactant: CO
Reactant: O=C(O)c1cc(Br)cc2[nH]ncc12
Agent: Cl
Product: COC(=O)c1cc(Br)cc2[nH]ncc12
Temperature: 70 °C

Procedure:
Concentrated hydrochloric acid (46.9 ml, 1543 mmol) was added to a stirred suspension of 6-bromo-1H-indazole-4-carboxylic acid (4.65 g, 19.29 mmol, available from Sinova) in methanol (100 ml) and the reaction mixture was heated to 70° C. for 18 h. The reaction mixture was allowed to cool to RT resulting in the precipitation of a solid. The mixture was cooled in ice and the yellow precipitate filtered off and washed with methanol to give the title compound as a yellow solid (2.54 g).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]([C:14]3[S:15][C:16]([C:19]4[CH:20]=[N:21][N:22]([CH2:24][C:25]5([CH3:31])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]5)[CH:23]=4)=[CH:17][CH:18]=3)=[O:13])=[CH:6][C:5]=12.CC(C)(OC(=O)[NH:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH2:47][CH2:48][O:49][CH2:50][CH2:51][C:52](O)=[O:53])C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>>[NH2:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH2:47][CH2:48][O:49][CH2:50][CH2:51][C:52]([N:28]1[CH2:29][CH2:30][C:25]([CH2:24][N:22]2[CH:23]=[C:19]([C:16]3[S:15][C:14]([C:12]([NH:11][CH2:10][C:7]4[CH:8]=[CH:9][N:4]5[CH:3]=[CH:2][N:1]=[C:5]5[CH:6]=4)=[O:13])=[CH:18][CH:17]=3)[CH:20]=[N:21]2)([CH3:31])[CH2:26][CH2:27]1)=[O:53]
Reactant: CC(C)(C)OC(=O)NCCOCCOCCOCCOCCC(=O)O
Reactant: CC1(Cn2cc(-c3ccc(C(=O)NCc4ccn5ccnc5c4)s3)cn2)CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Product: CC1(Cn2cc(-c3ccc(C(=O)NCc4ccn5ccnc5c4)s3)cn2)CCN(C(=O)CCOCCOCCOCCOCCN)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of N-(imidazo[1,2-a]pyridin-7-ylmethyl)-5-{1-[(4-methylpiperidin-4-yl)methyl]-1H-pyrazol-4-yl}thiophene-2-carboxamide (0.139 g, 0.274 mmol), 2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azaicosan-20-oic acid (0.100 g, 0.274 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.104 g, 0.274 mmol) and 4-methylmorpholine (0.105 ml, 0.958 mmol) was stirred at room temperature for 3 hours. The reaction mixture was purified directly by normal phase chromatography and the resulting material was treated with HCl/dioxane (4 M) then concentrated to give the title compound as a hydrochloride salt. 1H NMR (400 MHz, DMSO-d6) δ 14.71 (s, 1H), 9.58 (t, J=6.0 Hz, 1H), 8.89 (d, J=7.0 Hz, 1H), 8.35 (d, J=1.9 Hz, 1H), 8.16 (d, J=2.1 Hz, 2H), 8.06 (s, 3H), 7.92 (d, J=3.9 Hz, 1H), 7.83 (s, 2H), 7.50 (dd, J=7.0, 1.2 Hz, 1H), 7.26 (d, J=3.8 Hz, 1H), 4.64 (d, J=5.8 Hz, 2H), 4.05 (s, 2H), 3.80 (dd, J=11.8, 6.8 Hz, 2H), 3.66-3.58 (m, 4H), 3.55 (dd, J=9.2, 4.4 Hz, 4H), 3.50 (t, J=7.5 Hz, 8H), 3.37-3.26 (m, 1H), 3.23-3.13 (m, 1H), 2.99-2.90 (m, 2H), 2.55 (t, J=6.6 Hz, 2H), 1.53-1.19 (m, 4H), 0.95 (s, 3H); MS (ESI(+)) m/e 682 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:56]=[CH:55][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]4[NH:20][C:19]([CH:21]=[C:22]5[N:54]=[C:25]([C:26]([C:38]6[CH:43]=[CH:42][C:41]([O:44][C:45]7[CH:50]=[CH:49][C:48]([N+:51]([O-])=O)=[CH:47][CH:46]=7)=[CH:40][CH:39]=6)=[C:27]6[NH:37][C:30](=[CH:31][C:32]7[CH:33]=[CH:34][C:35]=3[N:36]=7)[CH:29]=[CH:28]6)[CH:24]=[CH:23]5)=[CH:18][CH:17]=4)=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-])=O.Cl.O.O.Cl[Sn]Cl.N>C(Cl)(Cl)Cl.O>[NH2:1][C:4]1[CH:56]=[CH:55][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]4[NH:20][C:19]([CH:21]=[C:22]5[N:54]=[C:25]([C:26]([C:38]6[CH:43]=[CH:42][C:41]([O:44][C:45]7[CH:50]=[CH:49][C:48]([NH2:51])=[CH:47][CH:46]=7)=[CH:40][CH:39]=6)=[C:27]6[NH:37][C:30](=[CH:31][C:32]7[CH:33]=[CH:34][C:35]=3[N:36]=7)[CH:29]=[CH:28]6)[CH:24]=[CH:23]5)=[CH:18][CH:17]=4)=[CH:11][CH:10]=2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(-c3c4nc(cc5ccc([nH]5)c(-c5ccc(Oc6ccc([N+](=O)[O-])cc6)cc5)c5nc(cc6ccc3[nH]6)C=C5)C=C4)cc2)cc1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: N
Solvent: O
Solvent: ClC(Cl)Cl
Product: Nc1ccc(Oc2ccc(-c3c4nc(cc5ccc([nH]5)c(-c5ccc(Oc6ccc(N)cc6)cc5)c5nc(cc6ccc3[nH]6)C=C5)C=C4)cc2)cc1
Reaction time: 24 h
Yield: 66.9 %

Procedure:
To a solution of 5,15-bis-[4-(4-nitrophenoxy)phenyl]porphyrin (70 mg, 0.095 mmol) in CHCl3 (10 ml), saturated with concentrated HCl, SnCl2.2H2O (105 mg, 0.475 mmol) was added and the mixture was kept under magnetic stirring, at room temperature for 24 h, then cold water was added, the mixture was neutralized with a solution 15% of ammonia, and the organic phase was extracted, dried on Na2SO4, then the solvent was removed by evaporation. The crude product was purified by chromatography on silica gel (THF to THF/DMF 9/1), to give 43 mg of title product (yield 67%).
Reaction SMILES: [CH2:1]([C:3]1([CH3:24])[CH2:8][C:7]([CH3:10])([CH3:9])[CH2:6][CH:5]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[C:14]=2[OH:22])[CH2:4]1)[CH3:2].[H][H].[C:27](OCC)(=[O:29])C>[Pd]>[CH:27]([NH:19][C:15]1[C:14]([OH:22])=[C:13]([CH:18]=[CH:17][CH:16]=1)[C:12]([NH:11][CH:5]1[CH2:6][C:7]([CH3:10])([CH3:9])[CH2:8][C:3]([CH2:1][CH3:2])([CH3:24])[CH2:4]1)=[O:23])=[O:29]
Reactant: CCC1(C)CC(NC(=O)c2cccc([N+](=O)[O-])c2O)CC(C)(C)C1
Reactant: [H][H]
Reactant: CCOC(C)=O
Agent: [Pd]
Product: CCC1(C)CC(NC(=O)c2cccc(NC=O)c2O)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-(3-ethyl-3,5,5-trimethylcyclohexyl)-2-hydroxy-3-nitrobenzamide (3.60 g) in ethyl acetate (75 ml) was added 5% Pd/C (0.40 g) catalyst. The resulting mixture was subjected to a hydrogen atmosphere (initial H2 pressure=50 psi) using a Parr shaker apparatus. When hydrogen uptake ceased (approximately 30 minutes), the hydrogen atmosphere was purged. A stir bar was added to the reaction bottle and to the stirred reaction mixture acetic-formic anhydride (3 ml) was added all at once. After stirring at room temperature for 30 minutes, the reaction was filtered, washed with saturated sodium bicarbonate solution (100 ml). then with a saturated sodium chloride solution (100 ml), dried (MgSO4) and the solvent evaporated to give the desired product as a white solid foam (3.5 g). An analytical sample could be prepared by recrystallization from a methanol/water mixture to give an off-white crystalline solid (m.p.=166-168° C.). 13C NMR (CDCl3) showed this material to be approximately a 6:4 mixture of diastereomers.
Reaction SMILES: ClN1C(=O)CCC1=O.[CH:9](=[N:11][OH:12])[CH3:10].[C:13]([C:15]1[CH:20]=[C:19]([O:21][C:22]2[CH:23]=[CH:24][C:25]([NH:29][C:30](=[O:32])[CH3:31])=[N:26][C:27]=2[CH3:28])[CH:18]=[CH:17][N:16]=1)#[CH:14].O>CN(C=O)C>[CH3:28][C:27]1[N:26]=[C:25]([NH:29][C:30](=[O:32])[CH3:31])[CH:24]=[CH:23][C:22]=1[O:21][C:19]1[CH:18]=[CH:17][N:16]=[C:15]([C:13]2[O:12][N:11]=[C:9]([CH3:10])[CH:14]=2)[CH:20]=1
Reactant: C#Cc1cc(Oc2ccc(NC(C)=O)nc2C)ccn1
Reactant: CC=NO
Agent: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(Oc2ccnc(-c3cc(C)no3)c2)c(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
A solution of N-chlorosuccinimide (0.153 g, 1.145 mmol) in DMF (1 mL) was treated with acetaldoxime (0.068 g, 1.145 mmol), stirred at RT for 30 min, then added to a solution of N-(5-((2-ethynylpyridin-4-yl)oxy)-6-methylpyridin-2-yl)acetamide (0.102 g, 0.382 mmol) and TEA (0.5 mL) in DMF (1 mL) and heated at 60° C. for 1 h. The mixture was cooled to RT, treated with H2O, extracted with EtOAc (2×) and the combined organics were washed with H2O, then brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford N-(6-methyl-5-((2-(3-methylisoxazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)acetamide (110 mg, 89%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.64 (s, 1 H), 8.55 (d, J=5.7 Hz, 1 H), 8.03 (d, J=8.8 Hz, 1 H), 7.64 (d, J=8.8 Hz, 1 H), 7.35 (d, J=2.5 Hz, 1 H), 6.96 (m, 2 H), 2.28 (s, 3 H), 2.25 (s, 3 H), 2.08 (s, 3 H); MS (ESI) m/z: 325.1 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([OH:10])[C:5]([O:11][CH3:12])=[CH:4][CH:3]=1.[C:13]([O-])([O-])=O.[K+].[K+].CN(C=O)C.COS(OC)(=O)=O>O>[Br:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([O:10][CH3:13])[C:5]([O:11][CH3:12])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(Br)c(C=O)c1O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: COc1ccc(Br)c(C=O)c1OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 6-bromo-2-hydroxy-3-methoxybenzaldehyde (66.8 g, 0.29 mole), K2CO3 (powdered, 79 g, 0.57 mole), and dry DMF (250 mL) was stirred under N2 at 110° as dimethylsulfate (33.5 mL, 0.35 mole) was added dropwise. The reaction mixture was stirred at 135° for 5 hours, was cooled to room temperature, and water was added. The aqueous mixture was extracted with CH2Cl2. The combined extracts were washed with water, saturated aqueous NaCl, dried (MgSO4), filtered, and evaporated to yield ca 80 g. tan solid. The crude product was recrystallized from 2-propanol to obtain 55.2 g cream colored solid, (77%); mp 92°-3°.
Reaction SMILES: C1(C)C=CC(S(O[C:11]2[C:12](Br)=[CH:13][CH:14]=[C:15]3[C:20]=2[N:19]=[CH:18][CH:17]=[CH:16]3)(=O)=O)=CC=1.[O:23]1[CH:27]=[CH:26][CH:25]=[CH:24]1.C([Li])CCC.O>C1COCC1>[O:23]1[CH:27]2[C:11]3[C:12](=[CH:13][CH:14]=[C:15]4[C:20]=3[N:19]=[CH:18][CH:17]=[CH:16]4)[CH:24]1[CH:25]=[CH:26]2
Reactant: c1ccoc1
Reactant: Cc1ccc(S(=O)(=O)Oc2c(Br)ccc3cccnc23)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: C1=CC2OC1c1ccc3cccnc3c12
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A stirred solution of the tosyl ester (4a) (5.00 g, 13.2 mmol) in dry THF (150 mL) and freshly distilled furan (24.3 mL, 22.6 g, 0.33 mol, 25 equiv.) cooled at −78° C. under nitrogen was treated dropwise with n-butyllithium in hexanes (2.5 M, 5.55 mL, 13.8 mmol, 1.05 equiv.). The reaction was stirred for 1 hr at −78° C. and then allowed to warm to room temperature over 3 hours. The reaction mixture was treated with water (5 mL) and then heated under reduced pressure to remove most of the THF. This mixture was then diluted with water (150 mL), extracted with dichloromethane (3×100 mL). The organic layers were combined, dried (MgSO4) and concentrated to give a crude brown solid (2.31 g). This material was dissolved in the minimum amount of dichloromethane/petroleum and absorbed onto a pad of neutral alumina. Gradient elution with ethyl acetate/petroleum ether afforded the product, which was recrystallized from dichloromethane/ether/petroleum ether to afford the endoxide (7,10-epoxy-7,10-dihydrobenzo[h]quinoline (6) as cream colored crystals (1.07 g, 42%). 1H NMR (CDCl3, 300 MHz) δ ppm 8.88 (dd, 1H, J=4.1, 1.7 Hz); 8.14 (dd, 1H, J=8.4, 1.7 Hz); 7.60 and 7.57 (ABq, 2H, J=7.8 Hz); 7.27–7.33 (m, 2H); 7.21 (dd, 1H, J=5.5, 1.8 Hz); 6.54 (bs, 1H); 5.95 (m, 1H).