Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[S:12](=O)(=[O:15])([OH:14])[OH:13]>>[CH:3]1[C:2]([OH:11])=[CH:1][C:10]2[CH:9]=[CH:8][C:7]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:6][C:5]=2[CH:4]=1
Reactant: O=S(=O)(O)O
Reactant: Oc1ccc2ccccc2c1
Product: O=S(=O)(O)c1ccc2cc(O)ccc2c1

Procedure:
In the conventional method for preparing Schaeffer's Salt, 2-naphthol is heated with concentrated sulfuric acid until sulfonation is complete. The temperature and reaction time are controlled to provide a high yield of 2-naphthol-6-sulfonic acid. The sulfonation mass is then drowned in water, the resulting solution is neutralized with sodium hydroxide or sodium carbonate, and the crude Schaeffer's Salt is isolated by filtration. The Schaeffer's Salt thus obtained is not pure enough for commercial use and, therefore, must be purified. The conventional method for doing this is to recrystallize the Schaeffer's Salt by dissolving the crude salt in water, treating the solution with activated carbon and, optionally, filter aids, clarifying the solution by filtration, salting out the Schaeffer's Salt by addition of common salt to the clarified solution, and filtering off the precipitated Schaeffer's Salt. Thus, the conventional recovery and purification of the salt requires many operations, including three filtration steps. The many operations thus involved have a serious adverse effect on the cost of manufacture of Schaeffer's Salt. Not only are there high equipment and labor costs, but product losses due to the several handling operations are also encountered. This processing leaves about 2-3% of the disodium salt of DONS in the product recovered.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10](=[O:31])[C:11]1[CH:16]=[CH:15][C:14]([CH:17]=[N:18][N:19]=[C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([F:29])[CH:27]=3)[NH:22][C:21]2=[O:30])=[CH:13][CH:12]=1.CO.[Li+].[OH-].Cl>O>[F:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:30])[C:20]2=[N:19][N:18]=[CH:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]([NH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:32])=[O:2])=[O:31])=[CH:16][CH:15]=1
Reactant: COC(=O)CCCCCNC(=O)c1ccc(C=NN=C2C(=O)Nc3ccc(F)cc32)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCCCCNC(=O)c1ccc(C=NN=C2C(=O)Nc3ccc(F)cc32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 28 %

Procedure:
6-(4-(((5-fluoro-2-oxoindolin-3-ylidene)hydrazono)methyl)benzamido)hexanoic acid methyl ester (438 mg, 1 mmol) and 300 ml of CH3OH were stirred at room temperature while 25 ml of 4 N solution of LiOH in H2O was added. The mixture was stirred for 24 hours at room temperature. The mixture is neutralized with concentrated hydrochloric acid to pH 7 and evaporated under vacuum to remove methanol. The residue was adjusted to pH 3 with concentrated hydrochloric acid. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (119 mg, 28% yield) as a brown solid. LC-MS (m/z) 425 (M+1).
Reaction SMILES: I[C:2]1[N:11]=[C:10]2[N:4]([CH2:5][CH2:6][C:7]3[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=3[CH:9]2[O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[CH:3]=1.[C:24]([NH:31][CH2:32][C:33]#[CH:34])([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].N(CC)CC.N>CN(C=O)C.[Cu]I.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.O>[C:27]([O:26][C:24](=[O:25])[NH:31][CH2:32][C:33]#[C:34][C:2]1[N:11]=[C:10]2[N:4]([CH2:5][CH2:6][C:7]3[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=3[CH:9]2[O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[CH:3]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: CN1CCC(OC2c3ccccc3CCn3cc(I)nc32)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: N
Solvent: O
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CN1CCC(OC2c3ccccc3CCn3cc(C#CCNC(=O)OC(C)(C)C)nc32)CC1
Temperature: 50 °C

Procedure:
To a solution of compound 2-iodo-4-(1-methyl piperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene (example 2A) (80 mg, 0.19 mmoles) in DMF (0.5 mL) in a screw-capped vial under argon are added CuI (7.2 mg, 0.038 mmole), (PPh3)2PdCl2 (13.3 mg, 19 μmole), N-Boc-propargylamine (91 mg, 0.57 mmole) and Et2NH (58 μL, 0.57 mmole). The reaction mixture is heated at 50° C. overnight. Water is added and pH adjusted to 9-10 with concentrated aqueous ammonia solution. The aqueous phase is extracted three times with AcOEt. The organic phase is dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is pre-purified by silica gel chromatography using (CH2Cl2:MeOH) as eluent with a gradient from (95:5) to (90:10) and the residue is submitted to a preparative thin-layer chromatography eluting with (CH2Cl2:MeOH:NH4OH) (9:1:1) to afford {3-[4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-2-yl]-prop-2-ynyl}-carbamic acid tert-butyl ester.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH3:9])[N:3]=1.[Na+].[I-].[CH2:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1)[CH2:13]C.[CH2:28](N(C(C)C)C(C)C)C>CCO>[CH3:9][NH:8][C:4]1[N:3]=[C:2]([NH:25][C:24]2[CH:23]=[CH:22][C:21]([N:18]3[CH2:17][CH2:16][N:15]([CH:12]([CH3:13])[CH3:28])[CH2:20][CH2:19]3)=[CH:27][CH:26]=2)[N:7]=[CH:6][N:5]=1
Reactant: CCCN1CCN(c2ccc(N)cc2)CC1
Reactant: CCN(C(C)C)C(C)C
Reactant: CNc1ncnc(Cl)n1
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Product: CNc1ncnc(Nc2ccc(N3CCN(C(C)C)CC3)cc2)n1
Temperature: 80 °C

Procedure:
A mixture of (4-chloro-[1,3,5]triazin-2-yl)-methyl-amine (290 mg, 2.00 mmol), NaI (28 mg) and 4-(4-propylpiperazin-1-yl)-aniline (500 mg, 2.0 mmol) in EtOH (20 ml) and N-ethyl-diisopropyl amine (350 μl, 2.0 mmol) is heated to 80° C. for 3 h under a nitrogen atmosphere. Workup as described in Example 228A gives the title compound: ESI-MS: 328 [MH]+; TLC: Rf=0.14 (DCM/MeOH, 9:1).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.F[C:11]1([CH:19]=[CH:18][N:17]=[CH:16][CH2:15]1)[C:12]([OH:14])=[O:13]>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][C:11]=2[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: NCc1ccc(F)cc1
Reactant: O=C(O)C1(F)C=CN=CC1
Product: O=C(O)c1ccncc1NCc1ccc(F)cc1
Yield: 55 %

Procedure:
The title compound was prepared in 55% yield from 4-fluorobenzylamine and 4-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. NMR (500 MHz, DMSO-d6): δ 13.45 (br s, 1H), 8.11 (s, 1H), 8.03 (br s, 1H), 7.83 (d, 1H, J=5.0 Hz), 7.58 (d, 1H, J=5.0 Hz), 7.36-7.42 (m, 1H), 7.16-7.23 (m, 2H), 7.05-7.11 (m, 1H), 4.60 (s, 2H). [M+H] calc'd for C13H11FN2O2, 247. Found 247.
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][N:13]=1)[C:7]([O:9][CH3:10])=[O:8])=[O:3].[OH:14]/[N:15]=[C:16](\[NH2:18])/[CH3:17].C(N(CC)CC)C>ClCCl>[NH2:18]/[C:16](=[N:15]\[O:14][C:2]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][N:13]=1)[C:7]([O:9][CH3:10])=[O:8])=[O:3])/[CH3:17]
Reactant: C/C(N)=N/O
Reactant: COC(=O)c1ccnc(C(=O)Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccnc(C(=O)O/N=C(/C)N)c1

Procedure:
To a solution of methyl 2-(chlorocarbonyl)isonicotinate in dichloromethane (500 mL) was added (Z)—N′-hydroxyacetimidamide and triethylamine, keeping the temperature at 25-30° C. for 1 day. The reaction was concentrated in vacuo to afford (Z)-methyl 2-((1-aminoethylideneaminooxy)carbonyl)isonicotinate as a yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:14]=[C:15]([NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[CH:16]=[CH:17][CH:18]=2)[CH2:9][CH2:8]1.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1[C:36]([C:37](Cl)=[O:38])=[C:35]([CH3:40])[O:34][N:33]=1>C1COCC1.C(Cl)Cl>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1[C:36]([C:37]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]2[CH2:8][CH2:9][CH:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20](=[O:24])[CH:21]([CH3:22])[CH3:23])[CH:14]=3)[CH2:11][CH2:12]2)=[O:38])=[C:35]([CH3:40])[O:34][N:33]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCN)CC2)c1
Reactant: Cc1onc(-c2ccccc2Cl)c1C(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1onc(-c2ccccc2Cl)c1C(=O)NCCCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1

Procedure:
Prepared by Procedure Q2 (THF/DCM, 1:3) and Scheme AT using N-{3-[1-(5-aminopentyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 3-(2-chlorophenyl)-5-methyl-4-isoxazolecarbonyl chloride: ESMS m/e: 551.0 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4](OS(C(F)(F)F)(=O)=O)[CH2:3][CH2:2]1.CC1(C)COB([C:22]2[CH:43]=[CH:42][C:25]3[C:26]4[N:30]([CH2:31][CH2:32][O:33][C:24]=3[CH:23]=2)[CH:29]=[C:28]([C:34]2[N:35]([CH:39]([CH3:41])[CH3:40])[N:36]=[CH:37][N:38]=2)[N:27]=4)OC1.C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC>C(Cl)Cl.O>[O:1]1[CH2:6][CH:5]=[C:4]([C:22]2[CH:43]=[CH:42][C:25]3[C:26]4[N:30]([CH2:31][CH2:32][O:33][C:24]=3[CH:23]=2)[CH:29]=[C:28]([C:34]2[N:35]([CH:39]([CH3:41])[CH3:40])[N:36]=[CH:37][N:38]=2)[N:27]=4)[CH2:3][CH2:2]1
Reactant: O=S(=O)(OC1=CCOCC1)C(F)(F)F
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(B3OCC(C)(C)CO3)cc1OCC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3=CCOCC3)cc1OCC2
Yield: 39.4 %

Procedure:
A mixture of trifluoro-methanesulfonic acid 3,6-dihydro-2H-pyran-4-yl ester (125 mg, 0.54 mmol), 8-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene (200 mg, 0.491 mmol), PdCl2dppf.DCM (41 mg, 0.05 mmol, 10 mol %), cesium carbonate (400 mg, 1.23 mmol), DME (2 mL) and water (0.2 mL) was heated at 80° C. for 90 min. The cooled reaction mixture was diluted with DCM, filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 100% ethyl acetate in cyclohexane) to give 8-(3,6-Dihydro-2H-pyran-4-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene (73 mg, 39%). LCMS RT=4.36, [M+H]+=378.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][N:10]=[CH:11]C(O)=O.C([N:17]([CH2:20]C)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:29])C=CC=CC=1.[OH-].[K+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N:9]1[C:20](=[O:29])[NH:17][CH:11]=[N:10]1
Reactant: CCN(CC)CC
Reactant: O=C(O)C=NNc1cc(F)ccc1Br
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=c1[nH]cnn1-c1cc(F)ccc1Br
Yield: 66.5 %

Procedure:
To a stirred suspension of 2-(2-(2-bromo-5-fluorophenyl)hydrazono)acetic acid (2.65 g, 10.2 mmol) in toluene (80 mL) was added triethylamine (1.42 mL, 10.2 mmol) and diphenylphosphoryl azide (2.2 mL, 10.2 mmol). The resulting mixture was slowly heated to reflux temperature and the reflux was maintained for 1 h. The clear orange solution was cooled and then poured onto 10% aqueous KOH (100 mL). The basic extract was acidified (pH 1) with concentrated HCl. The precipitate that formed was collected by filtration, washed with water and dried at reduced pressure to afford the title compound as a yellow solid (1.75 g, 67% yield): 1H NMR (400 MHz, DMSO-D6) δ ppm 11.87 (1H, s), 8.10-8.08 (1H, m), 7.83 (1H, dd, J=8.8, 5.8 Hz), 7.50 (1 H, dd, J=9.1, 3.0 Hz), 7.34 (1H, td, J=8.6, 3.0 Hz); LCMS (+ESI, M+H+) m/z 258-260.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]([OH:21])([CH3:20])[CH3:19])[CH2:14][CH2:13]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([Sn](CCCC)(CCCC)CCCC)=[N:6][C:7]=2[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.[C:41]1([S:47]([N:50]2[C:54]3=[CH:55][N:56]=[CH:57][C:58](Br)=[C:53]3[CH:52]=[CH:51]2)(=[O:49])=[O:48])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.O1CCOC[CH2:61]1>C1C=C(C([O-])=O)SC=1.[Cu+].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:41]1([S:47]([N:50]2[C:54]3=[CH:55][N:56]=[CH:57][C:58]([C:5]4[N:4]=[C:3]5[C:8]([N:9]=[C:10]([CH2:11][N:12]6[CH2:13][CH2:14][CH:15]([C:18]([OH:21])([CH3:19])[CH3:20])[CH2:16][CH2:17]6)[N:2]5[CH3:1])=[C:7]([N:22]5[CH2:23][CH2:24][O:25][CH2:26][CH2:27]5)[N:6]=4)=[C:53]3[CH:52]=[C:51]2[CH3:61])(=[O:49])=[O:48])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1
Reactant: C1COCCO1
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Br)cncc21
Agent: [Cu+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])c1cccs1
Product: Cc1cc2c(-c3nc(N4CCOCC4)c4nc(CN5CCC(C(C)(C)O)CC5)n(C)c4n3)cncc2n1S(=O)(=O)c1ccccc1
Temperature: 150 °C
Yield: 86 %

Procedure:
A 20 mL microwave vial was charged with a suspension of 2-[1-(9-methyl-6-morpholin-4-yl-2-(tributylstannanyl)-9H-purin-8-ylmethyl)piperidin-4-yl]propan-2-ol (0.5 g, 0.75 mmol), 1-benzenesulfonyl-4-bromo-1H-pyrrolo[2,3-c]pyridine (0.29 g, 0.83 mmol), CuTC (0.029 g, 0.015 mmol) and Pd(PPh3)4 (0.087 g, 0.075 mmol) in dioxane (8 mL). The reaction mixture was heated in a microwave for 30 min at 150° C. The cooled reaction mixture was loaded onto an SCX-2 cartridge. The cartridge was washed with 3 volumes of MeOH, then the product was recovered eluting with 2N ammonia in MeOH. The solution was concentrated and the residue loaded onto a 40g SiO2 column and purified by flash chromatography (Si—PCC; 40g SiO2 column, 0% to 6% MeOH in DCM) to give 2-{1-[2-(1-Benzenesulfonyl-2-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl]piperidin-4-yl}propan-2-ol as white foam (0.414 g, 86%). LCMS (Method A): RT=3.24 min, [M+H]+ 645.3
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:10]3[N:11]=[C:12]([O:19][CH2:20][C:21](F)(F)F)[C:13]4[C:18]([C:9]3=[N:8][N:7]=2)=[CH:17][CH:16]=[CH:15][CH:14]=4)=[N:2]1.[CH3:25][N:26]([CH3:36])[CH2:27][CH2:28][N:29]1C(CO)=[N:32][CH:31]=[N:30]1>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:10]3[N:11]=[C:12]([O:19][CH2:20][C:21]4[N:29]([CH2:28][CH2:27][N:26]([CH3:36])[CH3:25])[N:30]=[CH:31][N:32]=4)[C:13]4[C:18]([C:9]3=[N:8][N:7]=2)=[CH:17][CH:16]=[CH:15][CH:14]=4)=[N:2]1
Reactant: CN(C)CCn1ncnc1CO
Reactant: FC(F)(F)COc1nn2c(-c3ccon3)nnc2c2ccccc12
Product: CN(C)CCn1ncnc1COc1nn2c(-c3ccon3)nnc2c2ccccc12

Procedure:
The reaction was carried out using the procedure described in Example 1, Step 4, using 3-isoxazol-3-yl-6-(2,2,2-trifluoroethoxy)-[1,2,4]triazolo[3,4-α]phthalazine (WO-A-9850385) (100 mg, 0.29 mmol) instead of 6-chloro-3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[3,4-α]phthalazine with [2-(2-dimethylaminoethyl)-2H-[1,2,4]triazol-3-yl]methanol (Example 4, Step 2) (51 mg, 0.29 mmol). Crude residue was purified on silica eluting 2-6% MeOH/DCM, followed by crashing out from DCM using isohexane. The title compound was isolated by filtration to give a cream solid (47 mg, 39%).
Reaction SMILES: C([O:3][C:4](=[O:14])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([I:13])=[CH:9][CH:8]=1)C.O.[OH-].[Li+]>CO.O1CCCC1.O>[I:13][C:10]1[CH:9]=[CH:8][C:7]([CH:6]=[CH:5][C:4]([OH:14])=[O:3])=[CH:12][CH:11]=1
Reactant: CCOC(=O)C=Cc1ccc(I)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C=Cc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 100.8 %

Procedure:
A solution of ethyl-4-iodo-cinnamate (3.2 g, 10.5 mmol) in methanol (25 mL), tetrahydrofuran (25 ml) and water (15 mL) was treated with lithium hydroxide monohydrate (4.2 g, 100 mmol) and the resulting reaction mixture was stirred at ambient temperature over 2 days. The volatiles were evaporated in vacuo and the residue was neutralized with saturated aqueous ammonium chloride solution. The precipitated solid was filtered, washed with water and hexane and dried to afford the title product as a white solid (2.9 g, 91%). It was used as such for the next step.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:20]C)=[C:13]([O:18]C)[CH:14]=2)[CH:9]1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:31][CH:30]=2)=[CH:25][CH:24]=1)=O)(C)(C)C.B(Br)(Br)[Br:42]>ClCCl>[BrH:42].[C:26]1([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:31][CH:30]=2)[CH:27]=[CH:28][C:23]([CH2:22][CH:9]2[C:10]3[C:15](=[CH:14][C:13]([OH:18])=[C:12]([OH:20])[CH:11]=3)[CH2:16][CH2:17][NH:8]2)=[CH:24][CH:25]=1
Reactant: BrB(Br)Br
Reactant: COc1cc2c(cc1OC)C(Cc1ccc(-c3ccc(-c4ccccc4)cc3)cc1)N(C(=O)OC(C)(C)C)CC2
Solvent: ClCCl
Product: Br
Product: Oc1cc2c(cc1O)C(Cc1ccc(-c3ccc(-c4ccccc4)cc3)cc1)NCC2
Reaction time: 8 h

Procedure:
1-[1,1′;4′,1″]Terphenyl-4-ylmethyl-1,2,3,4-tetrahydro-isoquinoline-6,7-diol hydrobromide (13) was prepared as follows: To a stirred solution of 0.10 g (0.187 mmol) of 6,7-dimethoxy-1-[1,1′;4′,1″]terphenyl-4-ylmethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester in 10 ml of anhydrous dichloromethane under argon at −70° C., 1 ml (5 mol. equiv.) of 1M boron tribromide solution in n-hexanes was added. The mixture was allowed to reach room temperature with stirring overnight and then the solvents were evaporated under reduced pressure. The residue was dissolved in 10 ml of methanol and, again, the solvent was evaporated under reduced pressure. The solid residue was mixed with 10 ml of ether, separated on a glass filter funnel, washed with ether (3×20 ml) to afford an off-white solid, 82 mg (90%), mp 262-264° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:26])[C:5]([CH3:25])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH2:19][CH2:20][CH2:21][C:22]([OH:24])=O)[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH3:1][O:2][C:3]1[C:4](=[O:26])[C:5]([CH3:25])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH2:19][CH2:20][CH2:21][C:22]([N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:24])[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: C1CCNCC1
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(CCCC(=O)O)c2)=C(C)C1=O
Product: COC1=C(OC)C(=O)C(Cc2cccc(CCCC(=O)N3CCCCC3)c2)=C(C)C1=O
Yield: 19 %

Procedure:
4-[3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]-n-butyric acid (73 mg, 0.20 mmol) obtained in Example 62 and piperidine (0.030 ml, 0.30 mmol) were used, and a method similar to that described in Example 46 was employed to obtain the title compound (16 mg, 0.038 mmol, yield 19%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[NH2:18][C:19]1[NH:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1.O>CN(C=O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([N:20]2[C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[N:23]=[C:19]2[NH2:18])[N:7]=1
Reactant: Clc1ncnc(Cl)n1
Reactant: Nc1nc2ccccc2[nH]1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Nc1nc2ccccc2n1-c1ncnc(Cl)n1
Temperature: 0 °C
Reaction time: 1.9 h
Yield: 82.7 %

Procedure:
To 1.0 g (6.67 mmol) of 2,4-dichloro-1,3,5-triazine in 3 mL of DMF at 0° C. is added 1.16 mL (6.67 mmol) of DIEA. The resulting yellow solution is stirred at 0° C. for 10 min when-888 mg (6.67 mmol) of 2-aminobenzimidazole is added portionwise over 5 min, followed by an additional 1 mL of DMF. The resulting mixture is stirred at 0° C. for 1.9 h, then at RT for 3.25 h. At this point, the mixture is poured into 40 mL of stirring cold water with additional cold water rinses to a total volume of 100 mL. The light yellow solid is isolated by filtration, rinsed with cold water, and dried in vacuo, giving 1.36 g (83%) of 1-(4-chloro-[1,3,5]triazin-2-yl)-1H-benzoimidazol-2-ylamine (Compound 1174) as a light yellow solid: MS m/z=246 [M+H]+; HPLC Rt=5.79 min.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[NH2:12]/[C:13](/[CH3:23])=[CH:14]\[C:15]([N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:16].[CH3:24][S:25]([CH2:28][C:29](=O)[CH3:30])(=[O:27])=[O:26]>CN(C)P(=O)(N(C)C)N(C)C.C(OCC)(=O)C>[CH3:23][C:13]1[NH:12][C:29]([CH3:30])=[C:28]([S:25]([CH3:24])(=[O:27])=[O:26])[CH:6]([C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N+:1]([O-:3])=[O:2])[C:14]=1[C:15]([N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:16]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: CC(=O)CS(C)(=O)=O
Reactant: C/C(N)=C/C(=O)N1CCCCC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOC(C)=O
Product: CC1=C(C(=O)N2CCCCC2)C(c2ccccc2[N+](=O)[O-])C(S(C)(=O)=O)=C(C)N1

Procedure:
15.1 g of o-nitrobenzaldehyde, 16.8 g of 3-aminocrotonic acid piperidide and 13.6 g of methylsulphonylacetone are stirred in 100 ml of hexamethylphosphoric acid triamide for 10 hours under nitrogen at a bath temperature of 115° C. The mixture is cooled and dissolved in 600 ml of ethyl acetate and the solution is washed with a mixture of 600 ml of water, 90 ml of methanol and 90 ml of sodium chloride solution. The organic phase is separated off and the aqueous phase, in which a dark brown product precipitates, is filtered. The crystalline product is dried by azeotropic distillation on a rotary evaporator and treated twice in methanol/chloroform with animal charcoal. The filtrate is evaporated and the residue is recrystallised from isopropanol. 2,6-Dimethyl- 3-piperidinocarbonyl-4-(2-nitrophenyl)-5-methylsulphonyl-1,4-dihydropyridine, which is thus obtained, melts at 275°-276° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.Cl.[NH2:10][C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2.CCN(C(C)C)C(C)C>CC(O)C>[C:11]12([NH:10][C:2]3[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=3)[CH2:18][CH:17]3[CH2:16][CH:15]([CH2:14][CH:13]([CH2:19]3)[CH2:12]1)[CH2:20]2
Reactant: Clc1cc(Cl)ncn1
Reactant: NC12CC3CC(CC(C3)C1)C2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Clc1cc(NC23CC4CC(CC(C4)C2)C3)ncn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
200 mg of 4,6-dichloropyrimidine, 252 mg of 1-aminoadamantane hydrochloride and 452 mg of DIPEA were dissolved in 2 mL of i-PrOH and the mixture obtained was charged into a screw cap vial and the vial was kept overnight in a heating block at 90° C. The reaction was monitored by TLC and was completed after 12 hours. The mixture obtained was cooled to r.t., solvent was evaporated and N-adamant-1-yl-6-chloropyrimidin-4-amine was obtained by column chromatography using PE:EtOAc 10:1.
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]3)[N:12]=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)=[O:30])=[CH:24][CH:23]=3)[N:10]=1)[CH2:2]2.C(O)(C(F)(F)F)=O.Cl.[NH2:46][CH2:47][C:48]([NH2:50])=[O:49]>C(N(CC)CC)C>[CH:5]12[O:8][CH:1]([CH2:7][CH2:6]1)[CH2:2][N:3]([C:9]1[N:10]=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)=[O:30])=[CH:24][CH:23]=3)[N:12]=[C:13]([N:15]3[CH2:16][CH2:17][CH:18]([NH:46][CH2:47][C:48]([NH2:50])=[O:49])[CH2:19][CH2:20]3)[N:14]=1)[CH2:4]2
Reactant: O=C1CCN(c2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CC4CCC(C3)O4)n2)CC1
Reactant: NCC(N)=O
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: NC(=O)CNC1CCN(c2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CC4CCC(C3)O4)n2)CC1

Procedure:
Starting from 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea.TFA (50 mg) and glycinamide hydrochloride (18 mg) and triethylamine (10 drops) and following the procedure as outlined in example 118 the title compound was isolated as its di-TFA salt after HPLC purification; MS (ES+) 559.8 (M+H)+