Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[N:7]([CH3:14])[CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[N:19][N:18]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[C:1]([O:5][C:6](=[O:15])[N:7]([CH:8]1[CH2:13][CH2:12][N:11]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[N:19][N:18]=2)[CH2:10][CH2:9]1)[CH3:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)C1CCNCC1
Reactant: Fc1ccc(-c2nnc(Cl)c3ccccc23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CN(C(=O)OC(C)(C)C)C1CCN(c2nnc(-c3ccc(F)cc3)c3ccccc23)CC1
Yield: 95.1 %

Procedure:
Combine methyl-piperidin-4-yl-carbamic acid tert-butyl ester (75 g, 349 mmol), 1-chloro-4-(4-fluoro-phenyl)-phthalazine (75 g, 289 mmol), and potassium carbonate (80 g, 579 mmol) in dimethyl sulfoxide (500 mL) and heat the mixture to 110° C. for 3 h. Cool the reaction to ambient temperature and pour the slurry into water (1.0 L). Collect the solids by filtration and dry in a vacuum oven for 3 days to provide the title compound as a white solid (120 g, 95%). ES/MS m/z 437.3 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5](=[O:11])[NH:4][C:3]1=[O:12].Cl[CH2:14][C:15]([OH:18])([CH3:17])[CH3:16]>>[OH:18][C:15]([CH3:17])([CH3:16])[CH2:14][N:7]1[C:6]2[C:5](=[O:11])[NH:4][C:3](=[O:12])[N:2]([CH3:1])[C:10]=2[N:9]=[CH:8]1
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]cnc21
Reactant: CC(C)(O)CCl
Product: Cn1c(=O)[nH]c(=O)c2c1ncn2CC(C)(C)O
Yield: 51 %

Procedure:
The compound was also obtained, inter alia, by a two-stage synthesis from 3-methylxanthine, which was first reacted with 1-chloro-2-hydroxy-2-methylpropane to give 7-(2-hydroxy-2-methylpropyl)-3-methylxanthine (melting point: 268°-269° C.; yield 51% of theory), the product then being alkylated in the 1-position with 1-chloro-5-hydroxy-5-methylhexane from Example 1a analogously to Example 5b to give the end product (yield: 79.5% of theory).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@@H:13]([CH3:16])[CH2:14][OH:15])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[N:17]1([C:21]([C:23]2[CH:24]=[C:25]([Cl:30])[C:26](Cl)=[N:27][CH:28]=2)=[O:22])[CH2:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:17]1([C:21]([C:23]2[CH:24]=[C:25]([Cl:30])[C:26]([O:1][C:2]3[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@@H:13]([CH3:16])[CH2:14][OH:15])[CH:11]=3)[C:5]([O:7][CH3:8])=[O:6])=[N:27][CH:28]=2)=[O:22])[CH2:20][CH2:19][CH2:18]1
Reactant: O=C(c1cnc(Cl)c(Cl)c1)N1CCC1
Reactant: COC(=O)c1cc(O)cc(O[C@@H](C)CO)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(Oc2ncc(C(=O)N3CCC3)cc2Cl)cc(O[C@@H](C)CO)c1
Temperature: 160 °C
Reaction time: 6 h
Yield: 121.2 %

Procedure:
A mixture of methyl 3-hydroxy-5-[(1S)-2-hydroxy-1-methylethoxy]benzoate (2.35 g, 10.39 mmol), 5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine (2.41 g, 10.39 mmol) and potassium carbonate (2.87 g, 20.8 mmol) in acetonitrile (20 mL) was stirred in a microwave reactor at 160° C. for 6 hours. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer was washed with brine (50 mL), dried (MgSO4), and the solvent removed in vacuo. The crude oil was chromatographed on silica, eluting with 30-100% ethyl acetate in isohexane, to give the desired compound as a yellow oil (5.3 g).
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[F:19][C:20]1[CH:21]=[C:22]([CH:33]=[C:34]([F:36])[CH:35]=1)[CH2:23][NH:24][C:25](=[O:32])[CH:26]([CH2:30][CH3:31])[C:27](O)=[O:28]>>[F:19][C:20]1[CH:21]=[C:22]([CH:33]=[C:34]([F:36])[CH:35]=1)[CH2:23][NH:24][C:25](=[O:32])[CH:26]([CH2:30][CH3:31])[C:27]([NH:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2)=[O:28]
Reactant: CN1C(=O)C(N)c2ccccc2-c2ccccc21
Reactant: CCC(C(=O)O)C(=O)NCc1cc(F)cc(F)c1
Product: CCC(C(=O)NCc1cc(F)cc(F)c1)C(=O)NC1C(=O)N(C)c2ccccc2-c2ccccc21

Procedure:
The tide compound, MS: m/e=478.2 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and N-(3,5-difluoro-benzyl)-2-ethyl-malonamic acid.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.S(Cl)([Cl:13])=O>C(Cl)Cl>[F:1][C:2]1[N:3]=[CH:4][CH:5]=[CH:6][C:7]=1[C:8]([Cl:13])=[O:10]
Reactant: O=C(O)c1cccnc1F
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)c1cccnc1F
Temperature: 40 °C
Reaction time: 3.5 h

Procedure:
To a stirred solution of 2-fluoro-3-pyridinecarboxylic acid (6.3 g, 44.6 mmol) in DCM (112 mL) was added thionyl chloride (15.0 mL, 205 mmol). The reaction was heated to 40° C. and stirring continued for 3.5 h. After which, the reaction mixture was concentrated in vacuo to provide 2-fluoronicotinoyl chloride as a yellow solid. The product was taken on crude to the next step. To a stirred solution of 2-fluoronicotinoyl chloride (6.3 g, 39.5 mmol) in acetonitrile (197 mL, 39.5 mmol) was added diisopropylethylamine (27.5 mL, 158 mmol) followed by picolinimidamide (5.26 g, 43.4 mmol). The reaction was heated to 90° C. and stirring continued for 27 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was placed in Et2O (100 mL) and the mixture was filtered and was further washed with Et2O. The product was dried under vacuum and used crude in the next reaction. Mass Spectrum (ESI) m/e=225.1 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[OH:31])[CH2:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1)#[N:2].Br[CH2:33][CH2:34][CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH2:33][CH2:34][CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: COC(=O)c1ccc(CC(/C=C/c2ccccc2O)CCc2ccc(C#N)cc2)cc1
Reactant: BrCCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CC(/C=C/c2ccccc2OCCCCc2ccccc2)CCc2ccc(C#N)cc2)cc1

Procedure:
A solution of 200 mg (0.486 mmol) of methyl 4-[(3E)-2-[2-(4-cyanophenyl)ethyl]-4-(2-hydroxyphenyl)but-3-en-1-yl]benzoate in 5 ml of acetonitrile is mixed with 155 mg (0.73 mmol) of (4-bromobutyl)benzene and 100.76 mg (0.73 mmol) of potassium carbonate and then stirred under reflux for 12 h. After cooling, the potassium carbonate is filtered off and the filtrate is evaporated. 308 mg (0.41 mmol, 85% of theory, content 73%) of the title compound are obtained.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][N:10]3[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Al](C)C.C1(C)C=CC=CC=1.C[O:29][C:30]([C:32]1[C:37]([CH3:38])=[CH:36][CH:35]=[C:34]([CH3:39])[N:33]=1)=O>O1CCOCC1>[CH3:38][C:37]1[C:32]([C:30]([NH:15][C:13]2[CH:12]=[CH:11][N:10]3[CH:16]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]=[C:9]3[N:14]=2)=[O:29])=[N:33][C:34]([CH3:39])=[CH:35][CH:36]=1
Reactant: Nc1ccn2cc(-c3ccccc3)nc2n1
Reactant: COC(=O)c1nc(C)ccc1C
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Cc1ccc(C)c(C(=O)Nc2ccn3cc(-c4ccccc4)nc3n2)n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 43.7 %

Procedure:
To a white suspension of 2-phenyl-imidazo[1,2-a]pyrimidin-7-ylamine (example 1, step 1, 80 mg, 0.38 mmole) in dioxane (3 ml) is added at RT trimethyl aluminium sol. 2M in toluene (0.8 ml, 1.52 mmole, 4 eq.). The mixture is stirred for 45 min at RT. A solution of 3,6-dimethyl-pyridine-2-carboxylic acid methyl ester (63 mg, 0.38 mmole, 1 eq.) in dioxane (0.4 ml) is then added and the light brown solution is refluxed overnight. The brown solution is loaded on 2 g silica and purified by chromatography on a 12 g RediSep silica cartridge (eluent heptane/ethyl acetate 30-70% 15 min) affording 3,6-dimethyl-N-(2-phenylimidazo[1,2-a]pyrimidin-7-yl)picolinamide (57 mg, 43.6%) as a white solid. MS (m/e)=344.2 [M+H+].
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]([CH2:8][N:9]2[CH:13]=[C:12]([NH2:14])[CH:11]=[N:10]2)=[C:6]([CH3:15])[O:5][N:4]=1.[C:16](=O)(OC1C=CC=CN=1)[O:17]C1C=CC=CN=1.C(N(CC)CC)C>ClCCl>[N:14]([C:12]1[CH:11]=[N:10][N:9]([CH2:8][C:7]2[C:3]([CH3:2])=[N:4][O:5][C:6]=2[CH3:15])[CH:13]=1)=[C:16]=[O:17]
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Reactant: O=C(Oc1ccccn1)Oc1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1noc(C)c1Cn1cc(N=C=O)cn1

Procedure:
1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine hydrochloride (400 mg, 2.08 mmol), dipyridin-2-yl carbonate (450 mg, 2.08 mmol) and triethylamine (0.290 mL, 2.08 mmol) were stirred in dichloromethane (7 mL) for 12 hours at room temperature. The reaction was concentrated under vacuum to afford 4-((4-isocyanato-1H-pyrazol-1-yl)methyl)-3,5-dimethylisoxazole as an off-white solid in quantitative yield. Ethanol (1 mL) was added along with methyl 2-amino-3-(3-methoxyphenyl)propanoate (68 mg, 0.327 mmol) and triethylamine (0.064 mL, 0.461 mmol). The reaction was stirred at reflux for 12 hours, then allowed to cool to room temperature. The solvent was removed under a stream of nitrogen. The crude product was re-suspended in MeOH (1 mL) and purified by reversed phase HPLC (5 to 95% acetonitrile in H2O: 16 minutes gradient). The pure fractions were combined and solvent removed under vacuum to afford 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-5-(3-methoxybenzyl)imidazolidine-2,4-dione as a white solid yield: 50% 1H NMR (CDCl3, 400 MHz): δ 2.19 (s, 3 H), 2.41 (s, 3H), 3.34-3.33 (d, J=3.2 Hz, 1H), 3.31-3.29 (d, J=8 Hz, 1H), 3.76 (s, 3H), 4.33-4.30 (m, 1H), 5.05 (s, 2H), 5.95 (bs, 1H), 7.25-7.21 (t, 1H), 6.82-6.78 (m, 3H), 7.85 (s, 1H), 7.99 (s, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.13 μM.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH3:13])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[CH2:14]([NH2:17])[CH2:15][CH3:16]>C(O)C>[CH3:13][C:4]1[O:3][C:2]([NH:17][CH2:14][CH2:15][CH3:16])=[N:6][C:5]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCCN
Reactant: Cc1oc(Cl)nc1-c1ccccc1
Solvent: CCO
Product: CCCNc1nc(-c2ccccc2)c(C)o1
Temperature: 110 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
To a solution of 2-chloro-5-methyl-4-phenyl-1,3-oxazole (1.46 g, 7.56 mmol) in ethanol (15 mL) was added propylamine (5 mL), and the mixture was stirred in a sealed tube at 110° C. for 8 hr. The reaction mixture was concentrated and water was added. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2:1) to give the title compound (850 mg, yield 52%) as a yellow powder.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.[CH3:11][CH2:12]O.Cl>>[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: CCO
Reactant: N[C@H]1CC[C@H](C(=O)O)CC1
Agent: Cl
Product: CCOC(=O)[C@H]1CC[C@H](N)CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A suspension of (trans)-4-aminocyclohexanecarboxylic acid (5 g, 34.9 mmol) in EtOH (100 mL, 1713 mmol) was treated with HCl (9.09 mL, 105 mmol) and the mixture was stirred at 60° C. overnight. The reaction mixture turned to clear solution. It was concentrated under reduced pressure and the residue was triturated with Et2O in CH3CN (50%) and the resulting white solid was collected. There was some product left in the filtrate so it was concentrated and triturated with Et2O in CH3CN (50%), the white solid was collected by filtration and combined with the white solid that was collected previously to provide 13A.HCl (5.25 g, 25.3 mmol, 72.4% yield). 1H NMR (400 MHz, CDCl3) δ ppm 4.06 (q, 2H, J=7.1 Hz); 3.01-3.15 (m, 1H); 1.34-2.31 (m, 9H); 1.18 (t, 3H, J=7.1 Hz).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:20]([CH3:24])[CH:21]([CH3:23])[CH3:22])=[N:4][C:5]2[O:11][CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][C:6]=2[N:19]=1.C(OCC)(=O)C.[ClH:31].[OH-].[Na+]>>[ClH:31].[CH3:24][N:20]([CH:21]([CH3:23])[CH3:22])[C:3]1[C:2]([CH3:1])=[N:19][C:6]2[CH2:7][NH:8][CH2:9][CH2:10][O:11][C:5]=2[N:4]=1
Reactant: Cc1nc2c(nc1N(C)C(C)C)OCCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cc1nc2c(nc1N(C)C(C)C)OCCNC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 76 %

Procedure:
A mixture of tert-butyl 2-methyl-3-[methyl(1-methylethyl)amino]-6,7-dihydropyrazino[2,3-f][1,4]oxazepine-8(9H)-carboxylate (109 mg) and 2N hydrogen chloride-ethyl acetate (4 mL) was stirred at room temperature for 4 hr. The reaction mixture was basified with 1N sodium hydroxide, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. To the obtained residue were added methanol (5 mL) and 1 N hydrochloric acid (0.325 mL), and the mixture was concentrated under reduced pressure. The obtained residue was purified by recrystallization (ethanol-diisopropyl ether) to give the title compound (67 mg, 76%) as a colorless powder.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:9]2.[CH2:21]([N:28]=[C:29]=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(#N)C>[CH2:21]([NH:28][C:29]([NH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:9]2)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)CCc1cc2cc(OCCCN)ccc2[nH]1
Reactant: O=C=NCc1ccccc1
Solvent: CC#N
Product: COC(=O)CCc1cc2cc(OCCCNC(=O)NCc3ccccc3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.5 %

Procedure:
To the solution of methyl 3-[5-(aminopropoxy)indolyl]propanoate (140 mg, 0.5 mmol), as prepared in the preceding step, in acetonitrile (10 mL) was added benzyl isocynate (135 mg, 1.0 mmol), and the mixture was stirred at ambient temperature overnight. After evaporating the solvent in vacuo, the residue was purified by flash column chromatography on silica gel (methylene chloride to 5% ethyl acetate in methylene chloride) to give the title compound as a white solid (85 mg, 42%). 1H-NMR (400 MHz, CDCl3) δ 7.28 (m, 5H), 7.20 (d, J=8.9 Hz, 1H), 7.10 (d, J=2.8 Hz, 1H), 7.05 (d, J=2.5 Hz, 1H), 6.81 (dd, J=8.8, 2.5 Hz, 1H), 6.38 (d, J=2.9 Hz, 1H), 4.66 (br s, 2H), 4.41 (t, J=6.8 Hz, 2H), 4.35 (d, J=5.7 Hz, 2H), 4.06 (t, J=5.8 Hz, 2H), 3.66 (s, 3H), 3.43 (q, J=6.2 Hz, 2H), 2.81 (t, J=6.8 Hz, 2H), 1.99 (t, J=6.1, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([N:8]=[C:9]=[O:10])[CH:7]=1.[NH2:13][C:14]1[CH:15]=[C:16]([CH:25]=[CH:26][CH:27]=1)[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18]>C1(C)C=CC=CC=1>[C:17]([C:16]1[CH:15]=[C:14]([NH:13][C:9]([NH:8][C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:11][CH3:12])=[O:10])[CH:27]=[CH:26][CH:25]=1)(=[O:18])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COc1ccc(Cl)cc1N=C=O
Reactant: Nc1cccc(C(=O)c2ccccc2)c1
Solvent: Cc1ccccc1
Product: COc1ccc(Cl)cc1NC(=O)Nc1cccc(C(=O)c2ccccc2)c1
Yield: 92.4 %

Procedure:
A mixture of 5-chloro-2-methoxyphenyl isocyanate (1.00 g, 5.4 mmol) and 3-aminobenzophenone (1.29 g, 6.5 mmol) was stirred in toluene (20 ml) for two days. The reaction was filtered and the filter cake washed with toluene. 1.9 g of the title compound was isolated.
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.O>C1COCC1>[N:14]1([S:2]([C:5]2[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=2)(=[O:4])=[O:3])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(S(=O)(=O)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.2 %

Procedure:
To a solution of 4-(chlorosulfonyl)-benzoic acid (0.5 g, 2.2 mmol) in THF (20 ml) was added morpholine (0.434 ml, 5 mmol) dropwise over 5 min, and this mixture stirred at r.t. for 1 h. Water (50 ml) was then added and the mixture agitated, the phases were separated and the aqueous phase extracted with EtOAc (2×50 ml). The combined organic phases were washed with satd. aq. NaCl solution, dried, filtered and evaporated. The residue was chromatographed over SiO2 (Merck 230-400 mesh) eluting with a CHCl3/(acetone+10% HCO2H) (9:1), the product fractions were pooled, evaporated and dried in vacuo (0.05 mmHg, 50° C.) to afford the title compound as a beige solid (270 mg, 20% yield), MS: m/e=271 (M+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[NH2:17].C(N(C(C)C)C(C)C)C.[F:27][C:28]([F:46])([F:45])[C:29]1[CH:30]=[C:31]([C:39]([CH3:44])([CH3:43])[C:40](Cl)=[O:41])[CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1>C(Cl)Cl>[F:27][C:28]([F:45])([F:46])[C:29]1[CH:30]=[C:31]([C:39]([CH3:43])([CH3:44])[C:40]([NH:17][C:9]2[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:8]=2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])=[O:41])[CH:32]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:34]=1
Reactant: Cc1ccccc1-c1ccc([N+](=O)[O-])cc1N
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccccc1-c1ccc([N+](=O)[O-])cc1NC(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 2 h
Yield: 89 %

Procedure:
A solution of 925 mg (4.05 mmol) 2′-methyl-4-nitro-biphenyl-2-ylamine and 1.03 ml (6.08 mmol) N-ethyldiisopropylamine in 9 ml CH2Cl2 was cooled in an ice bath and a solution of 1.42 g (4.46 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride in 1 ml CH2Cl2 was added dropwise. The reaction mixture was kept at room temperature for 2 hrs. After addition of CH2Cl2, the organic layer washed with 1 N NaOH solution and 1 N HCl solution, dried (MgSO4) and evaporated to give 1.84 g (89%) 2-(3,5-bis-trifluoromethyl-phenyl)-N-(2′-methyl-4-nitro-biphenyl-2-yl)-isobutyramide as yellow crystals, MS (ISP): 511.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:18]=[CH:17][CH:16]=[N:15][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[N:7]=1.[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][N:24]=[C:23]2[NH2:29]>>[Cl:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[N:7]=[C:2]([NH:29][C:23]2[C:22]3[C:26](=[CH:27][CH:28]=[C:20]([F:19])[CH:21]=3)[NH:25][N:24]=2)[C:3]2[CH:18]=[CH:17][CH:16]=[N:15][C:4]=2[N:5]=1
Reactant: Clc1ccccc1-c1nc(Cl)c2cccnc2n1
Reactant: Nc1n[nH]c2ccc(F)cc12
Product: Fc1ccc2[nH]nc(Nc3nc(-c4ccccc4Cl)nc4ncccc34)c2c1

Procedure:
Prepared from 4-Chloro-2-(2-chloro-phenyl)-pyrido[2,3-d]pyrimidine (100 mg, 0.36 mmol) and 5-Fluoro-1H-indazol-3-ylamine (108 mg, 0.72 mmol). Purification by preparative HPLC afforded the title compound as a yellow, di-TFA salt (45 mg, 22% yield). HPLC-Method A, Rt 3.00 min; 1H NMR (DMSO, 500 MHz): δ 13.0 (1H, s), 10.90(1H, bs), 9.15-9.05 (2H, m), 7.70 (1H, m), 7.60-7.30 (6H, m), 7.20 (1H, m); MS (m/z), MH+ 391.1.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:19]([O:21][CH2:22]C)=[O:20])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>OS(O)(=O)=O.CO.O>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:19]([O:21][CH3:22])=[O:20])=[N:11][C:12]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1ccc(-c2ccccc2)c(-c2ccccc2)n1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(-c2ccccc2)c(-c2ccccc2)n1

Procedure:
General Procedure E. A solution of ethyl 5,6-diphenylpyridine-2-carboxylate (Compound 21, 30 mg, 0.1 mmol) and conc. H2SO4 (3 drops) in MeOH (5 ml) was heated at 50° C. overnight. The mixture was diluted with water, and the products were extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over Na2SO4. The filtered solvent was concentrated in vacuo and the residue was purified by column chromatography (20% ethyl acetate in hexane) to obtain the title compound as a yellow solid.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:13]([O:20][C:21]1[CH:29]=[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:27]([C:38]([CH3:40])=[CH2:39])=[CH:26][C:22]=1[C:23](O)=[O:24])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:41][N:42]1[CH2:47][CH2:46][N:45]([CH2:48][C:49]2[CH:50]=[C:51]3[C:55](=[CH:56][CH:57]=2)[CH2:54][NH:53][CH2:52]3)[CH2:44][CH2:43]1>CN(C=O)C>[CH2:13]([O:20][C:21]1[CH:29]=[C:28]([O:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:27]([C:38]([CH3:40])=[CH2:39])=[CH:26][C:22]=1[C:23]([N:53]1[CH2:52][C:51]2[C:55](=[CH:56][CH:57]=[C:49]([CH2:48][N:45]3[CH2:46][CH2:47][N:42]([CH3:41])[CH2:43][CH2:44]3)[CH:50]=2)[CH2:54]1)=[O:24])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CN1CCN(Cc2ccc3c(c2)CNC3)CC1
Reactant: C=C(C)c1cc(C(=O)O)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: C=C(C)c1cc(C(=O)N2Cc3ccc(CN4CCN(C)CC4)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 52.3 %

Procedure:
1,1′-Carbonyldiimidazole (4.82 Kg, 29.8 mol) was added to a solution of 2,4-bis-benzyloxy-5-isopropenyl-benzoic acid (10.58 Kg, 28.3 mol, step 5) in DMF (21.2 L) at 25° C. After 20 mins at 25° C. a solution of 5-(4-Methyl-piperazin-1-ylmethyl)-2,3-dihydro-1H-isoindole (7.2 Kg, 31.1 mol, step 10) in DMF (7.2 L) maintaining a temperature below 35° C. and the solution stirred at 25° C. for a minimum of 12 h. The solid which had formed was removed by filtration, washed with isopropyl acetate (2×21.6 L) and dried at 35° C. to constant weight to give the title compound 8.7 Kg (77% yield, purity by hplc 97.5%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]([C:9]2[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=2)[OH:8])=[CH:5][N:4]=[N:3]1>O1CCOCC1.CCOC(C)=O.[O-2].[O-2].[Mn+4]>[CH3:1][N:2]1[C:6]([C:7]([C:9]2[CH:10]=[N:11][C:12]([C:15]([F:17])([F:16])[F:18])=[CH:13][CH:14]=2)=[O:8])=[CH:5][N:4]=[N:3]1
Reactant: Cn1nncc1C(O)c1ccc(C(F)(F)F)nc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cn1nncc1C(=O)c1ccc(C(F)(F)F)nc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a 25 mL flask containing (1-methyl-1H-1,2,3-triazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol (1 g, 3.87 mmol, Intermediate 53: step a) in 1,4-dioxane (10 mL) was added manganese dioxide (2.67 g, 30.65 mmol). The mixture was stirred in an 80° C. oil bath for 2 hours, then cooled to room temperature, diluted with EtOAc and filtered through Celite®. The solvents were removed under reduced pressure and the residue chromatographed (0-100% EtOAc/heptane gradient) to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1.[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C(C)=CC=CC=1>[CH2:13]([N:20]=[C:6]([OH:7])[C:5]1[C:4](=[CH:3][C:2]([Cl:1])=[CH:12][CH:11]=1)[C:9]([OH:8])=[O:10])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1OC(=O)c2cc(Cl)ccc21
Reactant: NCc1ccccc1
Solvent: Cc1ccccc1C
Product: O=C(O)c1cc(Cl)ccc1C(O)=NCc1ccccc1

Procedure:
The 4-chlorophthalic acid N-benzylimide is prepared by refluxing 4-chlorophthalic anhydride (13 g; 71.2 mmol) with 7.63 g (71.2 mmol) of benzylamine in xylene, the water being separated off. After evaporation of the mixture and recrystallisation of the residue from toluene/cyclohexane, 18.01 g (93% of theory) of 4-chlorophthalic acid N-benzylimide are obtained; melting point: 117°-119° C.