Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20]1)[N:13]=2)[CH:5]=[O:6].[BH4-].[Na+]>C1COCC1.CO>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:20][CH2:21]1)[N:13]=2
Reactant: O=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: OCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution at 0° C. of 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzaldehyde (2.00 g, 5.34 mmol) in THF (50 mL) and MeOH (25 mL) was added sodium borohydride (0.188 mL, 5.34 mmol). The reaction mixture was allowed to warm up to ambient temperature. The crude reaction mixture, after 1 h, was concentrated in vacuo and purified by silica gel chromatography to afford (3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)methanol. MS (ESI) m/z: calculated: 376.1: Observed: 377.0 (M++1).
Reaction SMILES: [C:1]([N:4]1[C@H:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][O:7][C:6](=[O:16])[C@@H:5]1[CH3:17])(=[O:3])[CH3:2].[C:18]([O:22][C:23](=[O:27])[C@H:24]([CH3:26])[NH2:25])([CH3:21])([CH3:20])[CH3:19]>ClCCl>[C:18]([O:22][C:23](=[O:27])[C@H:24]([CH3:26])[NH:25][C:6](=[O:16])[C@H:5]([CH3:17])[N:4]([C:1](=[O:3])[CH3:2])[CH:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:8][OH:7])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(=O)N1[C@@H](C)C(=O)OC[C@H]1c1ccccc1
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Solvent: ClCCl
Product: CC(=O)N(C(CO)c1ccccc1)[C@@H](C)C(=O)N[C@@H](C)C(=O)OC(C)(C)C
Reaction time: 48 h
Yield: 33.7 %

Procedure:
(3S,5R)-4-N-acetyl-3-methyl-5-phenyl-3,4,5,6,-tetrahydro-2H-1,4-oxazin-2-one (68) (220 mg, 0.94 mmol) and L-alanine tert-butyl ester (66) (205 mg, 1.42 mmol, 1.5 equiv.) were dissolved in anhydrous dichloromethane (14 mL) in a doubly sealed PTFE cylinder and subjected to ultra-high pressure of 19 kbar for 48 hours. After releasing the pressure, the solution was filtered through a short pad of CELITE® diatomaceous earth and removal of solvent from the filtrate in vacuo yielded the crude product which was purified by flash column chromatography on silica eluting with diethyl ether and dichloromethane (4:1) to furnish the title product as fine colourless needles (120 mg, 34%); m.p. 38-40° C.; v(max)(KBr) 3411 (O—H), 2980 (C—H), 1735 (C═O, lactone), 1646 (C═O, amide) cm−1; δH (250 MHz, DMSO-d) 8.06 (0.5H, d, /6.95 Hz, NH×0.5), 7.55-7.24 (5H, m, Ph), 6.54 (0.5H, d, J 6.38 Hz, NH×0.5), 5.82 (0.5H, t, /4.88 Hz, OH×0.5), 5.14-5.06 (1H, m, PhCH), 4.83 (0.5H, t, J 6.56 Hz, OH×0.5), 4.35 (0.5H, q, J 6.99 Hz, CH3CH×0.5), 4.08-4.03 (2H, m, CH2OH), 3.98-3.76 (1.5H, m, CHCH3×0.5 and CHCH3×1), 2.23 (1.5H, s, COCH3), 2.14 (1.5H, s, COCH3), 1.46-1.39 (12H, m, CHCH3×3 and C(CH3)3×9), 1.19 (1.5H, d, /7.15 Hz, CHCH3×1.5), 0.97 (1.5H, d, J 7.23 Hz, CHCH3×1.5); δc (62.5 MHz, DMSO-d) 171.8, 171.7, 171.0, 170.8, 170.2, 140.0, 138.2, 129.1, 128.2, 128.0, 126.8, 80.7, 62.7, 62.5, 60.8, 56.3, 53.4, 48.8, 48.7, 27.9, 17.5, 16.9, 16.7, 15.2; m/z (CL, NH3), 379 (MH+, 70%), 361 (18%), 305 (20%), 249 (38%), 234 (100%), and 219 (40%); HRMS for C20H31N2O5 requires 379.2225 found 379.2240; [α]D20 −37.0 (c 1.06 CHCl3).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH:23][CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH:25]3[C:30]([OH:32])=[O:31])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[C:40]([N:44]=[C:45]=[O:46])([CH3:43])([CH3:42])[CH3:41]>C1COCC1>[C:40]([NH:44][C:45]([N:27]1[CH2:28][CH2:29][C@@H:24]([NH:23][S:20]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH2:12][C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=[C:2]([CH3:1])[CH:11]=3)=[CH:15][CH:16]=2)(=[O:21])=[O:22])[C@@H:25]([C:30]([OH:32])=[O:31])[CH2:26]1)=[O:46])([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(C)(C)N=C=O
Reactant: Cc1cc(COc2ccc(S(=O)(=O)NC3CCNCC3C(=O)O)cc2)c2ccccc2n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCN(C(=O)NC(C)(C)C)C[C@@H]3C(=O)O)cc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 19 h
Yield: 82 %

Procedure:
To a solution of 0.5 g (1.1 mmol) of 4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-piperidine-3-carboxylic acid (Example 29, Step 1) and triethylamine (0.3 mL, 2.197 mmol) in THF (10 mL) at 0° C. was added tert-butylisocyanate (0.130 g, 1.32 mmol). The reaction mixture was allowed to warm to 25° C. and then stirred for 19 h. The THF was removed in vacuo and the resulting oil was diluted with ethyl acetate (100 mL). The organics were washed with saturated aqueous sodium chloride (2×30 mL), dried over MgSO4, filtered and concentrated to obtain a crude solid (0.580 g). The crude product was purified by reverse phase HPLC (Gilson) on a Phenomex C-18 semi-prep column eluting an acetonitrile:water gradient, to afford (3S,4R)-1-tert-butylcarbamoyl-4-[4-(2-methyl-quinolin-4-yl methoxy)-benzenesulfonylamino]-piperidine-3-carboxylic acid as an amorphous white solid (0.5 g, 88.5%). MS: 555 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][N:6]=[CH:5][C:4]=2[C:3]=1[C:11]([O:13][CH3:14])=[O:12].F[B-](F)(F)F.[CH3:20][O+](C)C>C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[Br:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH3:20])[N:7]=2)[C:3]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: C[O+](C)C
Reactant: COC(=O)c1c(Br)ccc2[nH]ncc12
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)c1c(Br)ccc2nn(C)cc12
Reaction time: 2.5 h
Yield: 72.2 %

Procedure:
To a solution of methyl 5-bromo-1H-indazole-4-carboxylate (4.50 g, 17.6 mmol) in ethyl acetate (176 mL) was added trimethyloxonium tetrafluoroborate (3.38 g, 22.9 mmol) at room temperature, and the mixture was stirred for 2.5 hr. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=5/95→30/70) to give the title compound (3.42 g, yield 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([Cl:15])=[C:11](Cl)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[F:17][C:18]([F:28])([F:27])[C:19]1[CH:26]=[CH:25][C:22]([CH2:23][OH:24])=[CH:21][CH:20]=1.[OH-].[K+]>CN(C)C=O>[Cl:15][C:12]1[C:13](=[O:14])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=[CH:10][C:11]=1[O:24][CH2:23][C:22]1[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:27])[F:28])=[CH:26][CH:25]=1
Reactant: O=c1c(Cl)c(Cl)cnn1-c1ccc(Cl)cc1
Reactant: OCc1ccc(C(F)(F)F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=c1c(Cl)c(OCc2ccc(C(F)(F)F)cc2)cnn1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.7 %

Procedure:
In 30 ml of N,N-dimethylformamide were dissolved 1.0 g (3.6 m mol) of 2-(4-chlorophenyl)-4,5-dichloro-3(2H)-pyridazinone and 0.64 g (3.6 m mol) of p-trifluoromethylbenzyl alcohol, and thereto was added 0.24 g of powdery potassium hydroxide. The reaction mixture was stirred at room temperature for one day. Then, the procedures in Synthesis Example 2 were repeated to give 900 mg of the intended compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH:5]=[CH:6][C:7]([OH:9])=[O:8]>C(O)C.[Pt]=O>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][CH2:6][C:7]([OH:9])=[O:8])[CH:10]=[CH:11][C:12]=1[O:13][CH3:14]
Reactant: COc1ccc(C=CC(=O)O)cc1F
Agent: O=[Pt]
Solvent: CCO
Product: COc1ccc(CCC(=O)O)cc1F
Reaction time: 1.5 h

Procedure:
2.0 g of 3-fluoro-4-methoxy cinnamic acid was dissolved in 100 ml ethyl alcohol. To this was added 100 mg of platinum oxide as a catalyst. The mixture was hydrogenated in a Parr apparatus for 90 minutes. After the hydrogenation was over, the mixture was filtered and concentrated. The solid was crystallized by adding water. Yield=1.63 g, m.p. 107°-112° C.
Reaction SMILES: O[C:2]1[C:3]([C:11]([OH:13])=[O:12])=[N:4][N:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8].O=P(Cl)(Cl)[Cl:16]>CN(C=O)C>[Cl:16][C:2]1[C:3]([C:11]([OH:13])=[O:12])=[N:4][N:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8]
Reactant: Cc1c(O)c(C(=O)O)nn(C)c1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1c(Cl)c(C(=O)O)nn(C)c1=O
Temperature: 90 °C
Reaction time: 2 h
Yield: 30.1 %

Procedure:
A mixture of 4-hydroxy-1,5-dimethyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (35.4 g, 192 mmol), catalytic amount of DMF (3 drop), and POCl3 (178 mL, 1.92 mol) was heated for 2 days at 90° C., and then the POCl3 was removed under reduced pressure. The crude material was quenched with ice, and the reaction mixture was stirred for 2 hours at room temperature. The precipitates formed out of the solution was filtered off and washed with ether. The precipitates collected were triturated with ether to afford 11.7 g (30%) of the desired product. The filtrate was extracted with EtOAc (2×). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude product that was triturated with ether and dried under reduced pressure to afford additional 9.56 g (24%) of the desired product. A total of 21.29 g (55%) of the desired product was obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[CH3:36][C:37]([OH:41])([CH:39]=[CH2:40])[CH3:38]>>[CH3:14][C:13]([C:11]1[S:12][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH2:40][CH2:39][C:37]([OH:41])([CH3:38])[CH3:36])[N:7]=2)=[C:9]([C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[N:10]=1)([CH3:16])[CH3:15]
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Reactant: C=CC(C)(C)O
Product: CC(C)(O)CCc1nccc(-c2sc(C(C)(C)C)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 247 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (0.15 g, 0.278 mmol) and 2-methyl-3-buten-2-ol (0.087 ml, 0.835 mmol), the title compound was obtained as a solid (164 mg, 57% yield); 1H NMR (400 MHz, DMSO-d6) ppm 10.75 (s, 1H), 8.48 (d, J=5.31 Hz, 1H), 7.55 (m, 1H), 7.46 (m, 4H), 7.30 (t, J=8.33 Hz, 1H), 6.64 (d, J=5.31 Hz, 1H), 4.29 (s, 1H), 2.87 (m, 2H), 1.76 (m, 2H), 1.42 (s, 9H), 1.12 (s, 6H); MS (ESI): 592 [M+H]+.
Reaction SMILES: [H-].[Na+].CS(C)=O.[I-].[CH3:8][S+](C)(C)=O.[CH2:13]([O:15][C:16](=[O:31])[CH:17]=[C:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)[CH3:14]>O>[CH:17]1([C:16]([O:15][CH2:13][CH3:14])=[O:31])[C:18]2([CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[CH2:8]1
Reactant: CCOC(=O)C=C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C1CC12CCN(C(=O)OC(C)(C)C)CC2
Temperature: 15 °C
Reaction time: 0.33 h
Yield: 54.1 %

Procedure:
Sodium hydride (60% in mineral oil) (2.06 g, 85.8 mmol) was added to dimethylsulfoxide (100 mL) at 15° C., and the mixture was stirred at 15° C. for 20 min. See FIG. 6. Trimethylsulfoxonium iodide (19.0 g, 85.8 mmol) was added, and the reaction mixture was stirred for 2 h, then 165b (7.72 g, 28.7 mmol) was added and the resulting mixture was stirred at 15° C. for 50 h. Water (100 mL) was added, and the mixture was extracted with EtOAc (200 mL×3). The combined organic extracts were washed with brine (100 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether: EtOAc=2:1) to yield 6-tert-butyl 1-ethyl 6-azaspiro[2.5]octane-1,6-dicarboxylate 165c (4.4 g, 54%) as a colorless oil. 1H NMR (400 MHz, CD3CN): δ 4.06-4.04 (m, 2H), 3.40-3.18 (m, 4H), 1.92-1.90 (m, 1H), 1.59-1.50 (m, 3H), 1.39-1.30 (m, 10H), 1.19-1.16 (m, 3H), 1.03-1.01 (m, 1H), 0.91-0.93 (m, 1H).
Reaction SMILES: Br[CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1)[CH3:3].[Cl:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[O:20][C:19](=[O:24])[CH:18]=[C:17]2[NH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1>[C:10]([C:7]1[CH:8]=[CH:9][C:4]([CH:2]([N:29]2[CH2:30][CH2:31][CH:26]([NH:25][C:17]3[C:16]4[C:21](=[CH:22][CH:23]=[C:14]([Cl:13])[CH:15]=4)[O:20][C:19](=[O:24])[CH:18]=3)[CH2:27][CH2:28]2)[CH3:3])=[CH:5][CH:6]=1)(=[O:12])[CH3:11]
Reactant: O=c1cc(NC2CCNCC2)c2cc(Cl)ccc2o1
Reactant: CC(=O)c1ccc(C(C)Br)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C(C)N2CCC(Nc3cc(=O)oc4ccc(Cl)cc34)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 4.2 %

Procedure:
To a solution of 1-[4-(1-bromoethyl)-phenyl]-ethanone (0.35 g, 1.54 mmol) and 6-chloro-4-(piperidin-4-ylamino)-chromen-2-one (0.42 g, 1.50 mmol) in dry THF (15 mL) was added Cs2CO3 (2.44 g, 7.50 mmol). The reaction mixture was allowed to stir at room temperature for 12 h, after which time THF was removed in vacuo and the white residue was partitioned between H2O (250 mL) and ethyl acetate (250 mL). After removal of the organic layer, the aqueous layer was washed with an addition portion of ethyl acetate (250 mL), and the combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to provide a yellow oil. The crude product was purified by flash chromatography through a silica gel column with dichloromethane and methanol (95: 5 v/v). The resulting yellow residue was then treated with 4 M HCl in dioxane, solvent was removed in vacuo to provide a yellow solid. Crystallization from dichloromethane provided the HCl salt of the desired compound (0.027 g, 4%) as a white solid MS (ESI(+)Q1MS) m/z 425 (M+H)+; 1H NMR (300 MHz, DMSO) δ ppm 10.84-10.97 (m, 1H), 8.32-8.38 (m, 1H), 8.00-8.08 (m, 2H), 7.75-7.84 (m, 2H), 7.58-7.63 (m, 1H), 7.48-7.54 (m, 1H), 7.30-7.35 (m, 1H), 5.39 (s, 1H), 4.51-4.63 (m, 1H), 3.60-3.77 (m, 2H), 3.24-3.40 (m, 1H), 2.73-2.95 (m, 2H), 2.59 (s, 3H), 1.95-2.14 (m, 4H), 1.72 (d, 3H). The pure racemic mixture was separated into enantiomers by prep HPLC chiral chromatography using a CHIRALPAK AD column: 7.5/7.5/85 MeOH/EtOH/Hexanes at 0.8 ml/min. Enantiomers had retention times of 4.2 and 6.4 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[N+:9]([C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15])([O-:11])=[O:10]>>[N+:9]([C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:15])([O-:11])=[O:10]
Reactant: Nc1ccc(Br)cc1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Product: O=C(Nc1ccc(Br)cc1)c1ccccc1[N+](=O)[O-]
Yield: 92.9 %

Procedure:
Using the procedure described in Example 93, Part A, 4-bromoaniline (11.6 mmol) and 2-nitrobenzoyl chloride (12.8 mmol) yielded 3.46 g (93%) of the title compound.
Reaction SMILES: [OH-].[K+].[C:3]1([SH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[C:11]1[C:12]2[C:17]([C:18](Br)=[C:19]3[C:24]=1[CH:23]=[CH:22][CH:21]=[CH:20]3)=[CH:16][CH:15]=[CH:14][CH:13]=2>CC(N(C)C)=O>[S:9]([C:11]1[C:12]2[C:17]([C:18]([S:9][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[C:19]3[C:24]=1[CH:23]=[CH:22][CH:21]=[CH:20]3)=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Sc1ccccc1
Reactant: Brc1c2ccccc2c(Br)c2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Product: c1ccc(Sc2c3ccccc3c(Sc3ccccc3)c3ccccc23)cc1
Temperature: 170 °C

Procedure:
Potassium hydroxide (19.6 g) and thiophenol (35.5 ml) were heated at 170 degrees C. in dimethylacetamide for two hours. 9,10-dibromoanthracene (37.5 g) was added and the mixture heated at 170 degrees C. an additional two hours. (The corresponding dichloro compound has also been used successfully.) The mixture was quenched with water and the precipitate recrystallized from chloroform/ethanol to give DTPA.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[C:13]([CH3:14])=[CH:12][N:11]=[C:10]([NH:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.C([O-])(O)=[O:23].[Na+]>Cl>[CH3:14][C:13]1[C:8]([C:6]2[CH:5]=[CH:4][NH:3][C:2](=[O:23])[CH:7]=2)=[N:9][C:10]([NH:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[N:11][CH:12]=1
Reactant: O=C([O-])O
Reactant: Cc1cnc(NC2CCOCC2)nc1-c1ccnc(F)c1
Agent: Cl
Agent: [Na+]
Product: Cc1cnc(NC2CCOCC2)nc1-c1cc[nH]c(=O)c1
Reaction time: 2 h
Yield: 80.3 %

Procedure:
1M HCl (10 mL) was added to 4-(2-fluoropyridin-4-yl)-5-methyl-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-amine (0.158 g, 0.548 mmol). The mixture was heated at reflux. After 2 hours, the cooled reaction mixture was neutralized with solid NaHCO3. The resulting solid was collected by vacuum filtration and dried to afford 4-(5-methyl-2-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-4-yl)pyridin-2(1H)-one (0.126 g, 0.440 mmol, 80.3% yield) as a solid.
Reaction SMILES: C([N:8]1[CH2:16][CH2:15][CH:14]2[CH:10]([CH2:11][C:12]3[CH:19]=[CH:18][S:17][C:13]=32)[CH2:9]1)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].CC(Cl)OC(Cl)=O>ClC(Cl)C>[CH:19]1[C:12]2[CH2:11][CH:10]3[CH:14]([C:13]=2[S:17][CH:18]=1)[CH2:15][CH2:16][NH:8][CH2:9]3
Reactant: c1ccc(CN2CCC3c4sccc4CC3C2)cc1
Agent: CC(Cl)OC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(Cl)Cl
Product: c1cc2c(s1)C1CCNCC1C2
Temperature: 22 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
The product of step f) (1.16 g, 4.3 mmol) in dichloroethane (21 ml) was treated with K2CO3 (2.38 g, 17.2 mmol) and Ace-Cl (1.86 ml, 17.2 mmol) at 80° C. for 16 hours. Next, the reaction mixture was filtered, concentrated and the residue was dissolved in anhydrous MeOH (25 ml) and stirred for 1 hour at 22° C. The MeOH was concentrated and triturated with ether to give 874 mg (94%) of the subtitle compound. MS calculated for C10H13NS+H 180, observed 180.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]=[O:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:14][NH:15][CH3:16]>O1CCOCC1.O>[CH3:14][N:15]([CH3:16])[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]=[O:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: O=Cc1ccc2ncnc(Cl)c2c1
Reactant: CNC
Solvent: O
Solvent: C1COCCO1
Product: CN(C)c1ncnc2ccc(C=O)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Chloro-quinazoline-6-carbaldehyde (200 mg, 1 mmol) was dissolved in 10 ml dioxane. To this solution was added a solution of dimethylamine in water (Seq.). The mixture was stirred during 2 h at r.t. Evaporation of the solvents and remaining amine under high vacuum afforded pure 4-Dimethylamino-quinazoline-6-carbaldehyde as a yellow solid, which was used for the next step without further purification (190 mg=91%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2.[F:16][C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][C:18]=1[C:32]1[C:33]([C:38]#[N:39])=[CH:34][CH:35]=[CH:36][CH:37]=1>>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[C:3]3[C:8](=[N:7][C:6]([C:12]([F:15])([F:14])[F:13])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)=[CH:19][C:18]=1[C:32]1[C:33]([C:38]#[N:39])=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccccc3C#N)c2)OC1(C)C
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2n1
Product: N#Cc1ccccc1-c1cc(-c2ccnc3nc(C(F)(F)F)ccc23)ccc1F
Yield: 66 %

Procedure:
5-Chloro-2-trifluoromethyl[1,8]naphthyridine (50 mg, 0.22 mmol) was coupled to 2′-fluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile (prepared as described in Example 2, steps a) to e), 90 mg, 0.28 mmol) as described in Example 7 part g), affording 2′-fluoro-5′-(7-trifluoromethyl[1,8]naphthyridin-4-yl)biphenyl-2-carbonitrile (56 mg, 66%). δH (360 MHz, CDCl3) 7.47 (1H, t, J 9.3), 7.53-7.62 (5H, m), 7.71 (1H, td, J, 7.7 and 1.4), 7.85 (1H, dd, J 7.7 and 0.7), 7.88 (1H, d, J 8.4), 8.71 (1H, d, J 8.8), 9.28 (1H, d, J 4.6). m/z (ES+) 394 [MH]+.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[N:10]=[C:9]([OH:19])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][O:19][C:9]2[CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[N:10]=2)=[CH:23][CH:22]=1
Reactant: Oc1cc(-c2ccccc2)nc(-c2ccncc2)n1
Reactant: Fc1ccc(CBr)cc1
Product: Fc1ccc(COc2cc(-c3ccccc3)nc(-c3ccncc3)n2)cc1

Procedure:
The title compound was prepared from 6-phenyl-2-pyridin-4-yl-pyrimidin-4-ol (which was obtained in Intermediate 3) and 4-fluorobenzyl bromide according to Method A; 1H NMR (DMSO-d6, 300 MHz) δ 5.72 (s, 2H), 7.50-7.70 (m, 6H), 7.93 (d, J=15.0 Hz, 2H), 8.30-8.37 (m, 2H), 8.37-8.41 (m, 2H), 8.80-8.90 (m, 2H); LC retention time 3.02 min; MS: m/z (ESI) 358 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[NH:16][N:17]=2)=[CH:8][CH:7]=1.[N:19]1[CH:24]=[CH:23][C:22]([C:25](O)=[O:26])=[CH:21][N:20]=1>>[N:19]1[CH:24]=[CH:23][C:22]([C:25]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]2[CH:7]=[CH:8][C:9]([C:12]3[CH:13]=[CH:14][C:15](=[O:18])[NH:16][N:17]=3)=[CH:10][CH:11]=2)=[O:26])=[CH:21][N:20]=1
Reactant: O=C(O)c1ccnnc1
Reactant: NCCCCc1ccc(-c2ccc(=O)[nH]n2)cc1
Product: O=C(NCCCCc1ccc(-c2ccc(=O)[nH]n2)cc1)c1ccnnc1

Procedure:
By treating 6-[4-(4-aminobutyl)phenyl]pyridazin-3(2H)-one and pyridazin-4-carboxylic acid in the same manner as in Example 87, 6-[4-[4-(pyridazin-4-ylcarbonylamino)butyl]-phenyl]pyridazin-3(2H)-one was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[C:5]([NH:10][C:11](=O)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:4]([CH2:19][CH3:20])[CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.P(Cl)(Cl)(Cl)=O.CO[CH:34](OC)[CH2:35][NH2:36].Cl>CC(O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[C:5]([N:10]2[CH:34]=[CH:35][N:36]=[C:11]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:4]([CH2:19][CH3:20])[CH:3]=1
Reactant: COC(CN)OC
Reactant: CCc1cc(Br)cc(CC)c1NC(=O)c1ccccc1
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(C)O
Product: CCc1cc(Br)cc(CC)c1-n1ccnc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 82.6 %

Procedure:
In a 250 mL round-bottom flask added N-(4-bromo-2,6-diethylphenyl)benzamide (7.64 g, 23 mmol), phosphorus pentachloride (4.79 g, 23 mmol), and phosphorus oxychloride (40 mL). The reaction was heated up to reflux under nitrogen. After 2.5 h, the reaction mixture was cooled and phosphorus oxychloride was distilled off using short path distillation apparatus. 2-propanol (40 mL) and 2,2-dimethoxyethanamine (48.4 g, 460 mmol) was added. The reaction was stirred at room temperature for 4 h. Concentrated hydrochloric acid (40 mL) was added carefully, and the reaction was heated to reflux overnight. The solution was decanted from black solid and neutralized with 10% sodium hydroxide solution, extracted with ethyl acetate. The organic layers were dried over magnesium sulfate. The residue was purified by silica gel column chromatography eluting with 20 and 30% ethyl acetate/hexanes. 6.75 g (83% yield) of product was obtained after purification.