Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[N:10]=[C:9](Cl)[C:8]([F:12])=[C:7]([O:13][CH3:14])[N:6]=1.O.C(OCC)(=O)C.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[N:6]=[C:7]([O:13][CH3:14])[C:8]([F:12])=[C:9]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:10]=1
Reactant: C1COCCN1
Reactant: COC(=O)Cc1nc(Cl)c(F)c(OC)n1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)Cc1nc(OC)c(F)c(N2CCOCC2)n1

Procedure:
A solution of 8.36 g of (4-chloro-5-fluoro-6-methoxypyrimidin-2-yl)acetic acid methyl ester in 76 ml of morpholine is stirred at ambient temperature for one and a half hours. The reaction medium is concentrated under reduced pressure. The residue obtained is taken up with 50 ml of water and 200 ml of ethyl acetate. After settling out, the organic phase is dried over magnesium sulfate, filtered, and then concentrated under reduced pressure, so as to give 8.86 g of (5-fluoro-4-methoxy-6-morpholin-4-ylpyrimidin-2-yl)acetic acid methyl ester in the form of a beige solid, the characteristics of which are the following:
Reaction SMILES: C[Al](C)C.[NH2:5][CH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.C[O:13][C:14](=O)[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[C:24]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=3)=[N:25][O:26][C:27]=2[CH2:28][OH:29])=[N:17][CH:16]=1>O1CCOCC1>[F:37][C:32]1[CH:31]=[C:30]([C:24]2[C:23]([CH2:22][O:21][C:18]3[CH:19]=[CH:20][C:15]([C:14]([NH:5][CH:6]4[CH2:11][CH2:10][O:9][CH2:8][CH2:7]4)=[O:13])=[CH:16][N:17]=3)=[C:27]([CH2:28][OH:29])[O:26][N:25]=2)[CH:35]=[CH:34][C:33]=1[F:36]
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2CO)nc1
Reactant: NC1CCOCC1
Agent: C[Al](C)C
Solvent: C1COCCO1
Product: O=C(NC1CCOCC1)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2CO)nc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 49.9 %

Procedure:
A trimethylaluminium solution (2 M in toluene, 532 μL, 1.06 mmol) was added to a solution of 4-aminotetrahydropyran (111 mg, 1.06 mmol) in dioxane (5 mL). 6-[3-(3,4-Difluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (100 mg, 0.27 mmol) in dioxane (5 mL) was added after 1 h at 50° C. The reaction mixture was stirred at 85° C. overnight. Again trimethylaluminium solution (2 M in toluene, 500 μL, 1.0 mmol) was added and stirring was continued for 3 h at 85° C. The solvent was removed by distillation. The residue was purified by chromatography (silica, dichloromethane:methanol=100:0 to 95:5) to afford the title compound (60 mg, 50%) as a white solid. MS: m/e=446.4 [M+H]+.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][NH:10][CH2:9][CH2:8]2.C(N(CC)CC)C.Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>C(Cl)Cl>[CH2:24]([O:23][C:21]([N:10]1[CH2:9][CH2:8][C:7]2[C:12](=[C:3]([OH:2])[CH:4]=[CH:5][CH:6]=2)[CH2:11]1)=[O:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Oc1cccc2c1CNCC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCc2cccc(O)c2C1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To an-ice cooled suspension of 8-hydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (746 mg, 5.0 mmol, 1.0 eq.) and triethylamine (2.13 mL, 15.0 mmol, 3.0 eq.) in DCM (25 mL), benzyl chloroformate (0.83 mL, 5.5 mmol, 1.1 eq.) was added dropwise. The solution was stirred at 0° C. for 1 hour and further at r.t. for 4 hours. The reaction was quenched with 1M aq. citric acid soln. (50 mL). The layers were separated. The aq. phase was extracted with DCM (3×50 mL). The comb. org. phases were dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in THF (20 mL) and 1M aq. NaOH soln. (6 mL) was added. The mixture was stirred at r.t. for 68 hours. The org. solvent was removed in vacuo. The resulting aq. layer was acidified with 2N aq. HCl soln. and extracted with DCM (3×25 ml). The comb. org. phases were dried over MgSO4 and concentrated in vacuo. The residue was purified by CC (SiO2, Hept/AcOEt 8:2 to 7:3) to give the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[C:3]([CH:19]([F:21])[F:20])=[CH:4][C:5]2[C:14]3[C:9](=[C:10]([CH3:15])[N:11]=[CH:12][CH:13]=3)[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=1.[OH:22][CH2:23][C@@H:24]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:25][CH:26]([CH3:28])[CH3:27].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1>[F:20][CH:19]([F:21])[C:3]1[C:2]([O:22][CH2:23][C@@H:24]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])[CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:18][C:6]2[N:7]([CH3:17])[C:8](=[O:16])[C:9]3[C:14]([C:5]=2[CH:4]=1)=[CH:13][CH:12]=[N:11][C:10]=3[CH3:15]
Reactant: CC(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(Cl)c(C(F)F)cc21
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)c(C(F)F)cc21
Temperature: 25 °C
Yield: 38.2 %

Procedure:
A solution of 8-chloro-9-(difluoromethyl)-4,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (700 mg, 1.519 mmol), (S)-tert-butyl (1-hydroxy-4-methylpentan-2-yl)carbamate (660 mg, 3.04 mmol), 2-di-t-butylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (387 mg, 0.912 mmol), PdOAc2 (34.1 mg, 0.152 mmol) and Cs2CO3 (990 mg, 3.04 mmol) in toluene (20 mL) was heated at 80° C. for 16 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was taken up in ethyl acetate and filtered through diatomaceous earth (Celite®). The organic layer was washed with brine and water; dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography using EtOAc-hexane as the eluent to afford (S)-tert-butyl (1-((9-(difluoromethyl)-4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (0.6 g, 0.58 mmol, 54% yield) as a brown gummy solid. LC/MS (ESI) m/e 490.2 [(M+H)+, calcd for C26H34F2N3O4, 490.2]; LC/MS retention time (method B): tR=2.72 min.
Reaction SMILES: Cl.[S:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[NH2:11].[C:12]1([S:18]([Cl:21])(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1>[ClH:21].[S:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[NH:11][S:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:20])=[O:19]
Reactant: Nc1cc2ncccc2s1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc2ncccc2s1)c1ccccc1
Reaction time: 16 h
Yield: 25.2 %

Procedure:
To a suspension of compound 146-A (0.65 g, 2.91 mmol) in pyridine (30 mL), at rt, was added benzenesulfonyl chloride (0.751 mL, 5.83 mmol), and the reaction was stirred for 16 h. Additional benzenesulfonyl chloride (0.225 mL, 1.76 mmol) was added and the reaction mixture was stirred at rt for an additional 16 h. The solvent was evaporated in vacuo, the residue treated with 1N HCl and extracted several times with dichloromethane and ethyl acetate. The aqueous layer was filtered, dissolved in methanol, and the combined organic extracts were evaporated in vacuo. The resultant residue was purified by reverse phase HPLC, eluting with an MeCN—H2O gradient to afford compound 146-B as an orange solid (0.24 g, 20%). 1H-NMR (CD3CN): δ 6.92 (s, 1H), 7.2 8.0 (d of d, 1H), 7.46 (m, 2H), 7.56 (m, 1H), 7.85 (m, 2H), 8.27 (d, 1H), 8.35 (d, 1H); MS: m/z 291.09 (MH+).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8].CN1CCOCC1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH2:43]([O:45][C:46]1[CH:67]=[CH:66][CH:65]=[CH:64][C:47]=1[O:48][C@@H:49]1[CH2:54][CH2:53][CH2:52][N:51]([C:55]2[N:60]=[CH:59][C:58]([C:61](O)=[O:62])=[CH:57][N:56]=2)[CH2:50]1)[CH3:44]>C1COCC1.CS(C)=O>[CH2:43]([O:45][C:46]1[CH:67]=[CH:66][CH:65]=[CH:64][C:47]=1[O:48][C@@H:49]1[CH2:54][CH2:53][CH2:52][N:51]([C:55]2[N:60]=[CH:59][C:58]([C:61]([NH:2][CH2:3][C:4]3[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=3)[C:7]([O:9][CH3:10])=[O:8])=[O:62])=[CH:57][N:56]=2)[CH2:50]1)[CH3:44]
Reactant: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)O)cn2)C1
Reactant: COC(=O)c1cccc(CN)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)NCc3cccc(C(=O)OC)c3)cn2)C1
Temperature: 15 °C
Reaction time: 4 h
Yield: 74.5 %

Procedure:
To a 500-mL 3-neck flask was added methyl 3-(aminomethyl)benzoate hydrochloride (12.9 g, 64.1 mmol) followed by DMSO (26 mL). The solution was cooled to 15° C. N-Methyl morpholine (27 mL, 240 mmol) was added followed by EDCl (13 g, 68 mmol) and HOBT (4.09 g, 30 mmol), maintaining the temperature at 15° C. A solution of (R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylic acid (20.94 g, 60.98 mmol) in THF (100 mL) was added dropwise over 10 min. The reaction mixture was warmed to 20-25° C. and stirred for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between water (200 mL) and pentane-ethyl acetate (1:2, 300 mL). The aqueous phase was further extracted with ethyl acetate (2 times with 100 mL). The combined organic extracts were rinsed sequentially with water (200 mL), saturated aqueous sodium bicarbonate solution (2 times with 100 mL), and brine (2 times with 25 mL). The organic layer was then dried over sodium sulfate, filtered, and concentrated to afford (R)-methyl 3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)benzoate (22.3 g). MS (ES+) 491.3 (M+H).
Reaction SMILES: CC1C(C2C=C(NC(=O)C)C(=O)NC=2)=C(C)[O:4]N=1.N1C2C(=C(CO)C=CC=2)C=C1.[C:30]1([P:36]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[P:36]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:4]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(=O)Nc1cc(-c2c(C)noc2C)c[nH]c1=O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: OCc1cccc2[nH]ccc12
Solvent: C1CCOC1
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 31 (700 mg, 2.83 mmol), (1H-indol-4-yl)methanol (1.25 g, 8.50 mmol), and triphenylphosphine (2.97 g, 11.3 mmol) in tetrahydrofuran (30 mL) at 60° C. under nitrogen atmosphere was added diisopropyl azodicarboxylate (1.43 g, 7.07 mmol). The mixture was cooled to room temperature, concentrated, and purified by chromatography (silica gel, 0-100% ethyl acetate/hexanes) to give crude 59 (1.94 g, contained Ph3PO).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:17]3[CH:22]=[CH:21][N:20]=[N:19][CH:18]=3)=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.[CH:23]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([CH3:25])[CH3:24].Cl>C(O)CCCC>[C:11]1([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([N:29]4[CH2:30][CH2:31][N:26]([CH:23]([CH3:25])[CH3:24])[CH2:27][CH2:28]4)=[N:7][N:6]3[C:8]=2[C:17]2[CH:22]=[CH:21][N:20]=[N:19][CH:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)N1CCNCC1
Reactant: Clc1ccc2nc(-c3ccccc3)c(-c3ccnnc3)n2n1
Agent: Cl
Solvent: CCCCCO
Product: CC(C)N1CCN(c2ccc3nc(-c4ccccc4)c(-c4ccnnc4)n3n2)CC1
Temperature: 150 °C
Yield: 83.4 %

Procedure:
The mixture of 0.45 g (1.5 mmol) of 6-chloro-2-phenyl-3-(pyridazin-4-yl)imidazo[1,2-b]pyridazine and 0.38 g (2.9 mmol) of 1-isopropylpiperazine in 6 ml of pentanol is heated in a sealed tube at 150° C. for 2 days. The mixture is cooled and poured into a 1N aqueous solution of hydrochloric acid. This solution is washed with diethyl ether and then basified using an aqueous solution of sodium hydroxide. The product is finally extracted with dichloromethane, and the organic phase is dried over sodium sulfate, filtered and concentrated under reduced pressure. A brown oil is obtained, which is chromatographed on silica gel, elution being carried out with a mixture of aqueous ammonia, methanol and dichloromethane (0.4/4/96), to give 0.50 g of a solid.
Reaction SMILES: C([NH:8]C1C=C(C=C(S(Cl)(=O)=O)C=1C1C=CC=CC=1)C(O)=O)C1C=CC=CC=1.[CH2:28]([S:31][C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([S:47](Cl)(=[O:49])=[O:48])[C:40]=1[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]([OH:37])=[O:36])[CH:29]=[CH2:30]>>[CH2:28]([S:31][C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([S:47](=[O:49])(=[O:48])[NH2:8])[C:40]=1[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]([OH:37])=[O:36])[CH:29]=[CH2:30]
Reactant: C=CCSc1cc(C(=O)O)cc(S(=O)(=O)Cl)c1-c1ccccc1
Reactant: O=C(O)c1cc(NCc2ccccc2)c(-c2ccccc2)c(S(=O)(=O)Cl)c1
Product: C=CCSc1cc(C(=O)O)cc(S(N)(=O)=O)c1-c1ccccc1

Procedure:
By replacing in Example 1, step G, 3-benzylamino-5-chlorosulfonyl-4-phenylbenzoic acid with 3-allylthio-5-chlorosulfonyl-4-phenylbenzoic acid, and following the procedure described, 3-allylthio-4-phenyl-5-sulfamylbenzoic acid is obtained as a hydrate with a melting point of 78°-81° C.
Reaction SMILES: C([C:4]1[CH:5]=[N:6][N:7]([C:10]2[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[CH:13]=[CH:12][N:11]=2)[C:8]=1[OH:9])(O)=O>Cl>[OH:9][C:8]1[N:7]([C:10]2[CH:15]=[C:14]([CH:13]=[CH:12][N:11]=2)[C:16]([OH:18])=[O:17])[N:6]=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccnc(-n2ncc(C(=O)O)c2O)c1
Agent: Cl
Product: O=C(O)c1ccnc(-n2nccc2O)c1
Yield: 16.5 %

Procedure:
A solution of 2-(4-carboxy-5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carboxylic acid (1.7 g, 6.8 mmol) in conc. HCl (50 mL) was heated at 90° C. for 2 h. The reaction mixture was cooled, extracted with EtOAc (200 mL), and washed with water and brine. The organic phase was dried, concentrated, and recrystallized from EtOH to afford the title compound (230 mg, 47%) as a yellow solid. 1H NMR (400 MHz, CD3OD): δ 4.86 (1H, s), 7.68 (1H, s), 7.80 (1H, d, J=5.2 Hz), 8.60 (1H, d, J=1.6 Hz), 8.73 (1H, br). [M+H] Calc'd for C9H7N3O3, 206. Found, 206.
Reaction SMILES: [F:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]([NH:21][CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])=O)=[CH:16][CH:17]=3)[N:12]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[C:11]=2[CH:34]([CH3:36])[CH3:35])=[O:9])=[CH:4][CH:3]=1.C(N1C2C(=CC=C(C(NCC(O)(C)C)=O)C=2)C(C(NCC2C=CC(F)=C(F)C=2)=O)=C1C(C)C)C1C=CC=CC=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C1C=CC=CC=1>[CH3:25][C:23]1([CH3:24])[O:26][C:19]([C:15]2[CH:14]=[C:13]3[C:18]([C:10]([C:8]([NH:7][CH2:6][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:38][CH:37]=4)=[O:9])=[C:11]([CH:34]([CH3:36])[CH3:35])[N:12]3[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[CH:17][CH:16]=2)=[N:21][CH2:22]1
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)cc2)c2ccc(C(=O)NCC(C)(C)O)cc2n1Cc1ccccn1
Agent: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(C(=O)NCC(C)(C)O)cc2n1Cc1ccccc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: c1ccccc1
Product: CC(C)c1c(C(=O)NCc2ccc(F)cc2)c2ccc(C3=NCC(C)(C)O3)cc2n1Cc1ccccn1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a solution of N3-(4-fluorobenzyl)-N6-(2-hydroxy-2-methylpropyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-3,6-dicarboxamide (Compound 68, 23 mg, 0.043 mmol) in benzene (6 ml) at 25° C. was added P2O5 (120 mg, 0.86 mmol). The mixture was stirred at 50° C. for 4 h, quenched with 6N NaOH (1 ml), extracted several times with EtOAc, washed with H2O, brine, dried over Na2SO4, concentrated in vacuo. The residue was purified by chromatography on silica gel (100% EtOAc) to yield the title compound as yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1B(O)O>>[CH3:18][C:16]1[NH:15][N:14]=[C:13]([NH:12][C:4]2[N:3]=[C:2]([C:21]3[CH:20]=[CH:19][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:17]=1
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Product: Cc1cc(Nc2cc3ccccc3c(-c3ccc4ccccc4c3)n2)n[nH]1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and naphthalene-2-boronic acid to give (5-methyl-1H-pyrazol-3-yl)-(1-naphthalen-2-yl-isoquinolin-3-yl)-amine. LC-MS m/e 351 (MH+).
Reaction SMILES: O[CH:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4]2[CH:12]=[CH:13][CH:14]=[CH:15][C:3]1=2.Cl>C(O)(C)C>[N:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[CH2:2][C:3]3[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=3[O:5][C:6]=12
Reactant: OC1c2ccccc2Oc2ncccc21
Agent: Cl
Solvent: CC(C)O
Product: c1ccc2c(c1)Cc1cccnc1O2
Reaction time: 8 h
Yield: 81.5 %

Procedure:
A mixture of 10 g of 5-hydroxy-5H-[1]benzopyrano[2,3-b]pyridine, 100 ml of isopropyl alcohol and 10 ml of 20% hydrochloric acid in isopropyl alcohol is refluxed for 3 hours. The reaction mixture is allowed to stand overnight, and then the isopropyl alcohol is removed by distillation under reduced pressure. An aqueous potassium carbonate solution is added to the residue, and the mixture is extracted with chloroform. The chloroform layer is dried, and the chloroform is distilled off. The residue is recrystallized from isopropyl ether or carbon tetrachloride to give 7.5 g of 5H-[1]benzopyrano[2,3-b]pyridine as white crystals melting at 87°-88°C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=[O:27])[C@@H:7]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:8][C:9]1[CH:19]=[CH:18][C:12]2[O:13][C:14]([F:17])([F:16])[O:15][C:11]=2[CH:10]=1)(=[O:3])[CH3:2].[Li].CC([O-])(C)C.CC([O-])(C)C.CC([O-])(C)C.[Al+3]>C(O)C>[C:1]([O:4][CH2:5][C@@H:6]([OH:27])[C@@H:7]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:8][C:9]1[CH:19]=[CH:18][C:12]2[O:13][C:14]([F:16])([F:17])[O:15][C:11]=2[CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)[C@H](Cc1ccc2c(c1)OC(F)(F)O2)C(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Al+3]
Agent: [Li]
Solvent: CCO
Product: CC(=O)OC[C@@H](O)[C@H](Cc1ccc2c(c1)OC(F)(F)O2)C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
A solution of (S)-3-(tert-butoxycarbonyl)-4-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-2-oxobutyl acetate (1100 mg, 2741 μmol) in 45 mL of ethanol cooled to 0° C. was added to lithium aluminumtri-tert-butoxyhydride (1 M in THF, 5481 μA 5481 μmol) in 15 mL of ethanol at −78° C. dropwise via cannula over 5 minutes. After stirring at −78° C. for 2 hours the reaction was quenched with 10 mL of 1 N HCl and the mixture was diluted with ethyl acetate (500 mL). The reaction was poured into 200 mL of water, the layers were separated and the aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organics were washed with water, brine, and dried over sodium sulfate, filtered and concentrated to provide (2S,3S)-3-(tert-butoxycarbonyl)-4-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-2-hydroxybutyl acetate (1060 mg, 96% yield) as a white solid.
Reaction SMILES: [NH2:1][C@H:2]1[C@H:7]([OH:8])[CH2:6][CH2:5][O:4][CH2:3]1.S=[C:10]1[CH2:14][S:13][C:12](=[O:15])[NH:11]1>C(O)C>[O:15]=[C:12]1[N:11]=[C:10]([NH:1][C@H:2]2[C@H:7]([OH:8])[CH2:6][CH2:5][O:4][CH2:3]2)[CH2:14][S:13]1
Reactant: O=C1NC(=S)CS1
Reactant: N[C@@H]1COCC[C@H]1O
Solvent: CCO
Product: O=C1N=C(N[C@@H]2COCC[C@H]2O)CS1
Yield: 49.7 %

Procedure:
To a solution of 2-amino-1,5-anhydro-2,4-dideoxy-threo-pentitol (1.09 g) in ethanol (100 mL) was added 4-thioxo-1,3-thiazolidin-2-one (1.28 g), and the mixture was heated under reflux for 15 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate) to give the title compound (1.00 g).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][N:13]=[C:12]([O:20]C)[CH:11]=2)[CH:3]=1.Cl.[NH+]1C=CC=CC=1>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[C:15]([C:16]([F:17])([F:18])[F:19])=[CH:14][NH:13][C:12](=[O:20])[CH:11]=2)[CH:3]=1
Reactant: COc1cc(-c2cc(Cl)ccc2C#N)c(C(F)(F)F)cn1
Agent: Cl
Agent: c1cc[nH+]cc1
Product: N#Cc1ccc(Cl)cc1-c1cc(=O)[nH]cc1C(F)(F)F

Procedure:
450 mg (purity 71%, 1.02 mmol) of 4-chloro-2-[2-methoxy-5-(trifluoromethyl)pyridin-4-yl]benzonitrile and 20 eq. of pyridinium hydrochloride were reacted according to General Method 3A. After aqueous work-up, the crude product was purified by flash chromatography (silica gel 60, dichloromethane/methanol mixtures). Yield: 456 mg (purity 86%, quant.)
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][C:7]1[N+:8]([O-])=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:10][C:11]=1[CH3:12]>C(Cl)(Cl)Cl>[Cl:3][CH2:6][C:7]1[N:8]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:10][C:11]=1[CH3:12]
Reactant: Cc1oc(-c2ccccc2)[n+]([O-])c1C
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1oc(-c2ccccc2)nc1CCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
383 g of phosphorous oxychloride was slowly added dropwise into chloroform (2 L) solution of 430 g of 4,5-dimethyl-2-phenyloxazole N-oxide. After the dropwise addition, the solution was stirred for 2 hours at room temperature. The reaction mixture was concentrated in vacuo, and 2 L of ethyl acetate was added to the residue. The foregoing ethyl acetate solution was added to mixed solution of 2 L of ice water and 1.2 L of 25% sodium hydroxide solution under stirring. The liquid was separated, and the ethyl acetate layer was washed with 1 L of brine, and dried with 300 g of anhydrous sodium sulfate. After filtration in vacuo, the filtrate was concentrated. Ethanol:n-hexane=1:10 (1.1 L) was added to the crystalline residue, and then filtered off. The crystal was dried under reduced pressure at 40° C. for 1 hour, 321 g of the subject compound was prepared.
Reaction SMILES: [CH2:1]([C:4]([CH2:11][CH2:12][CH3:13])([CH2:8][CH2:9][CH3:10])[C:5]([OH:7])=[O:6])[CH2:2][CH3:3].C1(C)C=CC=CC=1.[OH-].[Na+:22]>CO>[CH2:11]([C:4]([CH2:1][CH2:2][CH3:3])([CH2:8][CH2:9][CH3:10])[C:5]([O-:7])=[O:6])[CH2:12][CH3:13].[Na+:22]
Reactant: CCCC(CCC)(CCC)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Product: CCCC(CCC)(CCC)C(=O)[O-]
Reaction time: 4 h
Yield: 89.5 %

Procedure:
In a flask equipped with a dropping-funnel and a mechanical strirrer were placed 30 g (0.161 mol) of pure tri-n-propylacetic acid prepared as described above and 75 g of toluene. The mixture was stirred until dissolution after which a hot solution of 6.45 g of sodium hydroxide in 30 g of methanol was added through the dropping-funnel. To the solution thus obtained was added 1 g of CECA WSL black after which the whole was refluxed for 1 hour while being stirred. The black was filtered off and the residual mixture was distilled by adding little-by-little through the dropping-funnel 88 g of toluene to prevent the mixture from forming a mass. Distillation was suspended when the temperature at the head of the column reached 105° C, after which the mixture was cooled to room-temperature. The precipitate which formed was centrifuged out and rinsed twice with 20 g of acetone. It was then dried in a rotatory evaporator at 80° C for 2 hours and then at 105° C under atmospheric pressure in a ventilated drying-oven for 4 hours. In this way, 30 g of sodium tri-n-propylacetate were obtained which represents a yield of 89.5%.