Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH:22]=[CH:21][C:20]3[C:15](=[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH3:31])[CH:17]=[C:18]([F:23])[CH:19]=3)[O:14]2)(=O)=O)=CC=1.[N-:32]=[N+:33]=[N-:34].[Na+]>CN(C=O)C>[N:32]([CH2:12][C@H:13]1[CH2:22][CH2:21][C:20]2[C:15](=[C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])[CH:17]=[C:18]([F:23])[CH:19]=2)[O:14]1)=[N+:33]=[N-:34]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccccc1-c1cc(F)cc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)C=C2
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1-c1cc(F)cc2c1O[C@@H](CN=[N+]=[N-])CC2
Reaction time: 0.17 h
Yield: 90.5 %

Procedure:
A solution ((R)-8-(2-methoxyphenyl)-6-fluoro-2H-chromen-2-yl)methyl 4-methylbenzenesulfonate (300 mg, 0.67 mmol) and sodium azide (0.22 g, 3.4 mmol) in anhydrous DMF (20 mL) was heated to 90° C. under nitrogen for 20 hours. The cooled reaction mixture was quenched by the addition of water (30 mL) and the resulting suspension stirred vigorously for 10 minutes. The mixture was then partitioned between ethyl acetate (100 mL) and water (100 mL), the organic phase separated, washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Chromatography with 0–30% ethyl acetate in hexanes afforded 190 mg (90%) of (2R)-2-azidomethyl-8-(2-methoxy-phenyl)-6-fluoro-chroman as a colorless oil.
Reaction SMILES: S(Cl)(Cl)=O.[N+:5]([C:8]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[C:10]([O:20][CH2:21][CH3:22])[CH:9]=1)([O-:7])=[O:6].[CH3:23]O>>[CH3:23][O:13][C:12](=[O:14])[C:11]1[CH:15]=[C:16]([N+:17]([O-:19])=[O:18])[C:8]([N+:5]([O-:7])=[O:6])=[CH:9][C:10]=1[O:20][CH2:21][CH3:22]
Reactant: CO
Reactant: CCOc1cc([N+](=O)[O-])c([N+](=O)[O-])cc1C(=O)O
Solvent: O=S(Cl)Cl
Product: CCOc1cc([N+](=O)[O-])c([N+](=O)[O-])cc1C(=O)OC
Reaction time: 16 h

Procedure:
Thionyl chloride (315 μl, 4.30 mmol) was slowly added to a mixture of 4,5-dinitro-2-ethoxy-benzoic acid (1.00 g, 3.91 mmol) in methanol (10 mL) at r.t. The mixture was stirred for 16 h, then reduced in vacuo azeotroping with toluene. The residue was then purified by column chromatography using P.E.-EtOAc (1:0-1:1) to give the title compound (606 mg) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.00 (s, 1H), 4.35 (q, 2H), 3.85 (s, 3H), 1.35 (t, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([CH3:11])=[CH:4][N:3]=1.[CH2:12]([NH:20][C:21](=O)[CH3:22])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:22][C:21]1[N:20]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:2]2=[N:3][CH:4]=[C:5]([CH3:11])[CH:6]=[C:7]2[N:8]=1
Reactant: Cc1cnc(Cl)c([N+](=O)[O-])c1
Reactant: CC(=O)NCCc1ccccc1
Product: Cc1cnc2c(c1)nc(C)n2CCc1ccccc1
Yield: 43 %

Procedure:
Method B applied to 2-chloro-5-methyl-3-nitropyridine (86 mg, 0.5 mmol) and N-phenethyl-acetamide (98 mg, 0.6 mmol) afforded the title compound as viscous oil (54 mg, 43%). 1H NMR (DMSO) δ 2.38 (s, 3H), 2.46 (s, 3H), 3.12 (t, 2H), 4.53 (t, 2H), 7.08-7.29 (m, 5H), 7.93 (s, 1H), 8.32 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH2:44]([O:46][C:47](=[O:70])[NH:48][C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([CH2:55][N:56]2[C:61](=[O:62])[CH:60]=[CH:59][C:58]([C:63]3[CH:68]=[CH:67][CH:66]=[C:65]([NH2:69])[CH:64]=3)=[N:57]2)[CH:50]=1)[CH3:45]>CN(C=O)C>[CH2:44]([O:46][C:47](=[O:70])[NH:48][C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([CH2:55][N:56]2[C:61](=[O:62])[CH:60]=[CH:59][C:58]([C:63]3[CH:68]=[CH:67][CH:66]=[C:65]([NH:69][C:12](=[O:14])[CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:64]=3)=[N:57]2)[CH:50]=1)[CH3:45]
Reactant: CCOC(=O)Nc1cccc(Cn2nc(-c3cccc(N)c3)ccc2=O)c1
Reactant: CC(C)(C)OC(=O)NCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)Nc1cccc(Cn2nc(-c3cccc(NC(=O)CCCNC(=O)OC(C)(C)C)c3)ccc2=O)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
138 mg (0.68 mmol) of 4-(tert-butoxycarbonylamino)butyric acid are suspended in 2 ml of DMF, 138 μl (1.23 mmol) of 4-methylmorpholine, 86 mg (0.617 mmol) of 1-hydroxybenzotriazole and 239 mg (1.23 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride are added. The reaction mixture is stirred at room temperature for 10 min, 274 mg (0.62 mmol) of ethyl{3-[3-(3-aminophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}carbamate are subsequently added, and the mixture is stirred at room temperature for 24 h.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([O:12][C:13](=[O:28])[NH:14][C:15]1[C:16]([CH3:27])=[N:17][O:18][C:19]=1[C:20]1[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=1)[CH3:11].[CH2:29]([O:31][C:32](=[O:49])[CH2:33][C:34]1[CH:39]=[CH:38][C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:35]=1)[CH3:30]>>[CH2:29]([O:31][C:32](=[O:49])[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:23]2[CH:24]=[CH:25][C:20]([C:19]3[O:18][N:17]=[C:16]([CH3:27])[C:15]=3[NH:14][C:13]([O:12][CH:10]([C:3]3[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=3[F:1])[CH3:11])=[O:28])=[CH:21][CH:22]=2)=[CH:36][CH:35]=1)[CH3:30]
Reactant: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: COc1ccc(C(C)OC(=O)Nc2c(C)noc2-c2ccc(Br)cc2)c(F)c1
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3NC(=O)OC(C)c3ccc(OC)cc3F)cc2)cc1

Procedure:
Following the procedure described in Example 36, Step 6, [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid 1-(2-fluoro-4-methoxy-phenyl)-ethyl ester and [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester were reacted to provide (4′-{4-[1-(2-fluoro-4-methoxy-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-acetic acid ethyl ester, which was hydrolyzed to the acid as described in Example 34, Step 2.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C@H:21]3[O:25][C:24](=[O:26])[CH2:23][C@H:22]3[CH3:27])=[CH:17][CH:16]=2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2].[OH-:32].[Na+:33].CO>C1COCC1>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]([OH:25])[CH:22]([CH3:27])[CH2:23][C:24]([O-:26])=[O:32])=[CH:17][CH:16]=2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2].[Na+:33]
Reactant: CCCc1c(OCCCOc2ccc([C@H]3OC(=O)C[C@H]3C)cc2)ccc(C(C)=O)c1O
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCc1c(OCCCOc2ccc(C(O)C(C)CC(=O)[O-])cc2)ccc(C(C)=O)c1O

Procedure:
The lactone from Example 13 (3.0 g, 7.0 mmol) was hydrolyzed with 1N NaOH (10.5 ml), methanol (1 ml) and THF (15 ml) at room temperature for 15 hours. The mixture was concentrated and the residue was Purified by chromatography on XAD-8 to provide the title compound as a foam.
Reaction SMILES: C[O:2][C:3](=[O:15])[C@@H:4]([OH:14])[C@@H:5]([CH2:10][CH2:11][CH2:12][CH3:13])[C:6]([O:8]C)=[O:7].[OH-].[Na+].Cl>CO.O>[CH2:10]([C@@H:5]([C:6]([OH:8])=[O:7])[C@H:4]([OH:14])[C:3]([OH:15])=[O:2])[CH2:11][CH2:12][CH3:13]
Reactant: CCCC[C@@H](C(=O)OC)[C@H](O)C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCC[C@@H](C(=O)O)[C@H](O)C(=O)O
Reaction time: 24 h

Procedure:
To (2S,3R)-3-(n-butyl)-2-hydroxysuccinic dimethyl ester B-3 in MeOH (28 mL) is added a solution of NaOH (2.2 g, 55 mmol) in water (28 mL). After 24 hours, the MeOH is removed, the crude reaction is acidified with HCl (6 N, 12 mL) to pH=1, and then extracted with EtOAc (3×50 mL). The combined organic layers are dried (Na2SO4) and concentrated to give (2S,3R)-3-(n-butyl)-2-hydroxysuccinic acid B-4.
Reaction SMILES: Cl.N[CH2:3][C:4]1[C:12]([OH:13])=[C:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][CH2:8]2.C1N2CN3CN(C2)CN1C3.FC(F)(F)C(O)=[O:31]>>[CH:3]([C:4]1[C:12]([OH:13])=[C:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][CH2:8]2)=[O:31]
Reactant: O=C(O)C(F)(F)F
Reactant: CS(=O)(=O)c1cc2c(c(CN)c1O)CCC2
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Product: CS(=O)(=O)c1cc2c(c(C=O)c1O)CCC2

Procedure:
0.83 g (0.003 mol) of 4-aminomethyl-5-hydroxy-6-methylsulfonylindane hydrochloride is reacted with 0.42 g of urotropine in 6 ml of trifluoroacetic acid in analogy to Example 1. Melting point: 152°-153° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[OH:6][C:7]1([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[OH:5][CH2:4][CH2:3][CH2:2][NH:1][C:8]1[C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:24])([F:26])[F:25])[CH:18]=2)([OH:6])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1
Reactant: NCCCO
Reactant: O=C1Nc2ccccc2C1(O)c1cccc(C(F)(F)F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: OCCCNC1=Nc2ccccc2C1(O)c1cccc(C(F)(F)F)c1

Procedure:
Reaction of 3-aminopropanol with 3-hydroxy-(3-(m-trifluoromethylphenyl)-)-3H-indol-2-one in presence of toluene-p-sulphonic acid by a procedure analogous to that of Example 1 gives 2-(3-hydroxypropylamino)-3-(m-trifluoromethylphenyl)-3H-indol-3-ol.
Reaction SMILES: CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[Cl:12][C:13]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:14]=1[CH2:15]Cl.[C:22]([O:31][CH3:32])(=[O:30])[C:23]1[C:24](=[CH:26][CH:27]=[CH:28][CH:29]=1)[OH:25]>C(OCC)(=O)C>[Cl:12][C:13]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:14]=1[CH2:15][O:25][C:24]1[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=1[C:22]([O:31][CH3:32])=[O:30]
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: COC(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1OCc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dimethylformamide (DMF)(100 ml), potassium carbonate (17.97 g) and 2,4-dichlorobenzyl chloride (21.50 g) were added to methyl salicylate (15.22 g), and the mixture was stirred at room temperature overnight. Ethyl acetate (1000 ml) was added to the reaction mixture, and the resulting mixture was washed with brine (700 ml) twice, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give crude methyl 2-(2,4-dichlorobenzyloxy)benzoate. Methanol (100 ml), THF (100 ml), water (20 ml) and 85% potassium hydroxide (7.92 g) were added to the crude product thus obtained, and the mixture was stirred at 60° C. for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure. Water (300 ml) was added to the residue, and the pH of the mixture was adjusted to not more than 2, and the resulting crystals were separated by filtration, dried to give 2-(2,4-dichlorobenzyloxy)benzoic acid (29.30 g) as colorless crystals.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]2[NH:9][CH:10]=[CH:11][C:6]2=[CH:5][CH:4]=1)#[CH:2].[C:12](O)(=[O:14])C.C1N2CN3CN(C2)CN1C3.C(=O)([O-])O.[Na+]>O>[C:1]([C:3]1[N:8]=[C:7]2[NH:9][CH:10]=[C:11]([CH:12]=[O:14])[C:6]2=[CH:5][CH:4]=1)#[CH:2]
Reactant: CC(=O)O
Reactant: C#Cc1ccc2cc[nH]c2n1
Agent: C1N2CN3CN1CN(C2)C3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: C#Cc1ccc2c(C=O)c[nH]c2n1
Temperature: 120 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
6-Ethynyl-1H-pyrrolo[2,3-b]pyridine (0.016 g, 0.11 mmol) was successively added with acetic acid (0.1 mL), water (0.2 mL), and hexamethylenetetramine (0.023 g, 0.17 mmol), and then the mixture was stirred overnight at 120° C. in a sealed tube. The reaction mixture was cooled to room temperature, and then added with saturated aqueous sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 6-ethynyl-1H-pyrrolo[2,3-b]pyridine-3-carboxaldehyde (0.016 g, 85%).
Reaction SMILES: [CH2:1]([C@:4]1([C:43]2[CH:48]=[C:47]([CH2:49][C:50]3[CH:55]=[CH:54][C:53]([CH2:56][CH3:57])=[CH:52][CH:51]=3)[C:46]([Cl:58])=[CH:45][C:44]=2[OH:59])[C@H:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@H:8]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@H:7]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@@H:6]([CH2:34][O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:5]1)[CH:2]=[CH2:3].B1C2CCCC1CCC2.[OH-:69].[Na+].OO>C1COCC1.O>[Cl:58][C:46]1[C:47]([CH2:49][C:50]2[CH:51]=[CH:52][C:53]([CH2:56][CH3:57])=[CH:54][CH:55]=2)=[CH:48][C:43]([C@@:4]2([CH2:1][CH2:2][CH2:3][OH:69])[C@H:9]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C@@H:8]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C@H:7]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@@H:6]([CH2:34][O:35][CH2:36][C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[O:5]2)=[C:44]([OH:59])[CH:45]=1
Reactant: C=CC[C@@]1(c2cc(Cc3ccc(CC)cc3)c(Cl)cc2O)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCc1ccc(Cc2cc([C@]3(CCCO)O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(O)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
To a stirred solution of 34 (200 mg, 0.247 mmol) in dry THF (4 mL) was added 9-BBN in THF (2.0 mL, 0.5 M, 4.1 equiv). The resulting mixture was stirred at ambient temperature for 4 hours and then cooled 0° C. Water (2.5 mL), 1 M aqueous NaOH (0.8 mL) and 30% H2O2 (0.25 mL) were added at 0° C. The mixture was stirred for 1 hour at ambient temperature and 16 hours at 60° C. in a sealed vial. After cooling, the mixture was partitioned between water and EtOAc. The organic layer was dried (MgSO4), filtered and evaporated. The residue was purified using preparatory TLC eluting with 18% EtOAc in petroleum ether to give 35 (200 mg, 99% yield). LCMS m/z 828 (M+H), 850 (M+Na).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@@H:4]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1.[C:22]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)(=[O:24])[NH2:23].C([O-])([O-])=O.[Na+].[Na+]>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.C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3](=[O:21])[C@@H:4]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:28]2[CH:29]=[CH:30][C:25]([C:22](=[O:24])[NH2:23])=[CH:26][CH:27]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)OC(C)(C)C
Reactant: NC(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C(N)=O)cc2)cc1)NC(=O)OC(C)(C)C
Temperature: 80 °C

Procedure:
(S)-3-(4-Bromo-phenyl)-2-tert-butoxycarbonylamino-propionic acid methyl ester and 4-carbamoylphenyl boronic acid (2 eq.) were coupled in 7:2 toluene-H2O with Na2CO3 (3 eq.) and Pd(PPh3)4 (0.1 eq.). After heating for 4 hours at 80° C., the reaction mixture was purified by flash chromatography to provide (S)-2-tert-butoxycarbonylamino-3-(4′-carbamoyl-biphenyl-4-yl)-propionic acid methyl ester. The product was deprotected according to General Procedure C to provide an amine-HCl salt, which was coupled with (3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester according to General Procedure L. The product was deprotected according to General Procedure C to provide an amine-HCl salt, which was treated with excess NEt3 in DCM to produce a free amine. The free amine was coupled with 2,5-dimethyloxazole-4-carboxylic acid (2 eq.) in dry DCM with HBTU (2.2 eq.) and NEt3 (3 eq.). After reacting for 2 hours at room temperature, the reaction mixture was purified by flash chromatography to provide the product, which was hydrolyzed according to general procedure B to give the title compound (11 mg). LCMS (m/z) 876.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]([CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])C(=O)C(F)(F)F)[CH:5]=[CH:6][CH:7]=1.O1C(C2C=C(N[C:33]3[N:38]=[C:37]([C:39]4[C:40]([C:48]5[CH:49]=[C:50]([NH:54][C:55](=[O:62])[CH2:56][C:57]6[S:58][CH:59]=[CH:60][CH:61]=6)[CH:51]=[CH:52][CH:53]=5)=[N:41][N:42]5[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=45)[CH:36]=[CH:35][N:34]=3)C=CC=2)=CN=C1>CC(O)C.Cl.C(Cl)Cl>[CH3:20][N:18]([CH3:19])[CH2:17][CH2:16][NH:9][CH2:8][C:4]1[CH:3]=[C:2]([NH:1][C:33]2[N:38]=[C:37]([C:39]3[C:40]([C:48]4[CH:49]=[C:50]([NH:54][C:55](=[O:62])[CH2:56][C:57]5[S:58][CH:59]=[CH:60][CH:61]=5)[CH:51]=[CH:52][CH:53]=4)=[N:41][N:42]4[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=34)[CH:36]=[CH:35][N:34]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: CN(C)CCN(Cc1cccc(N)c1)C(=O)C(F)(F)F
Reactant: O=C(Cc1cccs1)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(-c4cnco4)c3)n2)c1
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)O
Product: CN(C)CCNCc1cccc(Nc2nccc(-c3c(-c4cccc(NC(=O)Cc5cccs5)c4)nn4ccccc34)n2)c1
Temperature: 180 °C
Yield: 66 %

Procedure:
A suspension of N-[(3-aminophenyl)methyl]-N-[2-(dimethylamino)ethyl]-2,2,2-trifluoroacetamide (61 mg, 0.21 mmol) and N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2-(2-thienyl)acetamide (75 mg, 0.17 mmol) (see Example 2, Step B) in i-PrOH (3 mL) was acidified with 3 drops of 12 N HCl and heated in a microwave for 25 min. at 180° C. The reaction mixture was then diluted with DCM, washed with 2 N NaOH, dried over Na2SO4, and adsorbed onto silica gel. The crude product was purified by column chromatography to generate the title compound in 66% yield. 1H NMR (400 MHz, CDCl3) δ 8.47 (d, J=6.8 Hz, 1H), 8.36 (d, J=8.8 Hz, 1H), 8.16 (d, J=5.1 Hz, 1H), 7.80 (d, J=7.2 Hz, 1H), 7.73 (s, 1H), 7.53-7.61 (m, 3H), 7.32-7.45 (m, 4H), 7.01 (s, 2H), 6.90 (t, J=6.6 Hz, 1H), 6.55 (d, J=5.1 Hz, 1H), 3.94 (s, 2H), 3.79 (s, 2H), 2.70 (t, J=5.8 Hz, 2H), 2.42 (t, J=5.9 Hz, 2H), 2.18 (s, 6H). ES-LC/MS m/z=603 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]([OH:18])([CH2:16][CH3:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]([CH3:13])=[O:12])[C:5]=1[CH2:14][OH:15])[CH3:2]>O1CCCC1.[O-2].[O-2].[Mn+4]>[CH2:1]([C:3]1([CH2:16][CH3:17])[C:4]2[C:5](=[C:6]([NH:10][C:11]([CH3:13])=[O:12])[CH:7]=[CH:8][CH:9]=2)[C:14](=[O:15])[O:18]1)[CH3:2]
Reactant: CCC(O)(CC)c1cccc(NC(C)=O)c1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: CCC1(CC)OC(=O)c2c(NC(C)=O)cccc21
Yield: 62.2 %

Procedure:
To a solution of 8.0 g of α,α-diethyl-2-hydroxymethyl-3-acetaminobenzyl alcohol in 300 ml of tetrahydrofuran was added 32 g of activated manganese dioxide and the mixture was allowed to react for 6 hours under refluxing. After the reaction was over, the reaction mixture was left to stand for cooling and filtered on a glass filter having a bed of celite. The residue was washed with 100 ml of tetrahydrofuran. The filtrate and the washed solution were combined and concentrated to obtain an oily substance. The oily substance was purified by silica gel column chromatography to obtain 4.9 g of 3,3-diethyl-7-acetaminophthalide in the colorless oily substance.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][C:4]=1[O:12][CH3:13])#[N:2].[NH2:14][C:15]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)([CH3:20])[C:16](OC)=[O:17]>>[OH:27][C:24]1[CH:23]=[CH:22][C:21]([C:15]2([CH3:20])[C:16](=[O:17])[N:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([O:12][CH3:13])[CH:5]=3)[C:10](=[O:11])[NH:14]2)=[CH:26][CH:25]=1
Reactant: COc1cc(N=C=O)ccc1C#N
Reactant: COC(=O)C(C)(N)c1ccc(O)cc1
Product: COc1cc(N2C(=O)NC(C)(c3ccc(O)cc3)C2=O)ccc1C#N

Procedure:
The procedure of Example C is used, with 4-cyano-3-methoxyphenyl isocyanate starting from 2.2 g of methyl 2-amino-2-(4-hydroxyphenyl)propionate. After chromatography over silica and evaporation of the solvents 3.6 g of product, a yellowish solid, is obtained (Yd=92%).
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][N:14]([C:16]([N:18]3[CH2:23][CH2:22][S:21](=[O:24])[CH2:20][CH2:19]3)=[O:17])[CH2:13][CH:12]([C:25]([O:27]C)=[O:26])[CH2:11]2)=[CH:6][CH:5]=1.CC(C)([O-])C.[K+]>>[F:29][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:15][N:14]([C:16]([N:18]3[CH2:23][CH2:22][S:21](=[O:24])[CH2:20][CH2:19]3)=[O:17])[CH2:13][CH:12]([C:25]([OH:27])=[O:26])[CH2:11]2)=[CH:8][CH:9]=1
Reactant: COC(=O)C1CC(c2ccc(OC(F)F)cc2)CN(C(=O)N2CCS(=O)CC2)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: O=C(O)C1CC(c2ccc(OC(F)F)cc2)CN(C(=O)N2CCS(=O)CC2)C1

Procedure:
According to General Method 4A, 2.7 g (6.3 mmol) of methyl 5-[4-(difluoromethoxy)phenyl]-1-[(1-oxidothiomorpholin-4-yl)carbonyl]piperidine-3-carboxylate were reacted with 7.1 g (63.3 mmol) of potassium tert-butoxide. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in water and acidified with concentrated hydrochloric acid. The precipitate was filtered off, washed with water and dried under reduced pressure. Yield: 1.1 g (34% of theory)
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C(N(CC)CC)C.[CH2:14]([S:18](Cl)(=[O:20])=[O:19])[CH2:15][CH2:16][CH3:17]>C1COCC1>[CH2:14]([S:18]([NH:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1)(=[O:20])=[O:19])[CH2:15][CH2:16][CH3:17]
Reactant: CCCCS(=O)(=O)Cl
Reactant: Nc1nccs1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCS(=O)(=O)Nc1nccs1
Reaction time: 20 h
Yield: 55.4 %

Procedure:
7.4 g of 2-aminothiazole (73.7 mmol) and 10.2 ml of triethylamine (7.4 g, 73.7 mmol) were dissolved at room temperature in 100 ml of THF. Again at room temperature 9.6 ml of n-butanesulfonyl chloride (11.5 g, 73.7 mmol) were added dropwise to this solution over the course of one hour. After 21 h of stirring at room temperature a further 4 ml of n-butanesulfonyl chloride (4.8 g, 30.8 mmol) were added and stirring was continued at room temperature for 20 h. The reaction mixture was washed twice with 100 ml of 1 N NaOH and then washed to neutrality (pH 6–7) with water. The organic phase was dried over magnesium sulphate and then freed from the solvent. The 9.0 g of crude product obtained were recrystallized from 80 ml of tert-butyl methyl ether. This gave 3.2 g of the target compound, whose constitution was verified by NMR spectroscopy.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:10][CH:9]2[O:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]3[O:34][CH2:33][C:32](=[O:35])[N:31]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[C:30]=3[CH:41]=2)=[CH:4][CH:3]=1.[C:42]([O:46][C:47](=[O:52])[NH:48][CH2:49][CH2:50]O)([CH3:45])([CH3:44])[CH3:43].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:42]([O:46][C:47]([NH:48][CH2:49][CH2:50][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:15])[CH2:10][CH:9]2[O:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]3[O:34][CH2:33][C:32](=[O:35])[N:31]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[C:30]=3[CH:41]=2)=[CH:4][CH:3]=1)=[O:52])([CH3:45])([CH3:44])[CH3:43]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(O)cc3)cc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCNC(=O)OC(C)(C)C)cc3)cc21
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A solution of 1.197 g of benzyl 4-(4-hydroxyphenyl)-3-[4-(3-methoxypropyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate (Example 166c), 0.506 ml of tert-butyl(2-hydroxyethyl)carbamate and 0.848 g of triphenylphosphine in 10 ml of tetrahydrofuran at 0° C. is admixed dropwise with 0.66 ml of diisopropyl azodicarbonate. The reaction mixture is warmed to room temperature, stirred further for 22 hours and subsequently concentrated by evaporation. The title compound is obtained as a yellow oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.50 (2:1 EtOAc-heptane); Rt=5.39.