Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:11])[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[NH2:6].[S:12]1[C:16]([CH:17]=O)=[CH:15][N:14]=[CH:13]1>>[S:12]1[C:16]([CH2:17][NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]([OH:2])=[O:11])=[CH:15][N:14]=[CH:13]1
Reactant: O=Cc1cncs1
Reactant: COC(=O)c1ccccc1N
Product: O=C(O)c1ccccc1NCc1cncs1

Procedure:
Prepared by a similar procedure as described for preparation 1J, starting from anthranilic acid methyl ester and thiazole-5-carboxaldehyde (Combi-Blocks). 13C-NMR (DMSO-d6) δ 169.8, 153.6, 149.9, 140.8, 137.9, 134.3, 131.6, 115.0, 111.6, 110.7, 38.3.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=2)[C:11]2[C:16]3[CH2:17][CH2:18][CH2:19][CH2:20][C:15]=3[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=3)[C:11]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:15]=4[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: O=[N+]([O-])c1cccc(CNc2nc(Cl)nc3sc4c(c23)CCCC4)c1
Product: Cc1nccn1-c1nc(NCc2cccc([N+](=O)[O-])c2)c2c3c(sc2n1)CCCC3

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-5,6,7,8-tetrahydro-4-(3-nitrobenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-5,6,7,8-tetrahydro-4-(3-nitrobenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH3:18][N:19]([CH3:35])[C@H:20]1[CH2:24][CH2:23][N:22]([C:25]([C:27]2[CH:31]=[C:30]([CH3:32])[NH:29][C:28]=2[CH:33]=O)=[O:26])[CH2:21]1>C(O)C.N1CCCCC1>[CH3:18][N:19]([CH3:35])[C@H:20]1[CH2:24][CH2:23][N:22]([C:25]([C:27]2[CH:31]=[C:30]([CH3:32])[NH:29][C:28]=2[CH:33]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[NH:12][C:11]2=[O:17])=[O:26])[CH2:21]1
Reactant: Cc1cc(C(=O)N2CC[C@H](N(C)C)C2)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C(=O)N2CC[C@H](N(C)C)C2)c(C=C2C(=O)Nc3cccc(-c4cccc(F)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 53.1 %

Procedure:
To a solution of 4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 3-[(3S)-3-dimethylamino-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-[3-[(3S)-3-dimethylamino-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrol-2-ylmethylene]-4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (60.9 mg, 53%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([C:9]([OH:11])=O)[C:5]([F:12])=[C:4]([F:13])[C:3]=1[CH3:14].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH3:36][CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH:38]1[NH2:43]>C(Cl)Cl.CN(C=O)C>[F:12][C:5]1[C:4]([F:13])=[C:3]([CH3:14])[C:2]([F:1])=[C:7]([F:8])[C:6]=1[C:9]([NH:43][CH:38]1[CH2:39][CH2:40][CH2:41][CH2:42][CH:37]1[CH3:36])=[O:11]
Reactant: CC1CCCCC1N
Reactant: Cc1c(F)c(F)c(C(=O)O)c(F)c1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1c(F)c(F)c(C(=O)NC2CCCCC2C)c(F)c1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 89.7 %

Procedure:
2,3,5,6-tetrafluoro-p-toluic acid acid (4.00 g, 19.22 mmol), HOBt (5.19 g, 38.44 mmol) and EDCI (4.42 g 23.06 mmol) were mixed in 200 ml of anhydrous DCM and 30 ml of anhydrous DMF. The mixture was cooled to 0° C. and allowed to stir under Ar for 15 minutes. To the mixture was added 2-methylcyclohexanamine (3.05 mL, 23.06 mmol) and the reaction mixture was allowed to slowly warm to ambient temperature and stirred overnight. The reaction mixture was diluted with DCM, washed with 1N HCl, water, aqueous NaHCO3, water and brine, drying over MgSO4, filtration and removal of solvent in vacuo, afforded the crude product as a pale yellow solid Recrystallization (EtOH/H2O) and drying in vacuo gave 5.23 g of the title compound as a white solid (mixture of 2 diasteromers, 90%). 1H NMR (CDCl3) δ 0.95, 1.01 (d, J=7.0, 6.6 Hz, 3H) 1.1-2.1 (m, 9H), 2.29 (m, 3H), 3.70, 4.29 (m, 1H), 5.65, 5.92 (m, 1H). MS (304.1, M+H). m.p. 202-204° C.
Reaction SMILES: [Cl:1][CH:2]=[C:3]1[CH:9]=[CH:8][C:7]2[CH:10]=[C:11]([CH:14]=[CH:15][CH2:16][CH2:17][C:18]3([CH3:23])OCC[O:19]3)[CH:12]=[CH:13][C:6]=2[O:5][CH2:4]1.CC(C)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl.CC#N.CC#N.Cl[Pd]Cl>[Cl:1][CH:2]=[C:3]1[CH:9]=[CH:8][C:7]2[CH:10]=[C:11]([CH:14]=[CH:15][CH2:16][CH2:17][C:18](=[O:19])[CH3:23])[CH:12]=[CH:13][C:6]=2[O:5][CH2:4]1
Reactant: CC1(CCC=Cc2ccc3c(c2)C=CC(=CCl)CO3)OCCO1
Agent: Cl[Pd]Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: ClCCl
Solvent: CC(C)=O
Product: CC(=O)CCC=Cc1ccc2c(c1)C=CC(=CCl)CO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.4 %

Procedure:
6 mg (0.023 mmol) of bis(acetonitrile)palladium(II) chloride are added to 79 mg (0.237 mmol) of 3-(chloromethylene)-7-[4-(2-methyl-1,3-dioxolan-2-yl)-1-butenyl]-2,3-dihydro-1-benzoxepin, prepared according to example 74, in solution in 1.5 ml of dichloromethane. After stirring at ambient temperature for 3 hours, 0.5 ml of acetone and a catalytic amount of para-toluenesulfonic acid are added. The reaction medium is then stirred for 30 minutes. The crude reaction product is purified by chromatography on silica gel (ethyl acetate/heptane 10/90) to provide 55 mg (80%) of 6-[3-(chloromethylene)-2,3-dihydro-1-benzoxepin-7-yl]-5-hexen-2-one in the form of a mixture of isomers in an EZ/EE ratio (85/15) for the chloromethylene functional group; 1H NMR (300 MHz, CDCl3) EZ isomer: 2.18 (s, 3H), 2.45 (m, 2H), 2.61 (m, 2H), 4.86 (s, 2H), 6.10 (m, 1H), 6.33 (m, 4H), 6.96 (m, 3H).
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:25]1([NH:31][CH3:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>CN(C1C=CN=CC=1)C.CC#N>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21]([N:31]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH3:32])(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Reactant: CNC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CN(C1CCCCC1)S(=O)(=O)c1ccc2c(c1)nc(C(C)(C)C)n2CC1CCOCC1

Procedure:
Following the same procedure in Example 1, Step A, using 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (82 mg, 0.22 mmol), cyclohexyl(methyl)amine (50 mg, 0.44 mmol) and DMAP (54 mg, 0.44 mmol) in MeCN (4 mL). The crude product was purified by MPLC using Hex/EtOAc (1:1) on silica gel to give 58 mg (59% yield) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.22-1.32 (m, 2 H), 1.33-1.44 (m, 4 H), 1.47-1.62 (m, 6 H), 1.65 (s, 9 H), 1.66-1.74 (m, 2 H), 2.27-2.44 (m, 1 H), 2.76 (s, 3 H), 3.29-3.38 (m, 2 H), 3.68-3.81 (m, 1 H), 3.87-3.97 (m, 2 H), 4.50 (d, J=7.42 Hz, 2 H), 7.89 (dd, J=8.79, 1.76 Hz, 1 H), 8.00 (d, J=8.79 Hz, 1 H), 8.12 (d, J=1.17 Hz, 1 H); MS (ESI) (M+H)+=448.0; Anal. Calcd for C24H37N3O3S+1.00 TFA+0.30 EtOAc+0.2H2O (591.70): C, 55.21; H, 6.95; N, 7.10. Found: C, 55.22; H, 6.85; N, 7.08.
Reaction SMILES: C([O:9][C:10]([C:12]1[NH:13][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:24](=[O:25])[NH:23][CH2:22][CH2:21][C:20]=1[C:19]=23)=[O:11])CCCCCCC.[OH-].[Li+].CO>O>[O:25]=[C:24]1[C:18]2[C:19]3[C:20](=[C:12]([C:10]([OH:11])=[O:9])[NH:13][C:14]=3[CH:15]=[CH:16][CH:17]=2)[CH2:21][CH2:22][NH:23]1
Reactant: CCCCCCCCOC(=O)c1[nH]c2cccc3c2c1CCNC3=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1[nH]c2cccc3c2c1CCNC3=O

Procedure:
6-Oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indole-2-carboxylic acid octyl ester (Example FFF) (350 mg, 1.02 mmol) and lithium hydroxide (122 mg, 5.11 mmol) were dissolved in 10 mL 2:1 methanol:water and stirred at room temperature for 24 h. The reaction mixture was diluted with water then washed twice with dichloromethane. The aqueous solution was acidified to ca. pH 2 with conc. HCl. The white precipitate was collected by filtration, washed with water, and dried in vacuo to yield 6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indole-2-carboxylic acid, 235 mg (99%) as a white solid: m.p. 298-299° C. (dec); 1H NMR (300 MHz, d6-DMSO) δ 3.17 (m, 2H), 3.41 (m, 2H), 7.35 (t, J=7.8 Hz, 1H), 7.59 (d, J=8.1 Hz, 1H), 7.73 (d, J=7.5 Hz, 1H), 8.14 (br t, 1H), 11.77 (br s, 1H), 13.14 (br s, 1H). MS (electrospray, MH+): 231. Anal. (C12H10N2O3.1.0 H2O) C, H, N.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:14][C:15]1[CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[CH:18]=[CH:19][C:20]=1F.O>CS(C)=O>[F:14][C:15]1[CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[CH:18]=[CH:19][C:20]=1[N:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: c1nc[nH]n1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(-n2cncn2)c(F)c1
Temperature: 90 °C
Yield: 71.6 %

Procedure:
A solution of 5.0 g (72.4 mmol) of 1H-1,2,4-triazole and 25.22 g (144.8 mmol) of dibasic potassium phosphate in 150 mL DMSO was treated with 11.52 g (72.4 mmol) of 3,4-difluoronitrobenzene followed by warming at 90° C. for 3 h. The solution was cooled and added to 500 mL water, and the resulting white solid was collected by filtration and washed with water. The white solid obtained was dried in vacuo (60° C./10 mmHg) to afford 10.79 g (72%) of the title compound as a white solid. High Resolution Mass Spectrum: Calculated for C8H5FN4O2 : 208.0396. Found: 208.0408.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18](=[O:27])[NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:35]([O:37][C:38]1[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=1)=[O:36]>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([O:17][C:18](=[O:27])[NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:35]([O:37][C:38]2[CH:39]=[CH:40][C:41]([N+:44]([O-:46])=[O:45])=[CH:42][CH:43]=2)=[O:36])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCCCCCCO)OC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(NCCCCCCOC(=O)Oc1ccc([N+](=O)[O-])cc1)OC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.5 %

Procedure:
A solution of the alcohol (50 g, 0.13 moles) produced in Example 22 and pyridine (10.7 ml, 0.13 moles) in 500 ml of methylene chloride was added dropwise under nitrogen to a solution of 4-nitrophenyl chloroformate (26.64 g, 0.13 mol) in 500 ml of methylene chloride at room temperature. After the addition, the reaction was stirred overnight at room temperature. A solid had formed which was removed by filtration. The filtrate was extracted two times with 1N HCl, multiple times with saturated Na2CO3, dried (MgSO4) and the solvent removed under reduced pressure. Recrystallization of the crude reaction product from hexane gave 27.9 g (39%) of the title compound as a light yellow crystalline solid, mp 78-80° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH3:18][N:19]([CH3:35])[C@@H:20]1[CH2:24][CH2:23][N:22]([C:25]([C:27]2[CH:31]=[C:30]([CH3:32])[NH:29][C:28]=2[CH:33]=O)=[O:26])[CH2:21]1>C(O)C.N1CCCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10](=[CH:33][C:28]2[NH:29][C:30]([CH3:32])=[CH:31][C:27]=2[C:25]([N:22]2[CH2:23][CH2:24][C@@H:20]([N:19]([CH3:18])[CH3:35])[CH2:21]2)=[O:26])[C:11](=[O:17])[NH:12]3)=[CH:6][CH:7]=1
Reactant: O=C1Cc2c(cccc2-c2ccc(Cl)cc2)N1
Reactant: Cc1cc(C(=O)N2CC[C@@H](N(C)C)C2)c(C=O)[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C(=O)N2CC[C@@H](N(C)C)C2)c(C=C2C(=O)Nc3cccc(-c4ccc(Cl)cc4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-(4-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 3-[(3R)-3-dimethylamino-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 4-(4-chloro-phenyl)-3-[3-[(3R)-3-dimethylamino-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (44.8, 38%).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][OH:5].[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[C:11]([O:5][CH2:4][C:3]1[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:2]=1[CH3:1])(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cccc(C)c1CO
Product: CC(=O)OCc1c(C)cccc1C
Temperature: 70 °C
Yield: 100.5 %

Procedure:
A mixture of 2,6-dimethylbenzyl alcohol (8.17 g) and acetic anhydride (8.1 g) was heated at 70° C. for 3 hours and evaporated in vacuo. To the residue was added aqueous sodium bicarbonate and extracted with diethyl ether. The extract was washed with water, dried over magnesium sulfate, and evaporated in vacuo to give an oil of 2,6-dimethylbenzyl acetate (10.75 g).
Reaction SMILES: Cl[C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]([CH:8]=[C:9](Cl)[CH:10]=1)[C:5]([OH:7])=[O:6].[CH2:15]([SH:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(=O)([O-])[O-].[K+].[K+].Cl>C(O)C.O>[CH2:15]([S:27][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]([CH:8]=[C:9]([S:27][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:10]=1)[C:5]([OH:7])=[O:6])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCS
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCSc1cc(SCCCCCCCCCCCC)c([N+](=O)[O-])c(C(=O)O)c1
Temperature: 25 °C

Procedure:
An amount of 236 g. (1 mole) 3,5-dichloro-2-nitrobenzoic acid (Step 1) and 424 g. (2.1 moles) 1-dodecanethiol in 1.5 liter ethanol and 1 liter water was purged with nitrogen for 15-30 min. Then 430 g. (3.1 moles) anhydrous potassium carbonate were added and the reaction mixture was refluxed under an atmosphere of nitrogen for 60-72 hr. After cooling to room temperature, the solution was poured slowly into a rapidly stirred mixture of 6 liters water, 360 ml. conc. HCl and crushed ice. The precipitated solid was collected and washed well with water. The yellow material was slurried in 2.7 liters of glacial acetic acid, filtered, washed with a small amount of glacial acetic acid and dried in vacuo at 45° C. An amount of 560 g. of the product was obtained, m.p. 74°-77° C.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:46]=[CH:45][C:7]2[N:8]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:27]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([F:44])([F:43])[C:39]([F:42])([F:41])[F:40])[C:28]([O:30]CC)=[O:29])[C@H:9]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[CH2:10][O:11][C:6]=2[CH:5]=1.Cl.C(OCC)(=O)C.CCCCCC>C(O)C>[OH:3][C:4]1[CH:46]=[CH:45][C:7]2[N:8]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:27]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([F:44])([F:43])[C:39]([F:40])([F:41])[F:42])[C:28]([OH:30])=[O:29])[C@H:9]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[CH2:10][O:11][C:6]=2[CH:5]=1
Reactant: CCOC(=O)C(CCCCCCCCN1c2ccc(O)cc2OC[C@H]1c1ccc(O)cc1)CCCCCC(F)(F)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(O)C(CCCCCCCCN1c2ccc(O)cc2OC[C@H]1c1ccc(O)cc1)CCCCCC(F)(F)C(F)(F)F
Temperature: 50 °C
Reaction time: 7 h
Yield: 76.3 %

Procedure:
Aqueous sodium hydroxide (1N, 1 ml) was added to ethyl 10-[(R)-7-hydroxy-3-(4-hydroxyphenyl)-3,4-dihydro-2H-benzo[1,4]-oxazine-4-yl]-2-(6,6,7,7,7-pentafluoroheptyl)decanoate (56.8 mg, 0.0902 mmol) in ethanol (1 ml) under a nitrogen stream, followed by stirring for 7 hours at 50° C. After cooling, the reaction mixture was acidified with 1N aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/1, v/v) to give 10-[(R)-7-hydroxy-3-(4-hydroxyphenyl)-3,4-dihydro-2H-benzo[1,4]-oxazine-4-yl]-2-(6,6,7,7,7-pentafluoroheptyl)decanoic acid (41.4 mg, Yield 76%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)[CH:5]=[CH:4][C:3]=1[NH2:17].[Cl:18][C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[S:26](Cl)(=[O:28])=[O:27].N1C=CC=CC=1>C(Cl)Cl>[Cl:18][C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[S:26]([NH:17][C:3]1[CH:4]=[CH:5][C:6]([B:8]2[O:12][C:11]([CH3:13])([CH3:14])[C:10]([CH3:16])([CH3:15])[O:9]2)=[CH:7][C:2]=1[F:1])(=[O:28])=[O:27]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Reactant: CC1(C)OB(c2ccc(N)c(F)c2)OC1(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)OB(c2ccc(NS(=O)(=O)c3cccc(Cl)c3Cl)c(F)c2)OC1(C)C

Procedure:
Intermediate 25 was prepared in analogy to GP 4 from 1.78 g 2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (7.5 mmol) and 2.03 g 2,3-dichloro-benzenesulfonyl chloride (8.25 mmol, 1.1 eq.) in 20 mL DCM and in the presence of 0.66 mL pyridine (8.25 mmol, 1.1. eq.) yielding after trituration 2.42 g of the target compound (72% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][C:10]([OH:12])=[O:11].CO.[Si](C=[N+]=[N-])(C)(C)[CH3:16].CCOCC>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][C:10]([O:12][CH3:16])=[O:11]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)Cc1c(F)cccc1F
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)Cc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,6-Difluorophenylacetic acid (2.61 g, 15.16 mmol) was taken up in THF (52 mL)/MeOH (13 mL). TMS-Diazomethane, 2 M in Et2O (8.5 mL, 17.00 mmol) was added and the resulting mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo and the residue purified by MPLC (2-20% EtOAc-hexanes) to give methyl 2,6-difluorophenylacetate as a colourless oil.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl.[C:5]1([C:11]2([CH2:17][C:18](=O)[CH3:19])[CH:16]=[CH:15][CH2:14][CH:13]=[CH:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C([BH3-])#N.[Na+]>CCOCC.CO>[CH3:19][CH:18]([N:2]([CH3:3])[CH3:1])[CH2:17][C:11]1([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:16]=[CH:15][CH2:14][CH:13]=[CH:12]1
Reactant: CC(=O)CC1(c2ccccc2)C=CCC=C1
Reactant: CNC
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: CC(CC1(c2ccccc2)C=CCC=C1)N(C)C
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To 50 ml. of methanol, 10 ml. of dimethylamine and 1 g. of molecular sieve 3 A are added dropwise at about -5° C. 10 ml. of 5 N methanolic hydrochloric acid and subsequently at 0° C. a solution of 5.3 g. of (1-phenyl-2,5-cyclohexadien-1-yl)-2-propanone in 20 ml. of methanol. 1.1 g. of sodium cyanoborohydride are then added at 0° C. and the mixture is stirred at room temperature for 4 days. The mixture is worked-up as follows: Ether and ice-water are added to the mixture and the phases are separated. The ether phase is extracted with dilute aqueous hydrochloric acid. The acid extracts are made alkaline with concentrated ammonia and extracted with ether. The combined ether phases are filtered and concentrated. There is obtained crude α,N,N-trimethyl-1-phenyl-2,5-cyclohexadien-1-ethylamine which is dissolved in ether, converted with hydrogen chloride into the hydrochloride and recrystallized from methylene chloride/ether. According to melting point and mixed melting point, the thus-obtained product is identical with that obtained in accordance with Example 3.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[C:4]([NH2:18])=[N:5][CH:6]=[C:7]([C:9]2[S:13][C:12]3=[N:14][CH:15]=[C:16](I)[N:11]3[N:10]=2)[CH:8]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][C:28]=1[C:29]([O:31][CH3:32])=[O:30].C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:32][O:31][C:29](=[O:30])[C:28]1[CH:27]=[CH:26][C:25]([C:16]2[N:11]3[C:12]([S:13][C:9]([C:7]4[CH:6]=[N:5][C:4]([NH2:18])=[C:3]([C:2]([F:20])([F:19])[F:1])[CH:8]=4)=[N:10]3)=[N:14][CH:15]=2)=[CH:24][C:23]=1[O:22][CH3:21]
Reactant: COC(=O)c1ccc(B(O)O)cc1OC
Reactant: Nc1ncc(-c2nn3c(I)cnc3s2)cc1C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2cnc3sc(-c4cnc(N)c(C(F)(F)F)c4)nn23)cc1OC
Temperature: 90 °C
Yield: 0.9 %

Procedure:
To a suspension of 3-(trifluoromethyl)-5-(5-iodoimidazo[2,1-b][1,3,4]thiadiazol-2-yl)pyridin-2-amine (0.500 g, 1.216 mmol, 1 eq), 3-methoxy-4-methoxycarbonylphenylboronic acid (0.306 g, 1.459 mmol, 1.2 eq), Pd(dppf)Cl2.DCM (0.105 g, 0.126 mmol, 0.1 eq) in DME was added a sat. aq. solution of Na2CO3 (2 mL). The reaction mixture was heated in a sealed tube at 90° C. over the weekend. The solid was filtered off, washed with MeOH and treated with a mixture of DCM and MeOH. The solid was removed by filtration, and the filtrate was evaporated to dryness to give the desired product (0.005 g). HPLC-MS (5-100% B in 8 min at 0.8 mL): tR=5.50 min, [M+H]+ m/z 450.1; 1H NMR (300 MHz, DMSO) δ=8.82 (d, J=1.8, 1H), 8.24 (s, 1H), 8.01 (s, 1H), 7.87 (s, 1H), 7.80 (d, J=8.1, 1H), 7.71 (d, J=8.2, 1H), 7.42 (br s, 2H), 3.95 (s, 3H), 3.80 (s, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[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.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[OH-:34].[K+].Cl>CS(C)=O.O.[Cu]I>[Cl:1][C:2]1[C:3]([OH:34])=[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
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(Cl)c(I)cc21
Reactant: [OH-]
Agent: [Cu]I
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1nccc2c1c(=O)n(C)c1cc(Cl)c(O)cc21
Temperature: 100 °C
Yield: 79 %

Procedure:
To the stirred solution of 8-chloro-9-iodo-4,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (1.0 g, 2.60 mmol) in DMSO (5 mL) and Water (5 mL) in an inert atmosphere were added copper(I) iodide (0.050 g, 0.260 mmol) followed by 1,10-phenanthroline (0.047 g, 0.260 mmol) and KOH (2.188 g, 39.0 mmol). The reaction mixture was heated to 100° C. for 16 h and monitored by LC/MS. Upon completion, the reaction mixture was cooled and pH adjusted to between 3 to 4 with 1 N HCl. The reaction mixture was diluted with 50 mL of water and extracted with 80 mL of dichloromethane. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford 8-chloro-9-hydroxy-4,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (0.6 g, 2.053 mmol, 79% crude yield) as a green solid. The material was carried on without further purification. LC/MS (ESI) m/e 273.0 [(M)−, calcd for C14H10ClN2O2 273.05]; LC/MS retention time (method C): tR=2.06 min.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][CH2:13][OH:14])[CH:8]=[CH:9][CH:10]=1)=[O:4]>N1C=CC=CC=1.[O-2].[O-2].[O-2].[Cr+6]>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][CH:13]=[O:14])[CH:8]=[CH:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cccc(CCCO)c1
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Product: COC(=O)c1cccc(CCC=O)c1

Procedure:
3-(3-Methoxycarbonylphenyl)propanol (1.9 g) was oxidised with chromium trioxide (5.0 g) in pyridine (7.9 ml) as described in Example 1(e) to give the product as a pale oil.