Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]2[CH:22]2[CH2:24][CH2:23]2)[C:9]2[C:4](=[C:5]([O:25][CH3:26])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[C:30]([CH3:35])[CH:29]=1>CN(C)C=O>[ClH:1].[F:27][C:28]1[CH:34]=[CH:33][C:31]([NH:32][C:2]2[N:11]=[C:10]([N:12]3[CH2:21][CH2:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]3[CH:22]3[CH2:23][CH2:24]3)[C:9]3[C:4](=[C:5]([O:25][CH3:26])[CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[C:30]([CH3:35])[CH:29]=1
Reactant: COc1cccc2c(N3CCc4ccccc4C3C3CC3)nc(Cl)nc12
Reactant: Cc1cc(F)ccc1N
Solvent: CN(C)C=O
Product: COc1cccc2c(N3CCc4ccccc4C3C3CC3)nc(Nc3ccc(F)cc3C)nc12
Product: Cl
Yield: 71 %

Procedure:
In accordance with the same procedures as in Example 18, except that to a mixture of 2.25 g of the compound (6.15 mM) prepared in Example 11 and 15 ml of dimethyl-formamide, 1.05 ml of 4-fluoro-2-methylaniline(12.9 mM) was added, 2.15 g of the title compound was prepared.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([N:11]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[N:9][C:8]([CH:26]([F:28])[F:27])=[CH:7][N:6]=1)=[O:4].[OH-].[Na+:30].[ClH:31].C1(C)C=CC=CC=1>C1COCC1>[C:15]([O:14][C:12]([N:11]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:10]1[C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=[C:8]([CH:26]([F:28])[F:27])[N:9]=1)=[O:13])([CH3:18])([CH3:17])[CH3:16].[Cl-:31].[Na+:30]
Reactant: COC(=O)c1ncc(C(F)F)nc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(C(F)F)cnc1C(=O)O
Product: [Cl-]
Reaction time: 1.5 h

Procedure:
To a solution of 3-(di-tert-butoxycarbonyl-amino)-5-difluoromethyl-pyrazine-2-carboxylic acid methyl ester (75 mg, 0.186 mmol) in THF (2 ml) was added dropwise 1N NaOH (0.205 ml, 0.205 mmol) and the reaction mixture was stirred for 1.5 h. To the mixture was added 1N HCl (0.186 ml, 0.186 mmol) after stirring for 5 min toluene was added and the solvents were evaporated to provide the title compound together with sodium chloride as colorless solid. The mixture was used for coupling reactions without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20](=[O:22])C)=[CH:14][CH:13]=3)=[CH:9][S:8][C:7]=2[CH:23]=1.I[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH:31]([CH3:33])[CH3:32].CC(C)(C)[C:36](O)=[O:37].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O.CCOC(C)=O>[CH:31]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:9]1[S:8][C:7]2[CH:23]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([O:37][CH3:36])=[O:22])=[CH:14][CH:13]=1)([CH3:33])[CH3:32]
Reactant: COc1ccc2c(Oc3ccc(/C=C/C(C)=O)cc3)csc2c1
Reactant: CC(C)c1ccccc1I
Reactant: CC(C)(C)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COC(=O)/C=C/c1ccc(Oc2c(-c3ccccc3C(C)C)sc3cc(OC)ccc23)cc1
Temperature: 140 °C
Yield: 77.7 %

Procedure:
To a solution of (E)-4-(4-((6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)but-3-en-2-one (45 g, 132 mmol) in anhydrous DMA (450 mL) at room temperature was added 1-iodo-2-isopropylbenzene (57 g, 231.6 mmol), chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II) (BrettPhos Palladacycle 1st generation, 6.34 g, 7.93 mmol), trimethylacetic acid (40.5 g, 397 mmol) and potassium carbonate (55 g, 397 mmol). The resulting mixture was heated at 140° C. for 1.5 hours. The reaction mixture was cooled down to 50° C. The reaction was diluted with EtOAc (400 mL) and let to cool down to room temperature. As the reaction cooled, a precipitate formed and was removed by filtration. The mother liquor was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by column chromatography (SiO2, 10-20% EtOAc/heptane) to afford (E)-methyl 3-(4-((2-(2-isopropylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (47 g, 102.5 mmol). 1H NMR (400 MHz, CDCl3) δ ppm=7.61 (d, J=15.9 Hz, 1H), 7.42-7.29 (m, 7H), 7.15 (ddd, J=8.1, 5.7, 2.8 Hz, 1H), 6.97 (dd, J=8.8, 2.3 Hz, 1H), 6.91-6.85 (m, 2H), 6.29 (d, J=16.0 Hz, 1H), 3.91 (s, 3H), 3.80 (s, 3H), 3.26 (p, J=6.8 Hz, 1H), 1.19 (d, J=6.9 Hz, 6H), LC/MS (m/z, MH+): 459.5.
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]#[N:5].[Na].[CH3:7]O.ClC[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12]>C(O)(=O)C>[NH2:5][C:4]1([C:11](=[O:12])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:3][CH2:2][S:1][CH2:7]1
Reactant: O=C(CCl)c1ccccc1
Reactant: CO
Reactant: N#CCCS
Agent: [Na]
Solvent: CC(=O)O
Product: NC1(C(=O)c2ccccc2)CCSC1
Temperature: 22 °C
Reaction time: 0.17 h
Yield: 85 %

Procedure:
8.7 Parts of β-mercaptopropionitrile are added to a solution of 2.6 parts of sodium in 175 parts by volume of methanol at 22° C., whilst stirring. After 10 minutes, 15.5 parts of chloracetophenone at 35° C. is added in the course of 30 minutes and the temperature is maintained at 22°C. The mixture is stirred for a further 30 minutes at 22° C. and is then heated for 2 hours at 65° C. under reflux. When it has cooled, the reaction mixture is neutralized with acetic acid and is poured into 250 parts of ice water, and the batch is extracted with three times 50 parts by volume of chloroform. After evaporating the combined, dried chloroform extracts, an oily residue remains, which is triturated with 50 parts of cold alcohol and hereupon crystallizes. 17.5 parts (85% of theory) of 3-amino-3-benzoyl-dihydrothiophene of melting point 147°-149° C. are obtained.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[C:14](=[S:16])=[S:15].[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1>CN(C)C=O.O>[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][S:15][C:14]([S:16][CH2:23][C:22]2[CH:25]=[CH:26][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[CH:21][CH:20]=1
Reactant: COc1ccc(CCl)cc1
Reactant: S=C=S
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)=C(SCc1ccc(OC)cc1)SCc1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of dimethylformamide (50 mL) containing diethyl malonate (12.78 g, 0.08 mol) is added slowly to an ice-cooled suspension of sodium hydride (60% dispersion in mineral oil, 6.53 g, 0.16 mol) in dimethylformamide (500 mL). The rate of addition of diethyl malonate is such as to maintain the temperature of the reaction mixture below 5° C. After the addition of diethyl malonate is complete, the gray reaction mixture continues to stir at 0° C. for 15 min. Carbon disulfide (14.5 mL, 0.24 mol) is then added dropwise to give a red mixture that is allowed to warm to room temperature with stirring for 1 h. A solution of dimethylformamide (25 mL) containing 4-methoxybenzyl chloride (25.00 g, 0.16 mol) is added dropwise to the reaction mixture at room temperature. The resulting orange mixture is allowed to warm to room temperature with stirring for 15 h, diluted with water (500 mL), and extracted with ethyl acetate (4×500 mL). The combined extracts are concentrated under reduced pressure (˜1 L), washed with water (3×150 mL), washed with brine (3×150 mL), dried over magnesium sulfate, and evaporated under reduced pressure to give crude 1. The crude product is purified by flash column chromatography (eluting with ethyl acetate/hexanes=1:4; Rf 0.21) to give 1 as a yellow solid. mp 57-59° C. 1H NMR (CDCl3): δ 1.27 (t, J=7.0 Hz, 3H, CO2CH2CH3), 3.79 (s, 3H, OCH3), 4.07 (s, 2H, SCH2), 4.23 (q, J=7.0 Hz, 2H, CO2CH2CH3), 6.83 (m, 2H, H-3/H-5), 7.20 (m, 2H, H-2/H-6). 13C{1H} NMR (CDCl3): δ 14.0 (CO2CH2CH3), 40.3 (SCH2), 55.3 (OCH3), 61.4 (CO2CH2CH3), 114.1 (aromatic C-3/C-5), 128.1 (═C—CO2CH2CH3 or C—CH2S—), 128.7 (═C—CO2CH2CH3 or C—CH2S—), 130.4 (aromatic C-2/C-6), 155.6 (—CH2S—C═), 159.1 (aromatic C-4, C—OCH3), 163.9 (CO2CH2CH3). LCMS m/z calcd for C24H28O6S2 476 ([M+]). found 477 ([M+H]+). HRMS m/z calcd for C24H28NaO6S2 499.1225 ([M+Na]+). found 499.1230. Anal. Calcd for C24H28O6S2: C, 60.48; H, 5.92; S, 13.46. Found: C, 60.51; H, 5.97; S, 13.19.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[C:7](=[N:16]O)[CH2:6]1.[ClH:19]>[Pd].CO>[Cl-:19].[CH3:15][O:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH3+:16])[CH2:6][CH:5]2[CH2:4][C:3]([O:2][CH3:1])=[O:18]
Reactant: COC(=O)CC1CC(=NO)c2ccc(OC)cc21
Reactant: Cl
Agent: [Pd]
Solvent: CO
Product: COC(=O)CC1CC([NH3+])c2ccc(OC)cc21
Product: [Cl-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 10% palladium on carbon (3.0 g), (3-hydroxyimino-6-methoxy-indan-1-yl)-acetic acid methyl ester (12.5 g), and concentrated hydrochloric acid (4.7 mL) in methanol (150 mL) is stirred under hydrogen atmosphere at room temperature overnight. The mixture is filtered and the filtrate is concentrated under reduced pressure. The residue is azeotropically dried using toluene and washed with diisopropylether to give the product as a white solid after drying at 50° C.
Reaction SMILES: C(OC([N:8]1[C@@H:12]([C:13](O)=O)[C@@H:11]([CH3:16])[O:10]C1(C)C)=O)(C)(C)C.[NH2:19][C:20]1[CH:21]=[C:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=2)[CH:23]=[CH:24][C:25]=1[NH2:26]>>[NH2:8][C@@H:12]([C:13]1[NH:26][C:25]2[CH:24]=[CH:23][C:22]([C:27]3[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=3)=[CH:21][C:20]=2[N:19]=1)[C@H:11]([OH:10])[CH3:16]
Reactant: C[C@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1C(=O)O
Reactant: N#Cc1ccc(-c2ccc(N)c(N)c2)cc1
Product: C[C@@H](O)[C@@H](N)c1nc2cc(-c3ccc(C#N)cc3)ccc2[nH]1

Procedure:
The title compound was prepared according to Method 4 using (4R,5R)-3-(tert-butoxycarbonyl)-2,2,5-trimethyl-1,3-oxazolidine-4-carboxylic acid (Preparation 59A) and 3′,4′-diaminobiphenyl-4-carbonitrile (Preparation 82). The reaction mixture was concentrated in vacuo and purified by SCX-2 cartridge (16 mg, 72%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH2:20][CH2:21][N:22](C(OC(C)(C)C)=O)[CH2:23][CH:24]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)[N:3]=1.[ClH:39].O1CCOCC1>C(OCC)(=O)C.C(OCC)C>[CH3:38][N:35]1[CH2:36][CH2:37][N:32]([C:4]2[CH:5]=[C:6]([N:8]3[CH:17]([CH3:18])[CH2:16][C:15]4[C:10](=[CH:11][C:12]([C:19]5[CH2:20][CH2:21][NH:22][CH2:23][CH:24]=5)=[CH:13][CH:14]=4)[CH2:9]3)[N:7]=[C:2]([NH2:1])[N:3]=2)[CH2:33][CH2:34]1.[ClH:39]
Reactant: CC1Cc2ccc(C3=CCN(C(=O)OC(C)(C)C)CC3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC1Cc2ccc(C3=CCNCC3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
tert-Butyl 4-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-3,6-dihydropyridine-1(2H)-carboxylate (0.20 g, 0.38 mmol) in ethyl acetate (1.0 mL) was treated with 4.0 M of hydrogen chloride in 1,4-dioxane (1.0 mL, 4.0 mmol) at r.t. for 2 h. The mixture was diluted with ethyl ether, and centrifugalized. The solvents were decanted. The residue was dried in-vacuo to afford the desired product as HCl salt which was directly used in next step reaction without further purification. LCMS (M+H)+: m/z=420.2.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:28])=[C:5]([C:23]2[O:24][CH:25]=[N:26][N:27]=2)[CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[Cl:22])[C:7]=1[C:8]([O:10]CCC#N)=[O:9].[OH-].[Na+]>O.C(COC)OC>[CH3:1][C:2]1[NH:3][C:4]([CH3:28])=[C:5]([C:23]2[O:24][CH:25]=[N:26][N:27]=2)[CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[Cl:22])[C:7]=1[C:8]([OH:10])=[O:9]
Reactant: CC1=C(C(=O)OCCC#N)C(c2cccc(Cl)c2Cl)C(c2nnco2)=C(C)N1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: CC1=C(C(=O)O)C(c2cccc(Cl)c2Cl)C(c2nnco2)=C(C)N1

Procedure:
30 g of the 2-cyanoethyl 1,4-dihydro-2,6-dimethyl-4-(2,3-dichlorophenyl)-5-(1,3,4-oxadiazol-2-yl)-pyridine-3-carboxylate thus prepared are stirred in a solution of 8.7 g of NaOH in 220 ml of water and 110 ml of dimethoxyethane for 3 hours at room temperature. The mixture is diluted with 200 ml of water and is extracted by shaking with three times 100 ml of CH2Cl2. The water phase is acidified by adding concentrated hydrochloric acid. The precipitate which has been deposited is then filtered off with suction, washed with water until it is neutral and dried in vacuo at 50° C. This gives 22.0 g (corresponding to 91.1% of theory) of 1,4-dihydro-2,6-dimethyl-4-(2,3-dichlorophenyl)-5-(1,3,4-oxadiazol-2-yl)-pyridine-3-carboxylic acid of melting point 187°-190° C. Analysis:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH3:18][CH:19]([CH3:23])[C:20](Cl)=[O:21]>>[CH3:18][CH:19]([CH3:23])[C:20]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:21]
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: CC(C)C(=O)Cl
Product: CC(C)C(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2n1
Yield: 756.6 %

Procedure:
Beginning with 0.35 gm (0.154 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.20 mL (0.193 mMol) 2-methylpropanoyl chloride, 0.35 gm (75%) of the title compound were prepared essentially by the procedure described in Example 8.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](O)=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH:29]([C:31](=[O:38])[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[NH2:30]>>[N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:23])[F:24])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]3[O:38][C:31]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[N:29][N:30]=3)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CC(=O)NN
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: CCOC(=O)Cc1nnc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)o1

Procedure:
100 mg (0.249 mmol) of the compound from Example 44A and 40 mg (0.273 mmol) of ethyl 3-hydrazinyl-3-oxopropanoate were reacted according to the General Method 4. Yield: 9 mg (6% of theory).
Reaction SMILES: O1CCCC1.C(N(CC)CC)C.C1(=O)OC(=O)CC1.Cl.C[O:22][C:23](=[O:45])[C@H:24]([CH2:26][C:27]1[CH:34]=[C:32]([I:33])[C:31]([O:35][C:36]2[CH:43]=[C:41]([I:42])[C:40]([OH:44])=[C:38]([I:39])[CH:37]=2)=[C:29]([I:30])[CH:28]=1)[NH2:25]>>[NH2:25][C@H:24]([C:23]([OH:45])=[O:22])[CH2:26][C:27]1[CH:28]=[C:29]([I:30])[C:31]([O:35][C:36]2[CH:37]=[C:38]([I:39])[C:40]([OH:44])=[C:41]([I:42])[CH:43]=2)=[C:32]([I:33])[CH:34]=1
Reactant: COC(=O)[C@@H](N)Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1
Agent: Cl
Agent: O=C1CCC(=O)O1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N[C@@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)C(=O)O
Temperature: 4 °C
Reaction time: 8 h

Procedure:
In 150 ml of dried tetrahydrofuran 1.65 g (0.002 mol) of thyroxine methyl ester hydrochloride was dissolved. To the resulting solution 300 μl (0.0021 mol) of triethyl amine and 200 mg. (0.0022 mol) of succinic anhydride were added. The mixture was stirred at 4° C. overnight to effect reaction.
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4](C=[CH:6]1)[CH:3]1[C:9]([O:11][C:12](=[O:13])[CH:2]21)=[O:10].[OH-:14].[Na+:15]>CO>[CH:4]12[CH2:6][CH:1]([CH:8]=[CH:7]1)[CH:2]([C:12]([O-:11])=[O:13])[CH:3]2[C:9]([O-:10])=[O:14].[Na+:15].[Na+:15]
Reactant: [OH-]
Reactant: O=C1OC(=O)C2C3C=CC(CC3)C12
Agent: [Na+]
Solvent: CO
Product: O=C([O-])C1C2C=CC(C2)C1C(=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of bicyclo[2.2.2]-oct-5-en-2,3-dicarboxylic anhydride (2.01 g, 11.3 mmole) in MeOH (50 mL) was added 1 N aq. NaOH (22.4 mL, 22.4 mmol). The reaction mixture was stirred for 1 hour at room temperature. The solvent was removed in vacuo and the resulting colorless solid was dried: mp>400 C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([N+:20]([O-:22])=[O:21])[C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]([O:9]C)=[O:8])([O-:3])=[O:2].Cl>COCCO.[OH-].[Na+].O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([N+:20]([O-:22])=[O:21])[C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]([OH:9])=[O:8])([O-:3])=[O:2]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(-c2ccccc2)c([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COCCO
Product: O=C(O)c1cc([N+](=O)[O-])c(-c2ccccc2)c([N+](=O)[O-])c1
Reaction time: 0.25 h

Procedure:
To a stirred suspension of methyl 3,5-dinitro-4-phenylbenzoate (145 g) in 2-methoxyethanol (1.5 l), 2 N sodium hydroxide (300 ml) is added dropwise during about 30 minutes. After additional stirring for about 15 minutes, the resulting solution is acidified by the dropwise addition of 4 N hydrochloric acid (250 ml), and the mixture is thereafter diluted with water (about 3 l). After cooling, the resulting precipitate is collected by filtration, washed with water and dried. After recrystallization from aqueous ethanol, 3,5-dinitro-4-phenylbenzoic acid is obtained with a melting point of 219°-221° C.
Reaction SMILES: [Sn](Cl)Cl.[CH:4]([Si:7]([C:14]#[C:15][C:16]1(O)[C:27]2[C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[S:24][C:23]=2[C:22]([C:33]#[C:34][Si:35]([CH:42]([CH3:44])[CH3:43])([CH:39]([CH3:41])[CH3:40])[CH:36]([CH3:38])[CH3:37])(O)[C:21]2[C:20]3[CH:45]=[CH:46][CH:47]=[CH:48][C:19]=3[S:18][C:17]1=2)([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])([CH3:6])[CH3:5]>C(O)(=O)C.CC(C)=O>[CH:36]([Si:35]([C:34]#[C:33][C:22]1[C:21]2[C:20]3[CH:45]=[CH:46][CH:47]=[CH:48][C:19]=3[S:18][C:17]=2[C:16]([C:15]#[C:14][Si:7]([CH:4]([CH3:6])[CH3:5])([CH:8]([CH3:10])[CH3:9])[CH:11]([CH3:13])[CH3:12])=[C:27]2[C:23]=1[S:24][C:25]1[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=12)([CH:42]([CH3:44])[CH3:43])[CH:39]([CH3:40])[CH3:41])([CH3:37])[CH3:38]
Reactant: CC(C)[Si](C#CC1(O)c2sc3ccccc3c2C(O)(C#C[Si](C(C)C)(C(C)C)C(C)C)c2sc3ccccc3c21)(C(C)C)C(C)C
Agent: Cl[Sn]Cl
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: CC(C)[Si](C#Cc1c2sc3ccccc3c2c(C#C[Si](C(C)C)(C(C)C)C(C)C)c2sc3ccccc3c12)(C(C)C)C(C)C
Temperature: 2.5 °C

Procedure:
A solution of tin(II)chloride dehydrate (2.59 g, 11.5 mmol) in 50% acetic acid (40 ml) is added within ten minutes to a solution of 6,12-bis-[(triisopropylsilanyl)-ethynyl]-6,12-dihydro-dibenzo[d,d′]benzo[1,2-b;4,5-b′]dithiophene-6,12-diol (educt 3) in acetone (35 ml). There is a slight temperature increase (2-3° C.), and formation of a yellow suspension takes place. This suspension is stirred over night at ambient temperature, and then the solid is filtered off. The solid is then washed with 50% acetic acid (30 ml), water (twice with 40 ml), and acetone (2*40 ml). The residue is then dried to give crude product which is recrystallised from toluene (15 ml). The product is filtered off, washed with toluene (10 ml), and hexane (10 ml). After drying, the title product is obtained as pale yellow crystals. Mp. (DSC) 155° C. (broad probably phase transition), 208° C. (sharp, probably melting point). 1H-NMR (CDCl3, 300 MHz) δ 1.31-1.336 (m (higher order), 21H, CH(CH3)2); 7.48 (m, 1H, H-2), 7.53 (m, 1H, H-3), 7.92 (d, 1H, H-4); 9.37 (d, 1H, H-1). 13C-NMR (CDCl3, 75 MHz) δ 11.92 (CH); 19.22 (CH3); 103.42, 106.36 (C≡C); 112.56 (C-6); 122.78 (C-4); 124.33 (C-2); 125.16 (C-1); 127.46 (C-3); 132.78 (C-6a); 135.49 (C-6b); 140.47 (C-4-a); 143.30 (C-5a).
Reaction SMILES: C([NH:9][C:10]1[O:11][C@H:12]([C:28]([F:31])([F:30])[F:29])[CH2:13][C@:14]([C:18]2[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=2[F:27])[C:21]([OH:23])=O)([CH2:16][F:17])[N:15]=1)(=O)C1C=CC=CC=1.[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=1O>>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]2[N:32]=[C:21]([C:20]3[CH:24]=[CH:25][C:26]([F:27])=[C:18]([C@:14]4([CH2:16][F:17])[CH2:13][C@@H:12]([C:28]([F:29])([F:30])[F:31])[O:11][C:10]([NH2:9])=[N:15]4)[CH:19]=3)[O:23][C:34]=2[CH:35]=1
Reactant: O=C(O)c1ccc(F)c([C@]2(CF)C[C@@H](C(F)(F)F)OC(NC(=O)c3ccccc3)=N2)c1
Reactant: Nc1ccc(Cl)cc1O
Product: NC1=N[C@](CF)(c2cc(-c3nc4ccc(Cl)cc4o3)ccc2F)C[C@@H](C(F)(F)F)O1
Temperature: 160 °C
Reaction time: 0.43 h
Yield: 3.4 %

Procedure:
To a 3 mL microwave vial was added 3-((4S,6S)-2-benzamido-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorobenzoic acid (76.5 mg, 0.17 mmol). 2-amino-5-chlorophenol (74.0 mg, 0.52 mmol) and polyphosphoric acid (0.50 mL). The mixture was purged with Ar for 1 min, then the tube was sealed and heated to 160° C. for 1 h. The mixture was then diluted with Na2CO3 in water and extracted with DCM three times. The organic layer was dried over Na2SO4, and concentrated in vacuo. The crude was purified by reverse phase HPLC: 10-100% in 26 min, MeCN in water with 0.1% TFA. The combined fractions were neutralized with solid Na2CO3, and extracted with DCM three times. The organic phase was dried over Na2SO4 and concentrated in vacuo. The product was obtained as an off-white solid (2.6 mg, 3.6% yield). MS m/z=446 [M+H]+. Calculated for C19H13ClF5N3O2: 445.8.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[CH:29]=[C:30]([S:34]([NH:37][C:38]([CH3:42])([CH3:41])[CH2:39][OH:40])(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>>[OH:40][CH2:39][C:38]([NH:37][S:34]([C:30]1[CH:29]=[C:28]([NH:27][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:1])([F:26])[F:25])=[CH:4][C:5]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:19][CH:20]=4)=[N:6][C:7]=23)=[O:14])[CH:33]=[CH:32][CH:31]=1)(=[O:36])=[O:35])([CH3:42])[CH3:41]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CC(C)(CO)NS(=O)(=O)c1cccc(N)c1
Product: CC(C)(CO)NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) and 3-amino-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (example B.8) according to general procedure II. Yellow solid. MS (ISP) 600.1 [(M−H−]; mp 227° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[NH2:24][C:25]1[CH:26]=[N:27][CH:28]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:30]=1>>[NH2:24][C:25]1[CH:30]=[C:29]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]5[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)[CH:28]=[N:27][CH:26]=1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CC1(C)OB(c2cncc(N)c2)OC1(C)C
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cncc(N)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.106 mmol) and 3-aminopyridine-5-boronic acid pinacol ester (Apollo Scientific, Cheshire, United Kingdom, 29 mg, 0.132 mmol) to give the title compound as a white solid. (HPLC: tR 1.99 min (Method A); M+H=386 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.97 (s, 1H), 8.16-8.05 (m, 2H), 7.94-7.89 (m, 1H), 7.81-7.74 (m, 2H), 7.54-7.48 (m, 1H), 7.04-6.98 (m, 1H), 5.45 (s, br, 2H), 3.91 (s, 3H), 3.57 (s, 3H), 1.95 (s, 3H))