Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[C:13]([F:16])([F:15])[F:14])[C:7]([OH:9])=[O:8])([O-:3])=[O:2].Cl.[CH2:18](O)[CH3:19]>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[C:13]([F:14])([F:15])[F:16])[C:7]([O:9][CH2:18][CH3:19])=[O:8])([O-:3])=[O:2]
Reactant: O=C(O)c1ccc(C(F)(F)F)c([N+](=O)[O-])c1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1ccc(C(F)(F)F)c([N+](=O)[O-])c1
Yield: 64 %

Procedure:
A solution of 555 mg (2.36 mmol) of 3-nitro-4-(trifluoromethyl)benzoic acid (from Step B) in 10 mL of ethanol was treated with 1 mL of concentrated hydrochloric acid. The solution was stirred at reflux for 2 days, then cooled, and partitioned between ethyl acetate and H2O. The organic layer was washed successively with saturated NaHCO3, H2O, and brine. The ethyl acetate solution was then dried over Na2SO4 and concentrated to give 400 mg (64%) of the title compound as a pale yellow foam, homogeneous by TLC in 4:1 hexane-EtOAc; mass spectrum (EI) m/e 263 (M+). 200 MHz 1H NMR (CDCl3) δ1.43 (t, J=7.2 Hz, 3H), 4.46 (q, J=7.2 Hz, 2H), 7.92 (d, J=8 Hz, 1H), 8.36 (d, J=8 Hz, 1H), 8.49 (s, 1H).
Reaction SMILES: [C:1]([C:3]1([OH:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[CH3:9])#[CH:2].[CH3:11][CH2:12][NH:13][C:14]([C@H:16]1[O:20][C@@H:19]([N:21]2[C:25]3[N:26]=[C:27](I)[N:28]=[C:29]([NH2:30])[C:24]=3[N:23]=[CH:22]2)[CH:18]([OH:32])[C@H:17]1[OH:33])=[O:15]>>[CH2:12]([NH:13][C:14]([CH:16]1[CH:17]([OH:33])[CH:18]([OH:32])[CH:19]([N:21]2[CH:22]=[N:23][C:24]3[C:25]2=[N:26][C:27]([C:2]#[C:1][C:3]2([OH:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]2[CH3:9])=[N:28][C:29]=3[NH2:30])[O:20]1)=[O:15])[CH3:11]
Reactant: C#CC1(O)CCCCC1C
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(N)nc(I)nc32)C(O)[C@H]1O
Product: CCNC(=O)C1OC(n2cnc3c(N)nc(C#CC4(O)CCCCC4C)nc32)C(O)C1O
Yield: 65 %

Procedure:
The reaction of 1-Ethynyl-2-methyl-cyclohexanol (JR3169B) (100 mg, 0.72 mmol) with 2-iodo-NECA (25 mg, 0.06 mmol) under the general coupling conditions gave JR3177A (8.0 mg) and JR3177B (8.2 mg) (overall yield 65%) as white solids after purification by a silica plug and RP-HPLC. JR3177A: 1H NMR (CD3OD-d4) δ 8.47 (s, 1 H), 6.05 (d, J=6.9 Hz, 1 H), 4.77 (dd, J=6.9 Hz, J=4.9 Hz, 1 H), 4.45 (d, J=1.9 Hz, 1 H), 4.34 (dd, J=4.6 Hz, J=2.1 Hz, 1 H), 3.41 (m, 2 H), 2.13 (d, J=12.7 Hz, 2 H), 1.65 (m, 5 H), 1.32 (m, 2 H), 1.14 (t, J=7.0 Hz, 3 H), 1.13 (d, J=6.6 Hz, 3 H). 13C NMR (CD3OD-d4) δ. APCI m/z (rel intensity) 445.3 (MH+, 100), 427.4 (80), 254.4 (14). 1H NMR (CD3OD-d4) δ 8.49 (s, 1 H), 6.05 (d, J=6.9 Hz, 1 H), 4.78 (dd, J=6.4 Hz, J=4.9 Hz, 1 H), 4.45 (d, J=1.9 Hz, 1 H), 4.34 (dd, J=4.6 Hz, J=1.6 Hz, 1 H), 3.42 (m, 2 H), 2.12 (d, J=12.3 Hz, 2 H), 1.65 (m, 4 H), 1.35 (m, 4 H), 1.14 (t, J=7.3 Hz, 3 H), 1.12 (d, J=6.6 Hz, 3 H). 13C NMR (CD3OD-d4) δ. APCI m/z (rel intensity) 445.7 (MH+, 100), 427.3 (35), 254.4 (3.5).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:13])=[CH:4][C:5]2[O:9][C:8]([C:10]#[N:11])=[CH:7][C:6]=2[CH:12]=1.C1C(=O)N([Br:21])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:21][CH2:13][C:3]1[C:2]([F:1])=[CH:12][C:6]2[CH:7]=[C:8]([C:10]#[N:11])[O:9][C:5]=2[CH:4]=1
Reactant: Cc1cc2oc(C#N)cc2cc1F
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cc2cc(F)c(CBr)cc2o1
Yield: 76.6 %

Procedure:
To the solution of 5-fluoro-6-methylbenzofuran-2-carbonitrile (1.44 g, 8.22 mmol) in 82 mL of CCl4 was added NBS (1.536 g, 8.63 mmol) and AlBN (0.067 g, 0.411 mmol). After the reaction mixture was refluxed overnight, the solvent was removed. The residue was purified by silica gel flash chromatography (100% heptane-7% ethyl acetate/heptane) to give 6-(bromomethyl)-5-fluorobenzofuran-2-carbonitrile (1.6 g). 1H NMR (400 MHz, DMSO-d6) δ 4.82 (d, J=1.1 Hz, 2H), 7.75 (d, J=9.5 Hz, 1H), 8.02 (d, J=5.9 Hz, 1H), 8.10 (d, J=0.86 Hz, 1H).
Reaction SMILES: C(OC(=O)N)C1C=CC=CC=1.[CH2:12]([O:19][C:20](=[O:55])[NH:21][C:22]1[CH:27]=[C:26]([C:28]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:29]=2[CH:30]=[CH:31][N:32]3[Si](C(C)C)(C(C)C)C(C)C)[CH:25]=[C:24]([C:47]([C:49]2[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=2)=[O:48])[CH:23]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([O:19][C:20](=[O:55])[NH:21][C:22]1[CH:23]=[C:24]([C:47]([C:49]2[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=2)=[O:48])[CH:25]=[C:26]([C:28]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:29]=2[CH:30]=[CH:31][NH:32]3)[CH:27]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(-c3cc(NC(=O)OCc4ccccc4)cc(C(=O)c4cccnc4)c3)cccc21
Agent: NC(=O)OCc1ccccc1
Product: O=C(Nc1cc(C(=O)c2cccnc2)cc(-c2cccc3[nH]ccc23)c1)OCc1ccccc1

Procedure:
3-Bromo-5-(pyridine-3-carbonyl)-phenyl]-carbamic acid benzyl ester was converted to [3-(pyridine-3-carbonyl)-5-(1-triisopropylsilanyl-1H-indol-4-yl)-phenyl]-carbamic acid benzyl ester, then deprotected to give [3-(1H-indol-4-yl)-5-(pyridine-3-carbonyl)-phenyl]-carbamic acid benzyl ester by the method of Example 35. 1H NMR (400 MHz, methanol-d4): δ 9.07 (s, 1H), 8.77 (d, J=4.8 Hz, 1H), 8.57 (s, 1H), 8.14 (dt, J=4.9, 2.6 Hz, 1H), 8.08 (s, 1H), 7.84 (s, 1H), 7.77 (t, J=1.5 Hz, 1H), 7.42-7.29 (m, 8H), 7.26-7.13 (m, 3H), 6.69 (s, 1H), 5.20 (s, 2H).
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:18][C:13]3[N:14]=[CH:15][N:16]=[CH:17][C:12]=3[CH:11]=2)=[CH:6][CH:5]=1.C1COCC1.CO.[OH-].[Na+].Cl>O>[N:14]1[C:13]2[NH:18][C:10]([C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:19])=[O:2])=[CH:9][CH:8]=3)=[CH:11][C:12]=2[CH:17]=[N:16][CH:15]=1
Reactant: COC(=O)c1ccc(-c2cc3cncnc3[nH]2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(-c2cc3cncnc3[nH]2)cc1
Reaction time: 1 h
Yield: 61.8 %

Procedure:
To a solution of 4-(7H-pyrrolo[2,3-d]pyrimidin-6-yl)-benzoic acid methyl ester (0.601 g, 2.4 mmol) (reference example 43a) in 1:1 THF-methanol (10 mL) is added NaOH (10N) (2.4 mL, 24 mmol) and 0.5 ml H2O. The resulting solution is stirred for 1 hour then cooled to 0°-5° C. and adjusted to pH 3 with 2N HCl. The precipitated solid is filtered off, washed with a small volume of water and dried under high vacuum to give 0.355 g of title compound as a yellow solid. 1H NMR (DMSO) δ 7.59 (s, 1H), 8.10 (d, J=8 Hz, 2H), 8.20 (d, J=8 Hz, 2H), 9.22 (s, 1H), 9.50 (bs, 1H), 14.10 (bs, 1H). MS (EI) m/z 239 (M+).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([N:13]([CH2:21][C:22]([OH:24])=O)[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[N:8][CH:9]=1)([CH3:3])[CH3:2].[CH2:25]([NH:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[N:30]=1)[CH3:26]>>[CH2:25]([N:27]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[N:30]=1)[C:22](=[O:24])[CH2:21][N:13]([S:10]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][N:8]=1)(=[O:11])=[O:12])[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)[CH3:26]
Reactant: CCNCc1cccc(C)n1
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)C)cn2)cc1
Product: CCN(Cc1cccc(C)n1)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccc(C(C)C)cn1

Procedure:
prepared by reaction of [(5-isopropyl-pyridine-2-sulfonyl)-p-tolyl-amino]-acetic acid with ethyl-(6-methyl-pyridin-2-ylmethyl)-amine
Reaction SMILES: Br[C:2]1[C:3]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])[C@@H:7]([CH3:17])[CH2:6][CH2:5]2.[F-].[Cs+].[CH2:27]([Sn](CCCC)(CCCC)C#CC)[CH2:28][CH2:29]C>CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.CC(OC)(C)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].O1CCOCC1>[CH:14]1([C:12]([N:8]2[C:9]3[C:4](=[C:3]([O:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:2]([C:27]#[C:28][CH3:29])=[CH:11][CH:10]=3)[CH2:5][CH2:6][C@@H:7]2[CH3:17])=[O:13])[CH2:16][CH2:15]1
Reactant: C[C@H]1CCc2c(ccc(Br)c2Oc2ccccc2)N1C(=O)C1CC1
Reactant: CC#C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd+]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: NCCc1[c-]cccc1
Solvent: C1COCCO1
Solvent: COC(C)(C)C
Product: CC#Cc1ccc2c(c1Oc1ccccc1)CC[C@H](C)N2C(=O)C1CC1
Temperature: 160 °C

Procedure:
A mixture of (S)-(6-bromo-2-methyl-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone (0.050 g, 0.13 mmol), RuPhos Precatalyst 3rd generation ((2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate) (0.011 g, 0.01 mmol), cesium fluoride (0.099 g, 0.65 mmol), and tributyl(prop-1-ynyl)stannane (0.107 g, 0.32 mmol) in 1,4-dioxane (4 mL) was heated with microwave irradiation for 1 h at 160° C. The reaction mixture was cooled to room temperature, passed through a short pad of Celite and concentrated under vacuum. The residue was purified via preparative thin layer chromatography (eluting with 1:5, ethyl acetate/petroleum ether). The product was further purified by preparative-HPLC with the following conditions (Waters I): Column, SunFire Prep C18, 5 um, 19×100 mm; mobile phase, water (0.05% ammonium bicarbonate) and acetonitrile (50% to 100% acetonitrile in 10 min, flow rate: 20 mL/min); Detector: UV 220&254 nm. This afforded (S)-cyclopropyl(2-methyl-5-phenoxy-6-(prop-1-ynyl)-3,4-dihydroquinolin-1(2H)-yl)methanone (0.011 g, 26%) as a light brown semi-solid. 1H NMR (400 MHz, CD3OD) δ ppm 0.65-0.85 (m, 1H), 1.02-0.87 (m, 2H), 1.03-1.22 (m, 4H), 1.37-1.51 (m, 1H), 1.82 (s, 3H), 1.88-2.03 (m, 1H), 2.07-2.42 (m, 2H), 2.58-2.82 (m, 1H), 4.85-4.72 (m, 1H), 6.78 (d, J=7.80 Hz, 2H) 7.00 (t, J=7.50 Hz, 1H), 7.25-7.31 (m, 4H). MS (ESI, pos. ion) m/z 346 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:7][C:8]1[C:9]([F:16])=[CH:10][C:11]([F:15])=[C:12]([OH:14])[CH:13]=1.Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1.O>CN(C=O)C>[CH3:29][O:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][C:24]=1[O:30][CH3:31])[N:21]=[CH:20][N:19]=[C:18]2[O:14][C:12]1[C:11]([F:15])=[CH:10][C:9]([F:16])=[C:8]([CH:13]=1)[NH2:7]
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Nc1cc(O)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Oc3cc(N)c(F)cc3F)c2cc1OC
Temperature: 80 °C

Procedure:
To a stirred suspension of cesium carbonate (3.25 g, 10.0 mmoles) in dry DMF (20 mL) was added 5-amino-2,4-difluorophenol (1.00 g, 6.9 mmoles). This solution was heated to 80° C. for 1 hour, and 4-chloro-6,7-dimethoxyquinazoline (1.59 g, 7.1 mmoles) was added and the reaction heated for an additional hour. At the end of this time the reaction was poured into water (200 mL) and extracted with two portions (200 mL) of ethyl acetate. The extracts were combined and dried over MgSO4. Filtration and concentration afforded 5-(6,7-dimethoxyquinazolin-4-yloxy)-2,4-difluoroaniline as a crude red oil. Purification by silica gel chromatography eluting with an ethyl acetate/hexane gradient, 30%-70% over 70 minutes gave a slightly impure oil containing DMF. This oil was crystallized using ethyl acetate hexane to give a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:28]=[CH:27][C:6]([CH2:7][C@@:8]23[CH2:15][C@H:14]([NH2:16])[CH2:13][N:12]2[C:11](=[O:17])[N:10]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=2)[C:9]3=[O:26])=[CH:5][CH:4]=1)#[N:2].[C:29](O)(=[O:35])[CH2:30][CH2:31][C:32]([NH2:34])=[O:33].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C1COCC1.C(Cl)CCl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C@@:8]23[CH2:15][C@H:14]([NH:16][C:29](=[O:35])[CH2:30][CH2:31][C:32](=[O:33])[NH2:34])[CH2:13][N:12]2[C:11](=[O:17])[N:10]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=2)[C:9]3=[O:26])=[CH:27][CH:28]=1)#[N:2]
Reactant: N#Cc1ccc(C[C@@]23C[C@H](N)CN2C(=O)N(c2cc(Cl)cc(Cl)c2)C3=O)cc1
Reactant: NC(=O)CCC(=O)O
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(C[C@@]23C[C@H](NC(=O)CCC(N)=O)CN2C(=O)N(c2cc(Cl)cc(Cl)c2)C3=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
A mixture of (5S,7S)-5-(4-cyanobenzyl)-3-(3,5-dichlorophenyl)-7-amino-1,3-diazabicyclo[3.3.0]octane-2,4-dione (82.7 mg), succinamic acid (45.86 mg), EDC (93.12 mg), HOBT (61.24 mg) and DIEA (104.79 μL) in THF (5 mL) was stirred overnight at room temperature. The reaction mixture was concentrated and purified by high performance liquid chromatography (HPLC) (Beckman 5μ C18 column; eluted with a gradient of H2O/MeCN (10-100%)/0.1% TFA) to give 72 mg of the titled compound. MS (m/z) 536 (MNa+).
Reaction SMILES: [ClH:1].Cl.FC1C=CC(C2C=NC(N3CCNCC3)=NC=2)=CC=1.C(OC([N:29]1[CH2:34][CH2:33][N:32]([C:35]2[N:40]=[CH:39][C:38]([C:41]3[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=3)=[CH:37][N:36]=2)[CH2:31][CH2:30]1)=O)(C)(C)C>>[ClH:1].[ClH:1].[ClH:1].[N:32]1([C:35]2[N:40]=[CH:39][C:38]([C:41]3[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=3)=[CH:37][N:36]=2)[CH2:31][CH2:30][NH:29][CH2:34][CH2:33]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3cccnc3)cn2)CC1
Agent: Cl
Agent: Fc1ccc(-c2cnc(N3CCNCC3)nc2)cc1
Product: c1cncc(-c2cnc(N3CCNCC3)nc2)c1
Yield: 96 %

Procedure:
Prepared according to the method for the preparation of 5-(4-fluorophenyl)-2-piperazin-1-ylpyrimidine dihydrochloride, from 4-(5-pyridin-3-ylpyrimidin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.399 g), to furnish the title compound as an off-white solid (0.393 g, 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH:13]2[C:21]([O:23]C)=[O:22])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].CO.O1CCOCC1.[OH-].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH:13]2[C:21]([OH:23])=[O:22])(=[O:10])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)C1Cc2ccccc2N1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: O=C(O)C1Cc2ccccc2N1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 1-(3,4-dichlorophenylsulfonyl)indoline-2-carboxylate (49.8 g, 128.92 mmol) was dissolved in a mixture of methanol/dioxane/4 M NaOH (15/4/1, 960 ml, 193.38 mmol NaOH, 1.5 eq.), and further 4 M NaOH (145 ml, 580.14 mmol, 4.5 eq.) was added thereto. The solution was stirred overnight at room temperature and then concentrated using a rotary evaporator. Ethyl acetate was added to the residue, and the mixture was washed with 0.5 M KHSO4. The aqueous phase was then extracted three times with ethyl acetate, and the combined organic phases were washed with saturated NaCl solution (500 ml), dried (sodium sulfate) and concentrated in vacuo. The residue was washed with diethyl ether, filtered and dried.
Reaction SMILES: [C:1]1([P:7](=[O:10])([OH:9])[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:11](=[O:15])(=[O:14])([OH:13])[OH:12]>O>[S:11](=[O:13])(=[O:12])([OH:15])[OH:14].[S:11]([C:3]1[CH:2]=[C:1]([P:7](=[O:9])([OH:8])[OH:10])[CH:6]=[CH:5][CH:4]=1)([OH:14])(=[O:13])=[O:12]
Reactant: O=P(O)(O)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=P(O)(O)c1cccc(S(=O)(=O)O)c1
Temperature: 80 °C

Procedure:
Phenyl phosphonic acid (40.0 g, 0.25 mol) was taken in a 200 mL round-bottom flask, a 60% of fuming sulfuric acid (77.3 g, 0.58 mol) was added and stirred under heating at 80° C. for one day under a nitrogen gas stream. Then, after cooling the reaction mixture in an iced bath, water (86.0 g) was added to form a 12N sulfuric acid solution (32 wt %) of 3-sulfophenyl phosphonic acid. This stock solution was portioned into a predetermined small amount and used for the synthesis of the zirconium phosphonate copolymer.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:21][C:20]([CH3:23])([CH3:22])[O:19][C:18]([CH3:25])([CH3:24])[CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:26][C:27](=[CH2:35])[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:15][C:12]1[CH:13]=[CH:14][C:9]([C:8](=[C:16]2[CH2:21][C:20]([CH3:23])([CH3:22])[O:19][C:18]([CH3:24])([CH3:25])[CH2:17]2)[C:5]2[CH:6]=[CH:7][C:2](/[CH:26]=[C:27](\[CH3:35])/[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: C=C(C)C(=O)OC(C)(C)C
Reactant: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(Br)cc2)CC(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: C/C(=C\c1ccc(C(=C2CC(C)(C)OC(C)(C)C2)c2ccc(O)cc2)cc1)C(=O)OC(C)(C)C

Procedure:
The general Heck reaction procedure, described for 15 was followed. 4-[(4-bromophenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]phenol (211) (0.440 g, 1.096 mmol) was reacted with 1,1-dimethylethyl 2-methyl-2-propenoate in the presence of PdCl2(PPh3)2 to afford the title compound as a mixture of Z and E isomers. The pure E-isomer (212) was isolated by HPLC as a white solid. 1H NMR (300 MHz, CDCl3): δ 7.58 (s, 1H), 7.34 (d, J=8.1 Hz, 2H), 7.19 (d, J=8.1 Hz, 2H), 7.05 (d, J=8.4 Hz, 2H), 7.81 (d, J=8.4 Hz, 2H), 5.80 (br s, 1H), 2.30 (d, J=3.0 Hz, 4H), 2.10 (s, 3H), 1.56 (s, 9H), 1.27 (s, 12H). LCMS (ESI): m/z 461 (M−H)−.
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[N:10][C:9]2[C:8]3=[N:13]O[N:15]=[C:7]3[CH:6]=[CH:5][C:4]=2[N:3]=1.C(N(CC)CC)C>CN(C)C=O.[Pd]>[NH2:13][C:8]1[C:7]([NH2:15])=[CH:6][CH:5]=[C:4]2[C:9]=1[N:10]=[C:11]([OH:12])[C:2]([OH:1])=[N:3]2
Reactant: Oc1nc2ccc3nonc3c2nc1O
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ccc2nc(O)c(O)nc2c1N
Yield: 95.6 %

Procedure:
A solution of 5,0 g (24,5 mmol) 7,8-dihydroxy-1,2,5-oxadiazolo(3,4-f)quinoxaline and 6,B ml (49 mmol) triethylamine in 500 ml dimethylformamide was hydrogenated at atm. pressure using 5% Pd-C (0,5 g) as a catalyst. The reaction mixture was filtered and evaporated in vacuo. The residue was stirred with water, and the precipitate was fiItered off to give 4,5 g (96%) 5,6-diamino-2,3-dihydroxyquinoxaline, m.p. >300° C. NMR (DMSO-d6) 11.0 (2H, broad m), 6.43 (lH,d), 6.23 (lH,d), 4.5 (4H, broad m).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][C:11]2[C:6](=[CH:7][C:8]([N+:20]([O-:22])=[O:21])=[C:9](F)[CH:10]=2)[N:5]=1)[CH3:2].Cl.[OH:24][CH2:25][C:26]1[N:27]=[CH:28][NH:29][CH:30]=1.C(N(CC)CC)C>C(#N)C>[CH2:1]([O:3][C:4]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][C:11]2[C:6](=[CH:7][C:8]([N+:20]([O-:22])=[O:21])=[C:9]([N:29]3[CH:30]=[C:26]([CH2:25][OH:24])[N:27]=[CH:28]3)[CH:10]=2)[N:5]=1)[CH3:2]
Reactant: OCc1c[nH]cn1
Reactant: CCOC(=O)c1cc2cc(F)c([N+](=O)[O-])cc2nc1OCC
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc2cc(-n3cnc(CO)c3)c([N+](=O)[O-])cc2nc1OCC
Temperature: 120 °C
Reaction time: 16 h
Yield: 46.6 %

Procedure:
To a solution of ethyl 2-ethoxy-6-fluoro-7-nitroquinoline-3-carboxylate (1.00 g, 3.24 mmol) in acetonitrile (10 ml) were added 4-(hydroxymethyl)imidazole hydrochloride (2.18 g, 16.2 mmol) and successively triethylamine (3 ml), and the mixture was stirred for 16 hours at 120° C. in a sealed tube under shading. After cooling, solvent was distilled off and the residue was submitted to silica gel column chromatography [dichloromethane-methanol(50:1→20:1)] under shading to obtain 583 mg of title compound as light brown powder. Yield 47%. 1H-NMR(DMSO-d6, δ): 1.35(3H,t,J=7.3 Hz), 1.42(3H,t,J=7.3 Hz), 4.38 (2H,q,J=7.3 Hz), 4.42(2H,d,J=6.8 Hz), 4.58(2H,d,J=7.3 Hz), 5.05(1H, t,J=5.4 Hz), 7.27(1H,s), 7.88(1H,s), 8.39(1H,s), 8.50(1H,s), 8.87 (1H,s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21]([OH:23])=O)[CH:5]=[C:6]([Br:19])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH:16]([CH3:18])[CH3:17])[CH:10]=1.S(Cl)([Cl:26])=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21]([Cl:26])=[O:23])[CH:5]=[C:6]([Br:19])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH:16]([CH3:18])[CH3:17])[CH:10]=1
Reactant: CC(C)c1cc(Oc2c(Br)cc(CC(=O)O)cc2Br)ccc1O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)c1cc(Oc2c(Br)cc(CC(=O)Cl)cc2Br)ccc1O

Procedure:
3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetic acid (444 mg) was mixed with 10 ml thionyl chloride and heated at reflux for 3 h. The reaction mixture was co-evaporated with toluene to give the crude 3,5-dibromo-4-(4-hydroxy-3-isopropyl-phenoxy)phenylacetyl chloride. N,O-bis(trimethylsilyl)acetamide (670 mg) was added at 0° C., under nitrogen atmosphere, to a mixture of D-Aspargine (225 mg) and 10 ml acetonitrile. The reaction mixture was further stirred at room temperature and a solution of 3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl chloride in 10 ml acetonitrile was added. After stirring for 16 h, the reaction mixture was poured into water and the solid filtered off. The solid was dissolved in methanol and the organic phase removed in vacuo. The residue was purified by HPLC to give 76 mg (14%) of D-N-[3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]aspargine. LC-MS (electrospray): m/z 557 (M−H).
Reaction SMILES: FC(F)(F)C(O)=[O:4].S(=O)(=O)(O)O.[NH2:13][C:14]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[C:15]=1[C:16]#[N:17].[OH-].[NH4+]>O>[NH2:13][C:14]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[C:15]=1[C:16]([NH2:17])=[O:4]
Reactant: COc1cc(N)c(C#N)c(OC)c1
Reactant: O=C(O)C(F)(F)F
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: COc1cc(N)c(C(N)=O)c(OC)c1
Temperature: 75 °C
Yield: 40.5 %

Procedure:
Trifluoroacetic acid (6.52 g, 4.4 mL) was charged to a flask equipped with a magnetic stirring bar and thermocouple. Sulfuric acid (96%, 9.2 g, 5 mL) was charged to the flask. In small portions 2-amino-4,6-dimethoxybenzonitrile (1.01 g, ˜76% pure) was charged to the mixed acid solution in the flask. A condenser was added and the solution was heated at 75° C. for 17 h. After the dark mixture had cooled to room temperature it was charged to water (9.79 g) cooled in a large ice bath while maintaining the reaction temperature below 10° C. Concentrated ammonium hydroxide (19.37 g) was added dropwise to the cooled solution (reaction temperature kept below 15° C.). The solution was then extracted two times with dichloromethane. The organic extracts were dried over MgSO4 and evaporated to yield the desired product (0.45 g) as a light brown solid.
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[S:16]([NH:19][C:20](NCCCC)=[O:21])(=[O:18])=[O:17])=[CH:8][CH:9]=1)([O:3][CH3:4])=[O:2].CCCCCCCC.C(Cl)(Cl)=O>>[C:1]([C:5]1[O:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[S:16]([N:19]=[C:20]=[O:21])(=[O:17])=[O:18])=[CH:8][CH:9]=1)([O:3][CH3:4])=[O:2]
Reactant: CCCCNC(=O)NS(=O)(=O)c1ccccc1-c1ccc(C(=O)OC)o1
Agent: O=C(Cl)Cl
Solvent: CCCCCCCC
Product: COC(=O)c1ccc(-c2ccccc2S(=O)(=O)N=C=O)o1

Procedure:
A solution of 19.0 g of the product of Example 2 and 0.1 g of 1,4-diazabicyclo[2.2.2.]octane (DABCO) in 90 ml of dry xylenes was heated to reflux temperature (139°). To this solution was added 3.6 ml of liquid phosgene over a period of about 2 hours, keeping the temperature between 125° and 136° by adjusting the rate of phosgene addition. The reaction mixture was cooled to 25°, and filtered under nitrogen to remove DABCO hydrochloride. The filtrate was concentrated in vacuo to give the title compound as a viscous, moisture-sensitive oil. This material was carried on to the desired products without further purification.
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.[CH2:24]([O:26][C:27]1[CH:28]=[N:29][CH:30]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:32]=1)[CH3:25]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:31]5[CH:30]=[N:29][CH:28]=[C:27]([O:26][CH2:24][CH3:25])[CH:32]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: CCOc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: CCOc1cncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)c1

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) and 3-ethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (stage 56.1.1) to give the title compound as a white solid. (HPLC: tR 2.28 min (Method A); M+H=415 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.98 (s, 1H), 8.34-8.24 (m, 2H), 8.16-8.08 (m, 2H), 8.02-7.96 (m, 1H), 7.61-7.57 (m, 1H), 7.40-7.34 (m, 1H), 4.17 (q, 2H), 3.89 (s, 3H), 3.57 (s, 3H), 1.96 (s, 3H), 1.40 (t, 3H))