Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[N:11]=[CH:10][C:9]([C:12]3[CH:23]=[CH:22][C:15]([C:16]([NH:18][CH:19]4[CH2:21][CH2:20]4)=[O:17])=[CH:14][CH:13]=3)=[CH:8][C:6]=2[N:7]=1.[C:30]([O:34][C:35]([NH:37][C:38]1[N:43]=[CH:42][C:41](B(O)O)=[CH:40][N:39]=1)=[O:36])([CH3:33])([CH3:32])[CH3:31].P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C=O)C>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.O>[CH:19]1([NH:18][C:16]([C:15]2[CH:22]=[CH:23][C:12]([C:9]3[CH:10]=[N:11][C:5]4[C:4]([N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)=[N:3][C:2]([C:41]5[CH:42]=[N:43][C:38]([NH:37][C:35](=[O:36])[O:34][C:30]([CH3:32])([CH3:31])[CH3:33])=[N:39][CH:40]=5)=[N:7][C:6]=4[CH:8]=3)=[CH:13][CH:14]=2)=[O:17])[CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)Nc1ncc(B(O)O)cn1
Reactant: O=C(NC1CC1)c1ccc(-c2cnc3c(N4CCOCC4)nc(Cl)nc3c2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3ncc(-c4ccc(C(=O)NC5CC5)cc4)cc3n2)cn1
Temperature: 95 °C
Reaction time: 1 h
Yield: 48.9 %

Procedure:
To a 50 mL sealed tube, 4-(2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)-N-cyclo-propylbenzamide (0.15 g, 0.00036 mol), (2-((tert-butoxycarbonyl)amino)pyrimidin-5-yl)boronic acid (0.113 g, 0.00047), potassium phosphate (0.155 g, 0.00072 mol), DMF (10 mL) and water (2 mL) were added. The reaction mixture was degassed with N2 for 5-10 minutes. To the same reaction mixture, Pd(PPh3)4 (0.022 g, 0.000018 mol) was added and degassed with N2 for 5-10 minutes. The reaction mixture was stirred at 95° C. for 1 hour. The reaction mass was cooled to room temperature and added ice cold water. A precipitate was obtained and the solid was collected by filtration. The solid was dissolved in chloroform, dried over anhydrous sodium sulfate and evaporated under reduced pressure to provide the crude product. The crude product was purified by flash column chromatography (2% methanol in chloroform) to provide the title compound (0.1 g, 48%). 1H NMR (300 MHz, DMSO-d6): δ 10.41 (br s, 1H), 9.47 (s, 1H), 9.19 (d, J=1.8 Hz, 1H), 6.59 (d, J=4.2 Hz, 1H), 8.51 (d, J=1.8 Hz, 1H), 7.98-8.08 (m, 4H), 4.57 (br s, 4H), 3.83 (s, 4H), 2.88-2.89 (m, 1H), 1.48 (s, 9H), 0.73 (d, J=5.4 Hz, 2H), 0.61 (d, J=3.0 Hz, 2H): LC-MS (ESI): Calculated mass: 568.2; Observed mass [M+H]+: 569.2. (RT=1.57 min).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:2]1.Cl[CH2:18][CH2:19][N:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[C:28]3[CH:29]=[CH:30][CH:31]=[C:22]([C:23]=23)[S:21]1(=[O:33])=[O:32].C(=O)([O-])O.[Na+]>CN(C)C=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:18][CH2:19][N:20]3[C:24]4[CH:25]=[CH:26][CH:27]=[C:28]5[CH:29]=[CH:30][CH:31]=[C:22]([C:23]=45)[S:21]3(=[O:33])=[O:32])[CH2:13][CH2:12]2)=[CH:2]1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCl
Reactant: c1ccc2c(CC3CCNCC3)c[nH]c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S1(=O)c2cccc3cccc(c23)N1CCN1CCC(Cc2c[nH]c3ccccc23)CC1
Yield: 48.1 %

Procedure:
A mixture of 4-(3-indolylmethyl)piperidine (0.4 g), 2-(2-chloroethyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (0.53 g), sodium hydrogen carbonate (0.17 g) and dimethylformamide (10 cc) is brought to reflux for 12 hours. After evaporation to dryness at 80° C. under reduced pressure (20 mm Hg; 2.7 kPa), the residue is taken up with water (30 cc) and extracted with ethyl acetate (2×50 cc). The combined organic phases are dried over magnesium sulphate and taken to dryness at 80° C. under reduced pressure (20 mm Hg; 2.7 kPa). The residue is purified by flash chromatography on a silica column under a stream of nitrogen at moderate pressure (0.5-1.5 bar) with a dichloromethane/methanol mixture (99:1 by volume) as eluent. 2-{2-[4-(3-Indolylmethyl)piperidino]ethyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (0.4 g), m.p. 184° C., is obtained.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.O[C@H:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12]>>[C:3]1([CH3:8])[CH:4]=[CH:5][C:6]([O:7][C@@H:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12])=[CH:1][CH:2]=1
Reactant: COC(=O)[C@@H](C)O
Reactant: Cc1ccc(O)cc1
Product: COC(=O)[C@H](C)Oc1ccc(C)cc1

Procedure:
The title compound was prepared following the same protocol as described in Step 1, Example 42, using the p-cresol instead of the m-cresol and the (R)-methyl 2-hydroxypropanoate instead of the (S)-methyl 2-hydroxypropanoate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[C:5]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[O:6].[N+:15]([O-])([OH:17])=[O:16]>>[OH:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[C:5]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[O:6]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)CCC(=O)c1cccc(O)c1
Product: O=C(O)CCC(=O)c1ccc([N+](=O)[O-])c(O)c1
Temperature: 0 °C

Procedure:
3-(3-Hydroxybenzoyl)propionic acid was added in portions to well stirred fuming nitric acid at -15° C. The resultant mixture was stirred a further 10 minutes in the cold then poured into ice-water. The crude product was triturated with methanol to give 3-(3-hydroxy-4-nitrobenzoyl)propionic acid, which after recrystallisation from water had m.p. 158° - 160.3° C (Found: C, 50.25; H, 3.75; N, 5.88; M+, 239 C10H9NO6 requires: C, 50.21; H, 3.79; N, 5.86%; M, 239)
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.[CH3:10][NH2:11].CCO>>[CH3:10][NH:11][CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1
Reactant: ClCc1ccncc1
Reactant: CN
Agent: Cl
Solvent: CCO
Product: CNCc1ccncc1
Yield: 79 %

Procedure:
Using 4-chloromethyl-pyridine hydrochloride salt and 33% methylamine/EtOH the title compound was obtained as a colourless liquid (0.1 mm Hg, 60-62° C.) (79% yield), MS: m/e=122.1 (M+).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]3[CH2:20][CH2:19][NH:18][C@@H:17]([CH3:21])[CH2:16]3)[CH:9]=2)=[CH:6][C:5]([CH2:22][NH:23][C:24]([C:26]2[CH:27]=[C:28]([CH2:32][CH:33]3[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]3)[CH:29]=[CH:30][CH:31]=2)=[O:25])=[CH:4][CH:3]=1.[CH2:46]=O.[BH4-].[Na+]>CO>[CH3:21][C@@H:17]1[N:18]([CH3:46])[CH2:19][CH2:20][N:15]([CH2:14][C:10]2[CH:9]=[C:8]([C:7]3[C:2]([F:1])=[CH:3][CH:4]=[C:5]([CH2:22][NH:23][C:24]([C:26]4[CH:27]=[C:28]([CH2:32][CH:33]5[CH2:34][CH2:35][N:36]([C:39]([O:41][C:42]([CH3:44])([CH3:43])[CH3:45])=[O:40])[CH2:37][CH2:38]5)[CH:29]=[CH:30][CH:31]=4)=[O:25])[CH:6]=3)[CH:13]=[CH:12][CH:11]=2)[CH2:16]1
Reactant: C[C@H]1CN(Cc2cccc(-c3cc(CNC(=O)c4cccc(CC5CCN(C(=O)OC(C)(C)C)CC5)c4)ccc3F)c2)CCN1
Reactant: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@H]1CN(Cc2cccc(-c3cc(CNC(=O)c4cccc(CC5CCN(C(=O)OC(C)(C)C)CC5)c4)ccc3F)c2)CCN1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.4 %

Procedure:
To a solution of 1,1-dimethylethyl 4-{[3-({[(6-fluoro-3′-{[(3S)-3-methyl-1-piperazinyl]methyl}-3-biphenylyl)methyl]amino}carbonyl)phenyl]methyl}-1-piperidinecarboxylate (130 mg, 0.21 mmol) in MeOH (5 mL) was added formaldehyde (37% in water, 69 mg, 0.85 mmol). After 30 minutes stirring at rt, sodium borohydride (16 mg, 0.42 mmol) was added. After stirring at rt for additional 3 hours, the solvent was removed to give a residue which was purified by loading onto a 2 g aminopropyl SPE cartridge and eluting sequentially with DCM (3×5 mL), EtOAc (3×5 mL), and MeOH (3×5 mL). The dichloromethane and ethyl acetate fractions were combined and evaporated to give the title compound (130 mg, 99%). LC/MS: m/z, 629 (M+H), 1.97 min.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([CH2:9]Cl)=[N:5][CH:6]=[CH:7][CH:8]=1.BrCC1CCCCO1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]2([C:39]3[C:30](=[CH:31][C:32]4[O:37][CH2:36][CH2:35][O:34][C:33]=4[CH:38]=3)[O:29][CH2:28]2)[C:20]1=[O:40]>>[Cl:2][C:3]1[C:4]([CH2:9][N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]3([C:39]4[C:30](=[CH:31][C:32]5[O:37][CH2:36][CH2:35][O:34][C:33]=5[CH:38]=4)[O:29][CH2:28]3)[C:20]2=[O:40])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: ClCc1ncccc1Cl
Agent: BrCC1CCCCO1
Agent: Cl
Product: O=C1N(Cc2ncccc2Cl)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 3-chloro-2-(chloromethyl)pyridine hydrochloride to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1′-[(3-chloropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (67%) as a colorless solid: mp 176-178° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.35-8.31 (m, 1H), 7.47 (d, J=7.6 Hz, 1H), 7.27-7.15 (m, 3H), 7.09-7.02 (m, 1H), 6.75 (d, J=7.8 Hz, 1H), 6.50 (d, J=1.5 Hz, 1H), 6.23 (d, J=1.4 Hz, 1H), 5.13 (d, J=16.8 Hz, 1H), 5.02-4.89 (m, 2H), 4.67 (dd, J=8.9, 1.3 Hz, 1H), 4.22-4.06 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 177.8, 155.4, 150.0, 148.9, 144.8, 141.4, 138.4, 136.9, 132.0, 129.1, 129.8, 124.2, 124.0, 123.0, 120.6, 111.4, 109.1, 99.6, 80.2, 64.5, 63.9, 58.1, 41.2.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[C:12]([CH2:20][C:21](OCC)=[O:22])(=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[C:13]1([C:12]2[CH2:20][C:21](=[O:22])[C:3]3[C:2](=[CH:11][CH:10]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=3)[N:1]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc2c(c1)C(=O)CC(c1ccccc1)=N2
Temperature: 255 °C
Reaction time: 48 h
Yield: 79.4 %

Procedure:
Methyl p-aminobenzoate (3.0 grams) and 4.1 grams of ethyl benzoylacetate are dissolved in 100 ml of chloroform and the solution is subjected to azeotropic dehydration for two days after the addition of 0.5 gram of p-toluenesulfonic acid. Chloroform is evaporated therefrom, n-hexane is added to the residue, the extract with n-hexane is evaporated, 30 ml of diphenyl ether is added to the residue, the mixture is heated at 255° C. for twenty minutes, cooled, crystals separate out therefrom are collected by filtration, washed with n-hexane and dried to give 4.4 grams of methyl 2-phenyl-4-quinolone-6-carboxylate, needles, melting at higher than 300° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][C:15](=[O:17])[C:14]([C:18](=O)[CH2:19][CH3:20])=[C:13]([OH:22])[CH2:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH2:23]([O:25][NH2:26])[CH3:24]>O1CCCC1>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][C:15](=[O:17])[C:14]([C:18](=[N:26][O:25][CH2:23][CH3:24])[CH2:19][CH3:20])=[C:13]([OH:22])[CH2:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CCC(=O)C1=C(O)CC(c2ccc(NC(C)=O)cc2)CC1=O
Reactant: CCON
Solvent: C1CCOC1
Product: CCON=C(CC)C1=C(O)CC(c2ccc(NC(C)=O)cc2)CC1=O
Temperature: 0 °C
Reaction time: 15 h

Procedure:
Into 10 ml of tetrahydrofuran was dissolved 2.0 g of 5-(4-acetamidophenyl)-2-propionyl-3-hydroxy-2-cyclohexen-1-one and to the solution was added 1.0 g of aqueous solution containing 50% of ethoxyamine. The mixture was kept for 15 hours at room temperature and it was poured into ice water and the crystal sedimented was collected with a filtering step. The crystal was dissolved in 20 ml of chloroform and the solution was washed with water and extracted with 15 ml of aqueous solution containing 5% of sodium hydroxide. To the alkaline solution was added a dilute hydrochloric acid solution and the crystal sedimented was extracted with chloroform. The solution was washed with water and dried with anhydrous magnesium sulfate and the chloroform was distilled off from it under reduced pressure. Thus 1.4 g of the desired compound was obtained. It was in the form of pale yellow crystals having a melting point of 135°-136° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=O)[CH:10]=1>C(OC(=O)C)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]=[CH:15][C:11]2[CH:10]=[N:9][CH:14]=[CH:13][CH:12]=2)[N:3]=1
Reactant: O=Cc1cccnc1
Reactant: Cc1cccc(C)n1
Solvent: CC(=O)OC(C)=O
Product: Cc1cccc(C=Cc2cccnc2)n1

Procedure:
A solution of 2,6-dimethyl pyridine (5.8 ml, 50 mMol), pyridine-3-carbaldehyde (4.9 ml, 52 mMol) in acetic anhydride (9.5 ml) is heated under reflux for 10 hours. The acetic anhydride is then evaporated in vacuo and the residue purified on column chromatography (silica gel 900 g). The column is first eluted with toluene/acetone 9:1 (7 L), then with toluene/acetone 4:1 (5 L) and finally with toluene/acetone 2:1 (5 L). The fractions containing the desired compound are combined, and evaporated in vacuo. The solid residue is recrystallized from methylene chloride/diisopropyl ether and 4.28 g of a colorless oil which solidify upon standing at 6-8° C.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]([NH:12][C:13]3[CH:17]=[N:16][N:15]([CH3:18])[C:14]=3[C:19]([OH:21])=O)=[O:11])[C:7]([NH:22][C:23]3[CH:24]=[N:25][CH:26]=[N:27][CH:28]=3)=[N:6][CH:5]=2)[CH2:3][CH2:2]1.[NH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH:31]1[OH:35]>>[OH:35][CH:31]1[CH2:32][CH2:33][CH2:34][CH:30]1[NH:29][C:19]([C:14]1[N:15]([CH3:18])[N:16]=[CH:17][C:13]=1[NH:12][C:10]([C:8]1[C:7]([NH:22][C:23]2[CH:24]=[N:25][CH:26]=[N:27][CH:28]=2)=[N:6][CH:5]=[C:4]([CH:1]2[CH2:2][CH2:3]2)[N:9]=1)=[O:11])=[O:21]
Reactant: NC1CCCC1O
Reactant: Cn1ncc(NC(=O)c2nc(C3CC3)cnc2Nc2cncnc2)c1C(=O)O
Product: Cn1ncc(NC(=O)c2nc(C3CC3)cnc2Nc2cncnc2)c1C(=O)NC1CCCC1O

Procedure:
The product was obtained starting from 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyrazine-2-carbonyl]-amino}-2-methyl-2H-pyrazole-3-carboxylic acid (50 mg, 131 μmol; example 236, step 3) and 2-aminocyclopentanol (15 mg, 140 μmol) according to the method described in example 64, step 6 after purification by preparative HPLC using an acetonitrile/water gradient as yellow solid (24 mg, 40%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH:10]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:5][C:6]=1[C:7](=[S:9])[NH2:8].Br[CH2:31][C:32]([C:34]1[CH:35]=[C:36]([NH:40][C:41](=[O:48])[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:37]=[CH:38][CH:39]=1)=O>CO>[NH2:10][C:4]1[S:5][C:6]([C:7]2[S:9][CH:31]=[C:32]([C:34]3[CH:35]=[C:36]([NH:40][C:41](=[O:48])[C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[CH:37]=[CH:38][CH:39]=3)[N:8]=2)=[C:2]([NH2:1])[N:3]=1
Reactant: O=C(CBr)c1cccc(NC(=O)c2ccccc2)c1
Reactant: NC(=S)c1sc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)nc1N
Solvent: CO
Product: Nc1nc(N)c(-c2nc(-c3cccc(NC(=O)c4ccccc4)c3)cs2)s1
Yield: 38.3 %

Procedure:
A solution of 4-amino-2-(trityl-amino)-thiazole-5-carbothioic acid amide (304 mg, 0.73 mmol) and N-(3-Bromoacetyl-phenyl)-benzamide (300 mg, 0.94 mmol) in MeOH (30 ml) was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was dissolved in EtOAc (100 ml). The EtOAc solution was washed with a saturated aqueous solution of NaHCO3 (3×25 ml). The organic layer was separated, dried over MgSO4, and concentrated. Purification of the residue was achieved by silica gel chromatography (75% EtOAc/DCM) providing N-[3-(2′,4′-diamino-[2,5′]bithiazolyl-4-yl)-phenyl]-benzamide (110 mg, 39% yield). mp 159-163° C. (decomp). 1H NMR (CD3OD): δ 8.33 (s, 1H), 8.00-7.97 (m, 2H), 7.75-7.71 (m, 2H), 7.64-7.52 (m, 3H), 7.43 (t, J=7.74 Hz, 1H), 7.33 (s, 1H). FABMS Calcd for C19H15N5OS2: 394.0796. Found: 394.0802.
Reaction SMILES: [P:1]([O-:47])([O-:46])([O:3][C:4](C(C)(C)C)(C(C)(C)C)[N:5]1[C:9]2=[N:10][CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH:13]=[C:8]2[C:7]([C:21](=[O:37])[C:22]2[C:27]([F:28])=[CH:26][CH:25]=[C:24]([NH:29][S:30]([CH2:33][CH2:34][CH3:35])(=[O:32])=[O:31])[C:23]=2[F:36])=[CH:6]1)=[O:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[P:1]([OH:46])([OH:47])([O:3][CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH:13]=[C:8]2[C:7]([C:21](=[O:37])[C:22]2[C:27]([F:28])=[CH:26][CH:25]=[C:24]([NH:29][S:30]([CH2:33][CH2:34][CH3:35])(=[O:32])=[O:31])[C:23]=2[F:36])=[CH:6]1)=[O:2]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(C(OP(=O)([O-])[O-])(C(C)(C)C)C(C)(C)C)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(COP(=O)(O)O)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
To a solution of di-tert-butyl((5-(4-chlorophenyl)-3-(2,6-difluoro-3-(propyl sulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)methyl) phosphate (1 g, 1.4 mmol) in DCM (25 mL) was added TFA (1.6 mL, 2.4 g, 21 mmol). The reaction was stirred at rt for 2 h, and then concentrated in vacuo. The residue was washed with 20 mL of EtOAc to give the title compound as a white solid (0.56 g, 66.5%). The title compound was characterized by LC-MS and 1H NMR as shown below:
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1I)[CH2:8][C:9]1[O:10][CH:11]=[CH:12][N:13]=1)([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[C:25]([O:32][CH3:33])[CH:24]=1>CCCCCCC.CCOC(C)=O>[C:1]([O:5][C:6](=[O:21])[N:7]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[C:26]1[CH:27]=[CH:28][C:23]([F:22])=[CH:24][C:25]=1[O:32][CH3:33])[CH2:8][C:9]1[O:10][CH:11]=[CH:12][N:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(F)ccc1B(O)O
Reactant: CC(C)(C)OC(=O)N(Cc1ncco1)c1cnccc1I
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COc1cc(F)ccc1-c1ccncc1N(Cc1ncco1)C(=O)OC(C)(C)C

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-yl)-oxazol-2-ylmethyl-carbamic acid tert-butyl ester and 4-fluoro-2-methoxyphenyl-boronic acid (CAS RN 179899-07-1) and using a gradient of n-heptane:EtOAc (100:0 to 0:100) for the chromatographic purification. Colorless solid (70%). MS (ESI): m/z=400.167 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2.[CH3:15]S(O)(=O)=O.C(=O)(O)[O-].[Na+]>CO.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5]2
Reactant: O=C(O)c1ccc2cc(Br)ccc2n1
Reactant: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc2cc(Br)ccc2n1
Temperature: 20 °C
Reaction time: 8 h
Yield: 325 %

Procedure:
A mixture of 6-bromo-2-quinolinecarboxylic acid (331 g, from multiple batches, 1.31 mol) and methanesulfonic acid (22 mL, 33 g, 0.34 mol) in methanol (2 L) was refluxed for 6 hr. The mixture was treated with a solution of sodium bicarbonate (29 g, 0.34 mol) in water (350 mL) and the resulting suspension was slowly cooled to 20° C. and stirred overnight. The suspension was filtered and the cake was washed with water (1 L). The solid was dried in a vacuum oven at 50° C. for 3 days to yield methyl 6-bromo-2-quinolinecarboxylate (294 g, 85%). 1H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J=9 Hz, 1H), 8.40 (d, J=2 Hz, 1H), 8.14 (d, J=9 Hz, 1H), 8.08 (d, J=9 Hz, 1H), 7.97 (m, 1H), 3.93 (s, 3H). ES-LCMS m/z 267 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[C:10]([CH3:14])([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH2:20][CH2:21][OH:22]>>[CH3:12][N:11]1[C:4]2[N:5]([C:6](=[O:8])[N:7]=[C:2]([O:22][CH2:21][CH2:20][C:16]3[S:15][CH:19]=[CH:18][CH:17]=3)[CH:3]=2)[CH2:9][C:10]1([CH3:14])[CH3:13]
Reactant: OCCc1cccs1
Reactant: CN1c2cc(Cl)nc(=O)n2CC1(C)C
Product: CN1c2cc(OCCc3cccs3)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and 2-(thiophen-2-yl)ethanol.
Reaction SMILES: [CH2:1]([O:15][C:16]([C:18]1[CH:23]=[C:22]([N+:24]([O-])=O)[CH:21]=[C:20]([C:27]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[O:28])[CH:19]=1)=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>[Pd].C(OCC)(=O)C.C1COCC1>[CH2:30]([O:29][C:27]([C:20]1[CH:21]=[C:22]([NH2:24])[CH:23]=[C:18]([C:16]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:17])[CH:19]=1)=[O:28])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: CCCCCCCCCCCCCCOC(=O)c1cc(C(=O)OCCCCCCCCCCCCCC)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCOC(=O)c1cc(N)cc(C(=O)OCCCCCCCCCCCCCC)c1
Reaction time: 17 h
Yield: 98.7 %

Procedure:
A mixture of 2.09 g of 5-nitro-1,3-benzenedicarboxylic acid ditetradecyl ester and 0.5 g of 10% palladium on carbon in 80 ml of ethyl acetate and 25 ml of THF was shaken under an initial hydrogen pressure of 53 psi for 17 hours. The catalyst was removed by filtration and the filtrate was concentrated to give 1.96 g of pure 5-amino-1,3-benzenedicarboxylic acid ditetradecyl ester, mp 74°-75°.
Reaction SMILES: CN(C)C=O.[H-].[Na+].[OH:8][C:9]1[C:26]([OH:27])=[CH:25][C:24]2[C:23]3[C:18](=[CH:19][C:20]([OH:29])=[C:21]([OH:28])[CH:22]=3)[C:17]3[C:12](=[CH:13][C:14]([OH:31])=[C:15]([OH:30])[CH:16]=3)[C:11]=2[CH:10]=1.C1(C)C=CC(S(O[CH2:42][CH2:43][CH2:44][CH:45]([CH3:48])[CH2:46][CH3:47])(=O)=O)=CC=1>O>[CH3:48][CH:45]([CH2:46][CH3:47])[CH2:44][CH2:43][CH2:42][O:8][C:9]1[C:26]([O:27][CH2:42][CH2:43][CH2:44][CH:45]([CH3:48])[CH2:46][CH3:47])=[CH:25][C:24]2[C:23]3[C:18](=[CH:19][C:20]([O:29][CH2:15][CH2:16][CH2:17][CH:18]([CH3:23])[CH2:19][CH3:20])=[C:21]([O:28][CH2:42][CH2:43][CH2:44][CH:45]([CH3:48])[CH2:46][CH3:47])[CH:22]=3)[C:17]3[C:12](=[CH:13][C:14]([O:31][CH2:42][CH2:43][CH2:44][CH:45]([CH3:48])[CH2:46][CH3:47])=[C:15]([O:30][CH2:26][CH2:9][CH2:10][CH:11]([CH3:12])[CH2:24][CH3:25])[CH:16]=3)[C:11]=2[CH:10]=1
Reactant: CCC(C)CCCOS(=O)(=O)c1ccc(C)cc1
Reactant: Oc1cc2c3cc(O)c(O)cc3c3cc(O)c(O)cc3c2cc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)CCCOc1cc2c3cc(OCCCC(C)CC)c(OCCCC(C)CC)cc3c3cc(OCCCC(C)CC)c(OCCCC(C)CC)cc3c2cc1OCCCC(C)CC
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.8 %

Procedure:
At room temperature, 3 ml of N,N-dimethylformamide (DMF) was placed in a flask, and 0.27 g of NaH (60% in oil) was added thereto. Then, 0.3 g (0.925 mmol) of 2,3,6,7,10,11-hexahydroxytriphenylene was added thereto, and after 1 hour of stirring, a mixture liquid of 1.96 g (6.84 mmol) of 4-methylhexyl p-toluenesulfonate and 2 ml of DMF was added dropwise thereto, followed by 5 hours of stirring at 70° C. After the reaction, the system was cooled to room temperature, and water was added thereto to precipitate a crystal, which was recovered by filtration. The crystal was then purified by silica gel chromatography (with toluene) and re-cystallized from acetone/methanol to obtain 0.24 g of 2,3,6,7,10,11-hexa(4-methylhexyloxy)triphenylene.