Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[C:23][C:24]([NH2:26])=[O:25])=[CH:18][CH:17]=1)=[O:14].N1C2C(=CC=CC=2)C=CC=1.[H][H]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:9])[F:10])=[CH:4][C:3]=1[NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]\[C:24]([NH2:26])=[O:25])=[CH:18][CH:17]=1)=[O:14]
Reactant: NC(=O)C#Cc1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: c1ccc2ncccc2c1
Solvent: CCOC(C)=O
Product: NC(=O)/C=C\c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Reaction time: 1.75 h
Yield: 85 %

Procedure:
A mixture of 3-{4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}prop-2-ynamide (12.2 mg, 0.033 mmol), 0.005 mL quinoline, and 4 mg Lindlar catalyst in 1.5 mL EtOAc was reacted under a balloon of hydrogen. After 1.75 hours, an additional catalytic amount of Lindlar catalyst was added and the reaction continued for an additional 1 hour. The reaction mixture was partitioned between EtOAc and dilute aqueous HCl, the EtOAc layer washed with H2O, brine, dried with Na2SO4 and evaporated. The crude material was chromatographed eluting with hexane/acetone to give the title compound as a white solid (10.3 mg, 84%). 1H NMR (Acetone-d6) δ: 8.79 (d, J=7.9 Hz, 1H), 8.69 (br. s., 1H), 8.37 (br. s., 1H), 7.75 (d, J=8.5 Hz, 2H), 7.50 (d, J=8.8 Hz, 2H), 7.35-7.43 (m, 2H), 6.93 (br. s., 1H), 6.64 (d, J=12.9 Hz, 1H), 6.41 (br. s., 1H), 5.97 (d, J=12.9 Hz, 1H)
Reaction SMILES: [Cl:1][C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1.[CH:19]1([CH2:25][NH:26][CH3:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(Cl)Cl>[CH:19]1([CH2:25][N:26]([CH3:27])[C:2]([Cl:1])=[O:4])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CNCC1CCCCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(CC1CCCCC1)C(=O)Cl
Reaction time: 8 h

Procedure:
To a solution of triphosgene (77 mg, 0.259 mmol) in CH2Cl2 (1 mL) at −78° C. is added dropwise pyridine (63 μl, 0.786 mmol) followed by a solution of cyclohexylmethyl-methylamine (100 mg, 0.786 mmol) in CH2Cl2 (1 mL). The yellow mixture is allowed to reach RT and stirred overnight. The solvent is concentrated, and the residue taken up in AcOEt. An aqueous saturated solution of NaHCO3 is added, the layers are separated and the aqueous one is extracted twice with AcOEt. The combined organic extracts are washed with brine, dried over Na2SO4, filtered and concentrated to afford the title compound as a yellow oil. TLC, Rf (CH2Cl2/MeOH 95:5)=0.95. MS (LC-MS): 189.1 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[CH:7]=[CH:6][C:5]=1[NH2:20])([O-:3])=[O:2].[O:21]1[CH2:26][CH2:25][CH:24](/[CH:27]=[CH:28]/[C:29](O)=[O:30])[CH2:23][CH2:22]1>>[N+:1]([C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]([F:19])([F:17])[F:18])[CH:11]=2)[CH:7]=[CH:6][C:5]=1[NH:20][C:29](=[O:30])/[CH:28]=[CH:27]/[CH:24]1[CH2:25][CH2:26][O:21][CH2:22][CH2:23]1)([O-:3])=[O:2]
Reactant: Nc1ccc(-c2ccnc(C(F)(F)F)c2)cc1[N+](=O)[O-]
Reactant: O=C(O)/C=C/C1CCOCC1
Product: O=C(/C=C/C1CCOCC1)Nc1ccc(-c2ccnc(C(F)(F)F)c2)cc1[N+](=O)[O-]

Procedure:
Following the procedure as described in Example 3, STEP B, the title compound was prepared from 2-nitro-4-(2-trifluoromethyl-pyridin-4-yl)-phenylamine (84.5 mg, 0.298 mmol, as prepared in the previous step) and (E)-3-(tetrahydro-pyran-4-yl)-acrylic acid (prepared as described in PCT Publication WO 2005/101989 (A2, A3), 60.5 mg, 0.388 mmol) and was obtained as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][C:6]1[CH:7]=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH3:26])[CH:9]=[C:10]([Cl:12])[CH:11]=1)[CH3:2].[CH:28]1([C:31](Cl)=[O:32])[CH2:30][CH2:29]1>>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][C:6]1[CH:7]=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:22])[F:21])=[CH:15][C:14]=2[CH2:23][N:24]([C:31]([CH:28]2[CH2:30][CH2:29]2)=[O:32])[CH2:25][CH3:26])[CH:9]=[C:10]([Cl:12])[CH:11]=1)[CH3:2]
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(Cl)cc(CC(=O)OCC)c1
Reactant: O=C(Cl)C1CC1
Product: CCOC(=O)Cc1cc(Cl)cc(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)C2CC2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (5-chloro-2′-ethylaminomethyl-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester and cyclopropanecarbonyl chloride.
Reaction SMILES: CC(NC[C@@H]1OC(=O)N(C2C=CC(N3CCN(C(CO)=O)CC3)=C(F)C=2)C1)=[O:3].[CH2:29]([O:36][CH2:37][C:38](Cl)=[O:39])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.Cl>C(Cl)Cl>[CH2:29]([O:36][CH2:37][C:38]([OH:39])=[O:3])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCN(C(=O)CO)CC3)c(F)c2)C(=O)O1
Agent: Cl
Solvent: ClCCl
Product: O=C(O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 44 %

Procedure:
To a mixture of 200 mg (0.508 mmol) of U-100592 (Ex. 1), 149 mg (1.47 mmol, 0.205 mL), and 5 mL methylene chloride at 0° C. benzyloxyacetylchloride was added dropwise. The reaction was allowed to warm slowly up to room temperature. After stirring for 5 hours, 5 mL of 1N HCl was added, and the resulting layers were separated. The aqueous layer was extracted with methylene chloride (3×5 mL). The combined organic layers were washed with brine and dried (MgSO4) then filtered and concentrated to a white solid. The crude was dissolved in a small amount of methylene chloride and methanol and was placed on a 22 cm×2.5 cm 40-60 μ silica column. The column was eluted with ethyl acetate, 2% methanol/ethylacetate, 4% methanol/ethyl acetate, 6% methanol/ethyl acetate, 8% methanol/ethyl acetate, and 10% methanol/ethyl acetate (250 mL each). The appropriate fractions were pooled to provide 120 mg (44%) of benzyloxyacetic acid, 2-[-[4-[5-(acetylamino)methyl]-2-oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperazinyl]-2-oxoethyl ester, (S)-; as a white solid (mp=146°-148° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:15](=[O:22])[CH2:14][CH2:13][CH2:12]1)(=[O:10])=[O:9].C(O[CH:28](N(C)C)[N:29]([CH3:31])[CH3:30])(C)(C)C>ClCCl>[CH3:28][N:29]([CH:31]=[C:14]1[C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:11]([S:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])(=[O:10])=[O:9])[CH2:12][CH2:13]1)[CH3:30]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: Cc1ccccc1S(=O)(=O)N1CCCC(=O)c2ccccc21
Solvent: ClCCl
Product: Cc1ccccc1S(=O)(=O)N1CCC(=CN(C)C)C(=O)c2ccccc21

Procedure:
A mixture of 1.89 g of 1,2,3,4-tetrahydro-1-[(2-methylphenyl)sulfonyl]-5H-1-benzazepin-5-one and 2.47 ml of tert-butoxy-bis(dimethylamino)methane (Bredericks reagent) in 10 ml of dichloromethane is heated under argon on a steam bath for 16 hours. The mixture is concentrated to dryness under vacuum and the residue dissolved in CH2Cl2. The solution is filtered through a thin pad of hydrous magnesium silicate and the pad washed with 5% ethyl acetate in CH2Cl2. The filtrate is concentrated to dryness and the residue (1.96 g) crystallized from CH2Cl2 -hexane to give 0.85 g of crystals, m.p. 180°-185° C. A second crop of crystals (0.85 g) is recovered from the mother liquors and an additional 0.30 g is recovered from washing the pad of hydrous magnesium silicate with ethyl acetate.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[CH2:34]([N:38]=[C:39]=[O:40])[CH2:35][CH2:36][CH3:37]>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:39]([NH:38][CH2:34][CH2:35][CH2:36][CH3:37])=[O:40])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: CCCCN=C=O
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCCCNC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.33 h
Yield: 61.6 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.29 g, 1.90 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.85 mmol) in CH3CN (50 mL). After stirring for 20 min, n-butyl isocyanate (0.27 g, 2.77 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 mL). The CH2Cl2 solution was washed with 1N HCl (30 mL), H2O (30 mL), brine (30 mL) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by chromatography (SiO2, CH2Cl2:EtOAc 1:1) to give N-{[2-(2,6-dioxo(3-piperidyl))1,3-dioxoisoindolin-4-yl]methyl}(butylamino)carboxamide (0.44 g, 61%) as a white solid: mp 172-174° C.; 1H NMR (DMSO-d6) δ 11.13 (s, 1H), 7.86-7.68 (m, 3H), 6.42 (t, J=5.9 Hz, 1H), 6.12 (t, J=5.4 Hz, 1H), 5.18-5.11 (dd, J=5.2 and 12.4 Hz, 1H), 4.63 (d, J=5.9 Hz, 1H), 3.03-2.83 (m, 3H), 2.64-2.51 (m, 2H), 2.08-2.04 (m, 1H), 1.37-1.22 (m, 4H), 0.86 (t, J=7.0 Hz, 3H); 13C NMR (DMSO-d6) δ 172.70, 169.77, 167.54, 167.00, 157.98, 141.14, 134.56, 133.33, 131.47, 126.94, 121.58, 48.80, 38.98, 38.70, 32.01, 30.90, 21.95, 19.46, 13.64; Anal. Calcd. For C19H22N4O5: C, 59.06; H, 5.74; N, 14.50. Found: C, 59.24; H, 5.53; N, 14.37.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][NH:4][C:5]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[C:22](=O)([O:24]CC)[NH2:23]>C(Cl)(Cl)Cl.[Cl-].[Zn+2].[Cl-]>[F:1][C:2]([F:21])([F:20])[CH2:3][N:4]1[C:5]2[C:6](=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:23][C:22]1=[O:24]
Reactant: CCOC(N)=O
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1NCC(F)(F)F
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClC(Cl)Cl
Product: O=c1nc(-c2ccccc2)c2cc(Cl)ccc2n1CC(F)(F)F
Temperature: 190 °C
Yield: 73.1 %

Procedure:
A mixture of 62.7 g of 2-(2,2,2-trifluoroethylamino)-5-chlorobenzophenone, 107 g of ethyl carbamate and 10 g of zinc chloride was heated at 190° C. (oil bath temperature) for 3 hours. After cooling, the reaction mixture was dissolved in chloroform and the insoluble material was filtered off. The chloroform solution was washed successively with dilute hydrochloric acid and water, and dried over anhydrous sodium sulfate. Then the solvent was removed under reduced pressure and the residual solid was washed 3 times with 100 ml of isopropyl ether and dried to give 49.5 g of 1-(2,2,2-trifluoroethyl)-4-phenyl-6-chloro-2(1H)-quinazolinone as a pale gray powder. Recrystallization from ethanol gave pale yellow needles, m.p. 186.5°-187.5° C.
Reaction SMILES: [OH:1]/[N:2]=[C:3](\Cl)/[C:4]1[CH:15]=[CH:14][C:7]2[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=2[CH:5]=1.[Cl:17][C:18]1[CH:23]=[C:22]([C:24]([C:26]([F:29])([F:28])[F:27])=[CH2:25])[CH:21]=[C:20]([Cl:30])[C:19]=1[O:31][C:32]([F:35])([F:34])[F:33]>CN(C=O)C>[Cl:17][C:18]1[CH:23]=[C:22]([C:24]2([C:26]([F:29])([F:27])[F:28])[O:1][N:2]=[C:3]([C:4]3[CH:15]=[CH:14][C:7]4[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=4[CH:5]=3)[CH2:25]2)[CH:21]=[C:20]([Cl:30])[C:19]=1[O:31][C:32]([F:33])([F:35])[F:34]
Reactant: C=C(c1cc(Cl)c(OC(F)(F)F)c(Cl)c1)C(F)(F)F
Reactant: CC1(C)OB(O)c2ccc(/C(Cl)=N/O)cc21
Solvent: CN(C)C=O
Product: CC1(C)OB(O)c2ccc(C3=NOC(c4cc(Cl)c(OC(F)(F)F)c(Cl)c4)(C(F)(F)F)C3)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.2 %

Procedure:
To a solution of (Z)—N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoyl chloride (378 mg, 1.58 mmol) and 1,3-dichloro-2-(trifluoromethoxy)-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (567 mg, 1.74 mmol) in DMF (10 mL) at rt was added TEA (176 mg, 1.74 mmol). The reaction mixture was stirred at rt for 18 h, poured into ice-water and extracted with EA (20 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give the final desired title compound 5-(5-(3,5-dichloro-4-(trifluoromethoxy)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol (310 mg; 37% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.22 (s, 1H), 7.91 (s, 2H), 7.76 (d, J=7.6 Hz, 2H), 7.70 (d, J=8.4 Hz, 1H), 4.46 (d, J=18.4 Hz, 1H), 4.37 (d, J=18.0 Hz, 1H), 1.48 (s,6H) ppm; HPLC purity: 97.1% at 220 nm and 99.0% at 254 nm; MS: m/z=528.4 (M+, ESI+).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[C:14]1[C:15](OC(=O)C)=[C:16]([I:20])[CH:17]=[CH:18][CH:19]=1)(=O)C.[F:25][B-:26]([F:29])([F:28])[F:27].[Na+]>C(Cl)Cl>[F:25][B-:26]([F:29])([F:28])[F:27].[C:1]1([I+:20][C:16]2[CH:17]=[CH:18][CH:19]=[CH:14][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)Oc1cccc(I)c1OC(C)=O
Reactant: OB(O)c1ccccc1
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: ClCCl
Product: c1ccc([I+]c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 93.4 %

Procedure:
Phenylboronic acid (0.79 g, 6.5 mmol), methylene chloride (62 ml), and boron trifluoride ethyl ether complex (0.97 g, 6.8 mmol) were charged and cooled to 0° C. A solution of diacetoxy iodobenzene (2.0 g, 6.2 mmol) in methylene chloride (62 ml) was added dropwise. The reaction was carried out at 0° C. for 1.5 hours. A saturated aqueous solution of sodium fluoroborate (13.6 g, 124.2 mmol) was added dropwise, and the mixture was extracted with addition of water and methylene chloride. The organic layer was dried with anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and purified by recrystallization to give the title compound (2.13 g, 93.5%).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][CH2:4][NH:5][C:6](=[O:19])[C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([NH:16][CH3:17])=[CH:9][C:8]=1Cl.[F:22][C:23]([F:31])([F:30])[CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.Cl.CCN(C(C)C)C(C)C>CC#N>[F:1][C:2]([F:21])([F:20])[CH2:3][CH2:4][NH:5][C:6](=[O:19])[C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([NH:16][CH3:17])=[CH:9][C:8]=1[N:27]1[CH2:28][CH2:29][CH:24]([C:23]([F:31])([F:30])[F:22])[CH2:25][CH2:26]1
Reactant: FC(F)(F)C1CCNCC1
Reactant: CNc1cc(Cl)c(C(=O)NCCC(F)(F)F)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CNc1cc(N2CCC(C(F)(F)F)CC2)c(C(=O)NCCC(F)(F)F)cc1[N+](=O)[O-]

Procedure:
The sub-title compound is prepared in analogy to 6a from N-(3,3,3-trifluoro-propyl)-2-chloro-4-methylamino-5-nitro-benzoic acid amide (compound 81a; 2.0 g, 6.5 mmol), 4-trifluormethyl-piperidine×HCl (2.45 g, 13 mmol), DIPEA (4.9 mL, 29 mmol) and MeCN (25 mL) in a pressure flask at 80° C.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([N:50]=[N+:51]=[N-:52])[CH:46]([O:53][CH3:54])[CH2:45]2)[CH:7]([CH3:56])[CH:6](O)[CH2:5][C:4]1=[O:58])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([N:50]=[N+:51]=[N-:52])[CH:46]([O:53][CH3:54])[CH2:45]2)[CH:7]([CH3:56])[CH:6]=[CH:5][C:4]1=[O:58])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N=[N+]=[N-])C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N=[N+]=[N-])C(OC)C3)C(C)C=CC1=O)C(C)CC2OC

Procedure:
A solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-azido-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (210 mg, example 2, step E) and a catalytic amount of p-toluenesulfonic acid in 40 ml of dry benzene was refluxed for 2.5 h under nitrogen atmosphere. The solvent was removed under reduced pressure and the dark brown residue was purified by column chromatography on silica gel (40% ethyl acetate/hexane) to give the title compound.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:13]=[CH:12][N:11]([CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:28])C(=O)C1>C1COCC1>[Br:28][C:12]1[N:11]([CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:10]=[C:9]([S:6]([NH:5][C:1]([CH3:4])([CH3:2])[CH3:3])(=[O:8])=[O:7])[CH:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)NS(=O)(=O)c1ccn(CC2CCCCC2)c1
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1cc(Br)n(CC2CCCCC2)c1
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
To a stirred mixture of compound 27e (280 mg, 0.94 mmol) in dry THF (3 mL) was added NBS (200 mg, 1.13 mmol) at −78° C. and the solution was stirred at this temperature for 30 min, quenched with water and extracted with EA twice. The combined organic layers were washed with water (3×) and brine, concentrated and purified by CC (PE/EA=5/1) to give compound 27f (300 mg, 85%) as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:28]=[CH:27][CH:26]=[CH:25][C:4]=1[CH2:5][O:6][C:7]1[CH:11]=[C:10]([N:12]2[C:20]3[CH:19]=[CH:18][N:17]=[CH:16][C:15]=3[N:14]=[CH:13]2)[S:9][C:8]=1[C:21]([O:23]C)=O)#[N:2].[NH3:29]>CO>[C:1]([C:3]1[CH:28]=[CH:27][CH:26]=[CH:25][C:4]=1[CH2:5][O:6][C:7]1[CH:11]=[C:10]([N:12]2[C:20]3[CH:19]=[CH:18][N:17]=[CH:16][C:15]=3[N:14]=[CH:13]2)[S:9][C:8]=1[C:21]([NH2:29])=[O:23])#[N:2]
Reactant: N
Reactant: COC(=O)c1sc(-n2cnc3cnccc32)cc1OCc1ccccc1C#N
Solvent: CO
Product: N#Cc1ccccc1COc1cc(-n2cnc3cnccc32)sc1C(N)=O

Procedure:
In a similar manner as described for example 38, 55 mg of methyl 3-[(2-cyanobenzyl)oxy]-5-(1H-imidazo[4,5-c]pyridin-1-yl)thiophene-2-carboxylate and 20 ml of a saturated solution of ammonia in methanol yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8])=[CH:5][N:6]=1.Cl[C:14]1[N:19]=[C:18]([CH3:20])[N:17]=[C:16]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][OH:29])[CH2:23][CH2:22]2)[CH:15]=1>>[OH:29][CH2:28][CH2:27][N:24]1[CH2:23][CH2:22][N:21]([C:16]2[N:17]=[C:18]([CH3:20])[N:19]=[C:14]([NH:1][C:2]3[S:3][C:4]([C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8])=[CH:5][N:6]=3)[CH:15]=2)[CH2:26][CH2:25]1
Reactant: CC(C)OC(=O)c1cnc(N)s1
Reactant: Cc1nc(Cl)cc(N2CCN(CCO)CC2)n1
Product: Cc1nc(Nc2ncc(C(=O)OC(C)C)s2)cc(N2CCN(CCO)CC2)n1
Yield: 65.2 %

Procedure:
Prepared from isopropyl 2-aminothiazole-5-formate and Compound 4: isopropyl 2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-formate was obtained (yield: 65.2%).
Reaction SMILES: [I:1][C:2]1[C:3](O)=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.O=P(Cl)(Cl)[Cl:14].P(Cl)(Cl)(Cl)(Cl)Cl>O>[Cl:14][C:3]1[C:2]([I:1])=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[CH:5][N:4]=1
Reactant: O=[N+]([O-])c1cnc(O)c(I)c1
Reactant: O=P(Cl)(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O
Product: O=[N+]([O-])c1cnc(Cl)c(I)c1
Temperature: 140 °C
Yield: 68.4 %

Procedure:
A mixture of 3-iodo-5-nitropyridin-2-ol (37.6 mmol, 10 g), POCl3 (86.47 mmol, 7.94 ml) and PCl5 (48.87 mmol, 10.2 g) was heated at 140° C. for 1 h, under argon atmosphere. The crude mixture was poured into a mixture of ice and water and extracted with DCM. The solid residue was purified by chromatography over SiO2 eluting with hexane/dichloromethane mixtures affording 2-chloro-3-iodo-5-nitropyridine (7.32 g, yield 69%) of the expected product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([Mg]Br)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:13]1(=[O:23])[O:18][C:16](=[O:17])[C@H:15]2[CH2:19][CH:20]=[CH:21][CH2:22][C@@H:14]12>C1COCC1.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[C:13]([CH:14]1[CH:15]([C:16]([OH:18])=[O:17])[CH2:19][CH:20]=[CH:21][CH2:22]1)=[O:23]
Reactant: COc1ccc([Mg]Br)cc1OC
Reactant: O=C1OC(=O)[C@@H]2CC=CC[C@H]12
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(C(=O)C2CC=CCC2C(=O)O)cc1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 10 %

Procedure:
A solution of 3,4-dimethoxyphenylmagnesium bromide (59 mmol, 0.29 M) in THF was added dropwise to an ice-cooled solution of cis-1,2,3,6-tetrahydrophthalic anhydride in THF (120 mL) over a 1 h period. After the addition was complete, the resulting mixture was stirred for another 30 min at 0° C. The reaction mixture was allowed to warn to room temperature overnight. The reaction was quenched with sat. NH4Cl(aq) and then the pH was adjusted to 2 with concentrated HCl(aq) and extracted with diethyl ether. The combined organic extracts were washed with water and subsequently extracted with 1 M NaOH(aq). The combined aqueous extracts were neutralized with conc. HCl(aq) and extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered through paper, and concentrated under reduced pressure to give an oil. The oil was dissolved in CH2Cl2 and filtered through silica to remove any dicarboxylic acid formed during the reaction work up. The product was recrystallized in diethyl ether to afford a white solid (1.62 g, 5.58 mmol, 10%).
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[CH:13][N:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:23]([F:26])([F:25])[F:24])=[CH:5][C:4]=2[N:3]=1.[NH2:27][CH2:28][CH2:29][CH2:30][OH:31]>O1CCOCC1.C(OCC)(=O)C>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([N:14]2[C:10]3[C:9]4[CH:8]=[CH:7][C:6]([C:23]([F:26])([F:25])[F:24])=[CH:5][C:4]=4[N:3]=[C:2]([NH:27][CH2:28][CH2:29][CH2:30][OH:31])[C:11]=3[N:12]=[CH:13]2)=[CH:16][CH:17]=1
Reactant: NCCCO
Reactant: COc1ccc(-n2cnc3c(Cl)nc4cc(C(F)(F)F)ccc4c32)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(-n2cnc3c(NCCCO)nc4cc(C(F)(F)F)ccc4c32)cc1
Reaction time: 19 h
Yield: 85.4 %

Procedure:
To a solution of 4-chloro-1-(4-methoxy-phenyl)-7-trifluoromethyl-1H-imidazo[4,5-c]quinoline (153 mg; 0.41 mmol; 1 eq) in anhydrous 1,4-dioxane (18 mL), 3-aminopropanol (77 μL; 1.0 mmol; 2.5 eq) is added. The resulting solution is heated to reflux and allowed to stir for 19 hours after which period the reaction is still not complete on TLC. Thus, additional 3-aminopropanol (523 μL; 6.9 mmol; 17 eq) is added and the stirring is continued under reflux for 4 hours. The crude mixture is diluted with ethyl acetate (40 mL) and washed three times with a 1M aqueous solution of NaOH (3×40 mL). Aqueous layers are combined and re-extracted with ethyl acetate (75 mL). All organic layers are combined, dried over sodium sulfate and concentrated. The crude residue is purified on silica gel (cyclohexane/ethyl acetate 2:8) to afford the title compound as an off-white powder (145 mg; 0.35 mmol; 85%).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:22])[C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([N+:19]([O-])=O)[CH:13]=2)[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2]>CCOC(C)=O.[Pd]>[NH2:19][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[CH3:18])[C:11]([NH:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=1)=[O:22]
Reactant: Cc1ccc(C(=O)Nc2cccc(C(C)C)c2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)Nc2cccc(C(C)C)c2)cc1N
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To N-(3-Isopropyl-phenyl)-4-methyl-3-nitro-benzamide (3.00 g, 0.010 mol) dissolved in EtOAc (60 mL) in a 100 mL round bottom flask was added Pd/C (10%, 250 mg). The flask was capped with a rubber septum and flushed with H2 gas through a balloon/needle. Positive H2 pressure was applied through the balloon/needle and reaction was stirred vigorously at room temperature for 3 days. TLC indicated clean conversion of starting material. The reaction was filtered through a pad of sand/celite. After concentration, the mixture was purified by silica gel chromatography to afford a slightly orange oil. Trituration with a mixture of hexanes and EtOAc afforded the title compound as an off-white solid. MS m/z 269=[M+H]+. Calc'd for C17H20N2O: 268.36.