Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10][SiH2:11][C:12]([CH3:17])([CH3:16])[CH2:13][CH2:14][CH3:15])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:37](Br)(Br)([Br:39])[Br:38]>C(Cl)Cl>[F:1][C:2]1[CH:9]=[C:8]([O:10][SiH2:11][C:12]([CH3:17])([CH3:16])[CH2:13][CH2:14][CH3:15])[CH:7]=[CH:6][C:3]=1[CH:4]=[C:37]([Br:39])[Br:38]
Reactant: BrC(Br)(Br)Br
Reactant: CCCC(C)(C)[SiH2]Oc1ccc(C=O)c(F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCC(C)(C)[SiH2]Oc1ccc(C=C(Br)Br)c(F)c1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 26 mmol of 2-fluoro-4-dimethylbutylsilyloxy benzaldehyde in 50 ml of methylene chloride were added dropwise under ice-cooling 110 mmol of triphenyl phosphine and 52 mmol of carbon tetrabromide and the solution was stirred at the same temperature for one hour. The insoluble matter was removed from the reaction solution which was concentrated under reduced pressure to provide a yellow oily product. Purification of the product by a silica gel column chromatography gave 26 mmol of 2-fluoro-4-dimethylbutylsilyloxyphenyl-2,2-dibromoethylene as a colourless oily product.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([SH:11])=[CH:4][CH:3]=1.Br[CH:13]([CH2:17][CH2:18][CH2:19][CH3:20])[C:14]([OH:16])=[O:15].Cl>[OH-].[Na+]>[C:7]([C:6]1[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[S:11][CH:13]([CH2:17][CH2:18][CH2:19][CH3:20])[C:14]([OH:16])=[O:15])([OH:9])=[O:8]
Reactant: O=C(O)c1cc(Cl)ccc1S
Reactant: CCCCC(Br)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCCC(Sc1ccc(Cl)cc1C(=O)O)C(=O)O

Procedure:
A mixture of 5-chlorothiosalicylic acid [prepared by the process set forth in L. Katz et al., J. Org. Chem., 18 (1953) 1380] (2.0 g, 9.8 mmol) and 1N aqueous sodium hydroxide (100 ml) was heated at reflux temperature for 1 hour under a nitrogen atmosphere. 2-Bromohexanoic acid (1.9 g, 9.8 mmol) was then added, and refluxing was continued for an additional hour. The mixture was cooled in an ice bath and acidified with concentrated hydrochloric acid. The acidic mixture was extracted with diethyl ether, and the combined organic layers were washed with water, saturated aqueous sodium chloride solution, dried (sodium sulfate), and evaporated. The product was obtained as a light yellow solid (2.4 g) that was used without further purification in the subsequent step below.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[N+:19]([O-])([OH:21])=[O:20]>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N+:19]([O-:21])=[O:20])[C:5]([NH:12][C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=[N+]([O-])O
Reactant: CCCCC(=O)Nc1ccc(Cl)cc1C(=O)OC
Solvent: CC(=O)OC(C)=O
Product: CCCCC(=O)Nc1c(C(=O)OC)cc(Cl)cc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
To a solution of methyl 5-chloro-2valerylaminobenzoate (13.4 g) in acetic anhydride (10 ml) was added dropwise, while stirring under ice-cooling, fuming nitric acid. The mixture was stirred for one hour at room temperature, then there was added ice water. The mixture was allowed to stand to give crystals Recrystallization from isopropyl ether afforded pale yellow crystals (9.5 g, 61%), m.p. 84°-85° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:10](=[O:12])[O:9][C:8](=[O:13])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:16]I>CN(C)C=O>[Cl:1][C:2]1[C:11]2[C:10](=[O:12])[O:9][C:8](=[O:13])[N:7]([CH3:16])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: O=c1[nH]c2cccc(Cl)c2c(=O)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)oc(=O)c2c(Cl)cccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Under an atmosphere of nitrogen, 5-chloro-1H-benzo[d][1,3]oxazine-2,4-dione (10 g, 50.61 mmol, 1.00 equiv) was dissolved in N,N-dimethylformamide (100 ml) at about 5° C. Sodium hydride (2.8 g, 121.5 mmol, 2.4 equiv) and methyl iodide (5.7 ml, 2 equiv) were then added, and the resulting mixture was stirred at ambient temperature for about 16 hours. The mixture was purged with nitrogen for about 1 hour to give the title product as a yellow solid, which was used directly in the next step without any purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:18][CH:19]2[CH2:23][CH2:22][C:21](=O)[CH2:20]2)[C:10]([NH:12][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[NH2:26][OH:27]>CO.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:18][CH:19]2[CH2:23][CH2:22][C:21](=[N:26][OH:27])[CH2:20]2)[C:10]([NH:12][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NO
Reactant: O=C1CCC(CC(C(=O)Nc2nccs2)c2ccc(Cl)c(Cl)c2)C1
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: O=C(Nc1nccs1)C(CC1CCC(=NO)C1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 91.8 %

Procedure:
A solution of the 2-(3,4-dichloro-phenyl)-3-(3-oxo-cyclopentyl)-N-thiazol-2-yl-propionamide (prepared as in Example 43, 144.6 mg, 0.38 mmol) and hydroxylamine hydrochloride (39.7 mg, 0.57 mmol) in methanol (1.1 mL) and pyridine (1.1 mL) was heated under reflux for 3 h. The reaction mixture was allowed to cool to 25° C. and then was concentrated in vacuo. The resulting residue was diluted with ethyl acetate (75 mL). The organic layer was washed with a 1N aqueous hydrochloric acid solution (75 mL) and a saturated aqueous sodium chloride solution (75 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 70% ethyl acetate/hexanes) afforded 2-(3,4-dichloro-phenyl)-3-(3-hydroxyimino-cyclopentyl)-N-thiazol-2-yl-propionamide (138.9 mg, 92%) as a white foam: mp 98-101° C. (foam to gel); (ES)+-HRMS m/e calcd for C17H17Cl2N3O2S (M+H)+ 398.0492. found 398.0496.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:6][B:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[O:4][C:3]1([CH3:17])[CH3:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:43]1[CH2:47][CH2:46][CH2:45][C@H:44]1[C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:18][C:2]1([CH3:1])[C:3]([CH3:17])([CH3:16])[O:4][B:5]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([N:43]3[CH2:47][CH2:46][CH2:45][C@H:44]3[C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])=[O:13])=[CH:14][CH:15]=2)[O:6]1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: CC1(C)OB(c2ccc(C(=O)O)cc2)OC1(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.3 %

Procedure:
To a solution of 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (2.00 g, 8.06 mmol) in DMF (20 mL) was added HATU (6.20 g, 16.3 mmol), (S)-tert-butyl pyrrolidine-2-carboxylate (2.00 g, 11.7 mmol) and DIPEA (4.20 g, 32.5 mmol). The reaction mixture was stirred at rt overnight, and was quenched with H2O (20 mL). The resulting solution was extracted with DCM (3×100 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/petroleum ether (1:20-1:10 v/v) to obtain compound 17a as a yellow solid (1.40 g, 37% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C22H32BNO5: 402.2 (M+H). Found 402.1.
Reaction SMILES: [CH:1](C(O)=O)([C:17]([OH:19])=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]C.CC(OC(C)=O)=[O:25]>>[O:18]1[C:17](=[O:19])[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][CH2:14][C:15]1=[O:25]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCCCCCCCCC(C(=O)O)C(=O)O
Product: O=C1CCCCCCCCCCCCCCC(=O)O1

Procedure:
3 g hexadecanedicarboxlic acid and 4.5 ml acetanhydride were refluxed over night. Then the solvent was removed and the crude product recrystallized from acetonitril.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:12]2[C:7](=[CH:8][N:9]=[CH:10][CH:11]=2)[O:6][CH2:5]1.ClC1C=CC=C(C(OO)=[O:21])C=1>C(Cl)Cl>[CH3:1][O:2][N:3]=[C:4]1[C:12]2[C:7](=[CH:8][N+:9]([O-:21])=[CH:10][CH:11]=2)[O:6][CH2:5]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CON=C1COc2cnccc21
Solvent: ClCCl
Product: CON=C1COc2c[n+]([O-])ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of furo[2,3-c]pyridin-3(2H)-one O-methyl oxime (5.35 mmol) (A.2.4.4) in 15 mL DCM was added 3-chloroperbenzoic acid (16.0 mmol). The mixture was stirred at RT overnight, diluted with 20 mL DCM and extracted with sat. aq. NaHCO3 solution (2×), with sat. aq. Na2S2O3 solution (2×) and brine. The combined organic layers were dried over MgSO4 and concentrated in vacuo to give the desired product as yellow solid;
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:32][O:33][CH2:34][C:35](Cl)=[O:36]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:24][CH:23]=4)[C@@H:19]([NH:21][C:35](=[O:36])[CH2:34][O:33][CH3:32])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: C[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccc(C(F)(F)F)cc1
Reactant: COCC(=O)Cl
Product: COCC(=O)N[C@@H](C)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccc(C(F)(F)F)cc1

Procedure:
Prepared as described in Example 1 using (1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-[4-(trifluoromethyl)phenyl]propan-2-amine (59a, 21 mg, 50 μmol) and methoxyacetyl chloride (16 mg, 150 μmol). Yield 17 mg (69%).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([C:10]2[N:11]=[C:12]([NH2:15])[S:13][CH:14]=2)=[C:5]([CH3:16])[CH:4]=1.C(N(CC)CC)C.Cl.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1>C(Cl)Cl>[CH3:17][N:2]([CH3:1])[C:3]1[CH:4]=[C:5]([CH3:16])[C:6]([C:10]2[N:11]=[C:12]([NH:15][C:26](=[O:33])[C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)[S:13][CH:14]=2)=[C:7]([CH3:9])[CH:8]=1
Reactant: Cc1cc(N(C)C)cc(C)c1-c1csc(N)n1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(N(C)C)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
To a solution of 4-(4-(dimethylamino)-2,6-dimethylphenyl)thiazol-2-amine (1-4, 0.50 g, 2.0 mmol) in CH2Cl2 (5.1 mL) was added triethylamine (0.61 g, 6.1 mmol) followed by isonicotinoyl chloride hydrochloride (0.54 g, 3.0 mmol). The reaction mixture was stirred at room temperature overnight. The solution was concentrated under reduced pressure and added with hot water. The resultant precipitate was filtered and dried under vacuum to give N-{4-(4-(dimethylamino)-2,6-dimethylphenyl)thiazol-2-yl}isonicotinamide (1, 0.55 g) as yellow solids in 77% yield: 1H NMR (500 MHz, CDCl3) δ 8.64 (d, J=5.5 Hz, 2 H), 7.55 (d, J=5.5 Hz, 2 H), 6.74 (s, 1 H), 6.12 (s, 2 H), 2.89 (s, 6 H), 1.91 (s, 6 H). ESI-MS: m/z 352.6 (M+H)+.
Reaction SMILES: [CH:1]1([CH:6]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[CH2:29][C:28]4[C:23](=[CH:24][C:25]([F:31])=[C:26]([F:30])[CH:27]=4)[C:22]3=[O:32])=[CH:16][CH:15]=2)[C:7]([O:9]C(C)(C)C)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([CH:6]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][N:21]3[CH2:29][C:28]4[C:23](=[CH:24][C:25]([F:31])=[C:26]([F:30])[CH:27]=4)[C:22]3=[O:32])=[CH:18][CH:19]=2)[C:7]([OH:9])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)C(c1ccc(CN2Cc3cc(F)c(F)cc3C2=O)cc1)C1CCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C(c1ccc(CN2Cc3cc(F)c(F)cc3C2=O)cc1)C1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
27.0 mg (0.06 mmol) of tert-butyl(+/−)-cyclopentyl{4-[(5,6-difluoro-1-oxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}acetate were initially charged in 200 μl of dichloromethane, and 94 μl of trifluoroacetic acid were added. The mixture was stirred at RT for 2 h. The reaction mixture was then concentrated on a rotary evaporator, and the residue was dried under high vacuum. This gave 23.5 mg (99.7% of theory) of the target compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])(=[O:10])=[O:9])=[C:4]([F:18])[CH:3]=1.[F:19][C:20]1[CH:21]=[CH:22][C:23]([O:29][CH3:30])=[C:24](B(O)O)[CH:25]=1>>[F:18][C:4]1[CH:3]=[C:2]([C:22]2[CH:21]=[C:20]([F:19])[CH:25]=[CH:24][C:23]=2[O:29][CH3:30])[CH:7]=[CH:6][C:5]=1[S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])(=[O:10])=[O:9]
Reactant: O=S(=O)(c1ccc(Br)cc1F)c1ccccc1Cl
Reactant: COc1ccc(F)cc1B(O)O
Product: COc1ccc(F)cc1-c1ccc(S(=O)(=O)c2ccccc2Cl)c(F)c1

Procedure:
The subtitle compound was prepared by the method of example 2 step (ii) using the product of step (ii) and 5-fluoro-2-methoxybenzene boronic acid which was used directly in step (iv) without further characterisation.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[N:11]=[CH:10][NH:9][C:7](=O)[C:5]=2[CH:6]=1.P(Cl)(Cl)([Cl:14])=O.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[Cl:14][C:7]1[C:5]2[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=2)[N:11]=[CH:10][N:9]=1
Reactant: O=c1[nH]cnc2ccccc12
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: Clc1ncnc2ccccc12
Temperature: 25 °C
Yield: 153.2 %

Procedure:
Quinazolinone 2 (20.0 g, 79.3 mmol) was suspended in 500 mL dry benzene in a 1 L round-bottomed flask equipped with a reflux condenser. N,N-Dimethylanaline (14.4 g, 119 mmol) was added and the reaction was refluxed for 30 minutes under nitrogen. Upon cooling to room temperature, phosphorus oxychloride (12.2 g, 79.3 mmol) was added and the reaction mixture was then refluxed for an additional 3 hours under nitrogen. The mixture was cooled to room temperature, poured over ice, and neutralized with saturated aqueous sodium bicarbonate. The solution was then extracted four times with toluene and the combined organic layers dried over magnesium sulfate, filtered, and concentrated in vacuo to a reddish-brown solid. The resulting 4-chloroquinazoline 3 was purified via flash chromatography (40% hexanes, 60% dichloromethane) to afford 20 g (93%) 3 as a yellow solid.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][NH:6][CH2:5][C@H:4]1[CH2:8][N:9]([CH2:19][CH:20]([CH3:22])[CH3:21])[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:12])=[O:11].CC#N.O.CC#N>O>[CH:2]([C@@H:3]1[CH2:7][NH:6][CH2:5][C@H:4]1[CH2:8][N:9]([CH2:19][CH:20]([CH3:22])[CH3:21])[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:12])=[O:11])=[O:1]
Reactant: CC(C)CN(C[C@@H]1CNC[C@H]1CO)S(=O)(=O)c1ccccc1
Solvent: CC#N
Solvent: O
Product: CC(C)CN(C[C@@H]1CNC[C@H]1C=O)S(=O)(=O)c1ccccc1

Procedure:
The title compound is prepared as described above for Example 9/step E (Scheme 5) from N-((3S*,4S*)-4-Hydroxymethyl-pyrrolidin-3-ylmethyl)-N-isobutyl-benzenesulfonamide. MS (LC-MS): 325.0 [M-Boc+H]+; tR (HPLC, Waters Symmetry C18 column, 20-95% CH3CN/H2O/3.5 min, 95% CH3CN/H2O, 2 min, CH3CN and H2O containing 0.1% TFA, flow 0.6 mL/min): 4.24 min.
Reaction SMILES: C[Al](C)C.C([O:7][C:8]([C:10]1[C:11]2[N:12]=[CH:13][CH:14]=[N:15][C:16]=2[C:17]([C:20]2[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[CH:21]=2)=[CH:18][CH:19]=1)=O)C.[CH2:30]([N:32]1[CH2:37][CH2:36][N:35]([CH2:38][C:39]2[CH:40]=[CH:41][C:42]([NH2:45])=[N:43][CH:44]=2)[CH2:34][CH2:33]1)[CH3:31].O>C1(C)C=CC=CC=1>[CH2:30]([N:32]1[CH2:33][CH2:34][N:35]([CH2:38][C:39]2[CH:40]=[CH:41][C:42]([NH:45][C:8]([C:10]3[C:11]4[N:12]=[CH:13][CH:14]=[N:15][C:16]=4[C:17]([C:20]4[CH:21]=[C:22]([O:28][CH3:29])[CH:23]=[C:24]([O:26][CH3:27])[CH:25]=4)=[CH:18][CH:19]=3)=[O:7])=[N:43][CH:44]=2)[CH2:36][CH2:37]1)[CH3:31]
Reactant: CCOC(=O)c1ccc(-c2cc(OC)cc(OC)c2)c2nccnc12
Reactant: CCN1CCN(Cc2ccc(N)nc2)CC1
Agent: C[Al](C)C
Solvent: O
Solvent: Cc1ccccc1
Product: CCN1CCN(Cc2ccc(NC(=O)c3ccc(-c4cc(OC)cc(OC)c4)c4nccnc34)nc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.1 %

Procedure:
Trimethyl aluminum (2 M in toluene, 0.37 mL, 0.74 mmol, 2.5 equiv) was added to a mixture of 8-(3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 115.1) (100 mg, 0.30 mmol) and 5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Step 26.1; purified by column chromatography) (78 mg, 0.36 mmol, 1.2 equiv) in toluene (2 mL). The reaction mixture was stirred for 1 h at rt, heated to reflux, stirred for 3 h, allowed to cool, poured onto EtOAc and H2O, and filtered through a pad of celite. The filtrate was extracted with EtOAc. The organic phase was washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH/NH3aq, 94:5:1) followed by reverse-phase preparative HPLC to afford 54 mg of the title compound as a pale yellow solid. Title compound: ESI-MS: 513.2 [M+H]+; tR=3.54 min (System 1); TLC: Rf=0.29 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:32][CH:33]1[CH:37]([OH:38])[CH2:36][N:35]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:34]1.O>C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:32][CH:33]2[CH:37]([OH:38])[CH2:36][N:35]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:34]2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: CC(C)(C)OC(=O)N1CC(N)C(O)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(O)C(NC(=O)c2ccc(Cl)s2)C1
Reaction time: 0.5 h

Procedure:
201 mg (1.2 mmol) 5-chlorothiophene-2-carboxylic acid and 436 mg (1.4 mmol) TBTU are suspended in 5 ml DCM and combined with 260 μl (1.9 mmol) TEA. The mixture is stirred for 30 minutes and then a solution of 250 mg (1.2 mmol) tert. Butyl (3SR,4SR)-3-amino-4-hydroxy-pyrrolidine-1-carboxylate in 5 ml DCM is added and the mixture is stirred for 16 hours at RT. Then the reaction mixture is poured into water and extracted with DCM. The organic phase is washed with sat. sodium chloride solution and, after being mixed with activated charcoal, dried on sodium sulphate. The mixture is filtered and the filtrate is evaporated to dryness. The residue thus obtained is purified by column chromatography (silica gel, eluant DCM/MeOH 10:1).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)[CH2:2][CH3:3].Br[CH:13]([CH3:25])[C:14]([C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([OH:23])=[C:18]([CH3:24])[CH:17]=1)=O>>[OH:23][C:19]1[C:18]([CH3:24])=[CH:17][C:16]([C:14]2[NH:9][C:8]3[C:10]([C:13]=2[CH3:25])=[CH:11][C:5]([O:4][CH2:1][CH2:2][CH3:3])=[CH:6][CH:7]=3)=[CH:21][C:20]=1[CH3:22]
Reactant: CCCOc1ccc(N)cc1
Reactant: Cc1cc(C(=O)C(C)Br)cc(C)c1O
Product: CCCOc1ccc2[nH]c(-c3cc(C)c(O)c(C)c3)c(C)c2c1
Temperature: 0 °C

Procedure:
3 g of 4-n-propoxyaniline and 2.56 g of 4-(2-bromo-1-oxopropyl)-2,6-dimethylphenol were heated at 150° C. for 40 minutes in a stream of nitrogen. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was purified by silica gel column chromatography, and recrystallized from ether-hexane to give 2-(4-hydroxy-3,5-dimethylphenyl)-3-methyl-5-n-propoxyindole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)=[O:12])=[CH:9][N:10]=2)[N:7]=1.[CH3:24][Mg]I>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)([OH:12])[CH3:24])=[CH:9][N:10]=2)[N:7]=1
Reactant: O=C(c1cc2cccnc2cc1F)c1cnc2ccc(Cl)nn12
Reactant: C[Mg]I
Solvent: C1CCOC1
Product: CC(O)(c1cc2cccnc2cc1F)c1cnc2ccc(Cl)nn12
Temperature: 25 °C
Yield: 95.4 %

Procedure:
To a solution of (6-chloroimidazo[1,2-b]pyridazin-3-yl)(7-fluoroquinolin-6-yl)methanone (2.93 g, 6.73 mmol) in THF (80 mL) was added MeMgI solution (3 M in THF, 4.48 mL, 13.45 mmol) and the resulting solution was stirred at reflux for 5 h. Then the reaction mixture was cooled to rt, quenched with water, washed with NH4Cl solution and extracted by DCM. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to afford 2.2 g (95%) of the title compound which was used to next step.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[O:12]1[CH2:16][CH2:15][CH2:14][CH:13]1[C:17]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]Cl)=[O:18].[I-].[K+].C(#N)C>O>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([O:6][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][O:19][C:17]([CH:13]1[CH2:14][CH2:15][CH2:16][O:12]1)=[O:18])=[O:5]
Reactant: O=C(OCCCCCCCCCl)C1CCCO1
Reactant: O=C(O)c1cc(O)ccc1O
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C(OCCCCCCCCOC(=O)C1CCCO1)c1cc(O)ccc1O

Procedure:
A mixture of 2,5-dihydroxybenzoic acid (3.9 g), 1,8-diazobicyclo[5.5.0]undec-7-ene (3.8 g), 8-chlorooctyl tetrahydro-2-furancarboxylate (6.0 g), potassium iodide (30.2 g) and acetonitrile (110 ml) was heated, under reflux for 72 h. The cooled reaction mixture was added to water (500 ml) and extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with 1N-hydrochloric acid (150 ml) and water (2×15 ml), dried over magnesium sulphate and filtered. The solvent was removed in vacuum. The residue (8.0 g) was purified by column flash chromatography on silica gel using toluene/ethyl acetate (3:1) as eluent, to give 8-[(2,5-dihydroxybenzoyl)oxy]octyltetrahydro-2-furancarboxylate as colourless oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:7][CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]([O:11][CH3:12])=[O:10].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>>[CH3:21][O:20][C:19]1[CH:18]=[CH:17][C:6]([CH2:7][CH:8]([C:9]([O:11][CH3:12])=[O:10])[C:13]([O:15][CH3:16])=[O:14])=[CH:5][C:4]=1[CH2:3][CH2:2][O:1][C:31]([NH:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=1)=[O:32]
Reactant: COc1ccc(N=C=O)cc1
Reactant: COC(=O)C(Cc1ccc(OC)c(CCO)c1)C(=O)OC
Product: COC(=O)C(Cc1ccc(OC)c(CCOC(=O)Nc2ccc(OC)cc2)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(2-hydroxyethyl)-4-methoxybenzyl]malonate and 4-methoxyphenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [CH:1]1([N:4]([CH:30]2[CH2:32][CH2:31]2)[C:5]([C:7]2[N:27]([CH2:28][CH3:29])[C:10]3=[N:11][C:12]([NH:19]/[C:20](/SC)=[CH:21]/[C:22](=O)[CH3:23])=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:33][N:34](C(OC(C)(C)C)=O)[NH2:35].C(O)=O>C(O)(=O)C>[CH:1]1([N:4]([CH:30]2[CH2:31][CH2:32]2)[C:5]([C:7]2[N:27]([CH2:28][CH3:29])[C:10]3=[N:11][C:12]([NH:19][C:20]4[CH:21]=[C:22]([CH3:23])[N:34]([CH3:33])[N:35]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N/C(=C/C(C)=O)SC)nc21
Reactant: CN(N)C(=O)OC(C)(C)C
Solvent: CC(=O)O
Solvent: O=CO
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3cc(C)n(C)n3)nc21
Temperature: 35 °C
Reaction time: 4 h
Yield: 67.1 %

Procedure:
A mixture of (Z)—N,N-dicyclopropyl-6-ethyl-1-methyl-4-(1-(methylthio)-3-oxobut-1-enylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 72B, 70 mg, 0.155 mmol) and tert-butyl 1-methylhydrazinecarboxylate (0.046 mL, 0.309 mmol) in acetic acid (1 mL) wan stirred at 35° C. for 4 h (monitored by LC/MS until no starting material left). Formic acid (0.5 mL) was added and stirred at 60° C. for 6 h. Solvent was evaporated and the crude product was purified by flash chromatography on silica gel using an automated ISCO system (12 g column, eluting with 2-10% methanol/dichloromethane). The impure product was further purified by preparative HPLC to give N,N-dicyclopropyl-4-(1,5-dimethyl-1H-pyrazol-3-ylamino)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (45 mg, 63.9% yield) as an off-white solid.