Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10]O)=[CH:4][CH:3]=1.N1C=CC=CC=1.P(Br)(Br)[Br:19].O>CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][Br:19])=[CH:4][CH:3]=1
Reactant: OCC#Cc1ccc(Cl)cc1
Reactant: BrP(Br)Br
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: O
Product: Clc1ccc(C#CCBr)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 141.3 %

Procedure:
A suspension of p-iodochlorobenzene [formula (VII), 7.15 g, 30.0 mmol], propargyl alcohol (1.75 mL, 30 mmol), dichlorobis(triphenylphosphine)palladium (II) (0.21 g, 0.3 mmol), copper (I) iodide (29 mg, 0.15 mmol) and diethylamine (50 mL) was stirred under a N2 atmosphere at room temperature and dissolution occurred within 20 min. After 5 h, the diethylamine was removed, and the crude product was partitioned between water and ether. The ether phase was dried (brine), concentrated and flash chromatographed (4:1 petroleum ether: ethyl acetate) to provide 3-(4-chlorophenyl)-prop-2-yn-ol (compound of formula VIII, 4.09 g, 82%). This compound of formula (VIII) (3.47 g, 20.83 mmol) was suspended in dry ether (12 mL) and pyridine (0.42 mL) was added. The reaction mixture was cooled in an ice bath and a solution of phosphorus tribromide (1.0 mL, 10.42 mmol) in dry ether (6 mL) was added dropwise over a 15 min period. The reaction mixture was then stirred at room temperature for 2.5 h, cooled in an ice bath and crushed ice was added. The reaction mixture was added to water (200 mL) and extracted with ether (200 mL). The ether phase was washed with water, sat. aqueous NaHCO3 and brine. The extract was concentrated and flash chromatographed (9:1 petroleum ether:ethyl acetate) to provide the product as a white solid (3.38 g, 86%): mp 41°-43 ° C.; NMR (CDCl3): δ 7.37 (d, J=8.7 Hz, 2H, ArH), 7.27 (d, J=8.7 Hz, 2H, ArH), 4.16 (s, 2H, CH2).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH:9](=O)[CH:10]([CH3:12])[CH3:11].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(C)C=O
Reactant: Nc1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)CNc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 64 h
Yield: 54.3 %

Procedure:
To a solution of 4-fluoroaniline (1 g, 9 mmol) in DCM (20 mL) at room temperature was added isobutyraldehyde (985 μL, 10.8 mmol) followed by portionwise sodium triacetoxyborohydride (2.86 g, 13.5 mmol) and the reaction was stirred at room temperature for 64 hours. The reaction was concentrated and then dissolved in DCM and MeOH, dry loaded onto silica then purified by silica gel column chromatography (0-25% DCM in cyclohexane) to give (4-fluoro-phenyl)-isobutyl-amine (817 mg, 54%). LCMS (m/z, Method A) ES+ 168 [M+1]+.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][CH:7]=[CH:6]1.O=[C:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.CC1C=CC(S(O)(=O)=O)=CC=1.O>C(O)C>[CH3:1][N:2]1[C:11]2([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[C:6]2=[CH:7][CH:8]=[CH:9][N:5]2[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CNCCn1cccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: CN1CCn2cccc2C12CCN(C(=O)OC(C)(C)C)CC2
Temperature: 70 °C
Yield: 78 %

Procedure:
N-Methyl-2-pyrrol-1-yl-ethanamine (2.19 g, 17.64 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (3.51 g, 17.64 mmol), and pTsOH.H2O (0.334 g, 1.76 mmol) were combined in ethanol (87.60 mL) and heated at 70° C. for 4 h. The reaction was concentrated and the residue was dissolved in dichloromethane. The organics were washed with a saturated NaHCO3 solution and brine. The organics were dried over sodium sulfate and evaporated. The crude material was purified by silica gel chromatography eluting with 0-10% methanol in dichloromethane with 2% triethylamine to give tert-butyl 2-methylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (4.2 g, 78%). ESI-MS m/z calc. 305.4, found 306.3 (M+1)+; Retention time: 0.97 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 6.55-6.52 (m, 1H), 6.15-6.11 (m, 1H), 5.92-5.89 (m, 1H), 3.92 (t, J=6.0 Hz, 2H), 3.91-3.75 (m, 2H), 3.29 (t, J=6.0 Hz, 2H), 3.26-3.12 (m, 2H), 2.36 (s, 3H), 2.10-1.99 (m, 2H), 1.83-1.69 (m, 2H), 1.47 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:33]=[CH:32][C:5]2[N:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([C:22]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=4)[CH2:11][CH2:10]3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[N:34]1[CH:39]=[CH:38][C:37]([NH:40][C:41](=O)[O:42]C2C=CC=CC=2)=[CH:36][CH:35]=1>O1CCOCC1>[F:28][C:27]([F:30])([F:29])[C:22]([C:19]1[CH:18]=[CH:17][C:16]([CH2:15][N:12]2[CH2:13][CH2:14][CH:9]([N:6]3[C:5]4[CH:32]=[CH:33][C:2]([NH:1][C:41]([NH:40][C:37]5[CH:38]=[CH:39][N:34]=[CH:35][CH:36]=5)=[O:42])=[CH:3][C:4]=4[N:8]=[CH:7]3)[CH2:10][CH2:11]2)=[CH:21][CH:20]=1)([OH:31])[C:23]([F:24])([F:25])[F:26]
Reactant: O=C(Nc1ccncc1)Oc1ccccc1
Reactant: Nc1ccc2c(c1)ncn2C1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Solvent: C1COCCO1
Product: O=C(Nc1ccncc1)Nc1ccc2c(c1)ncn2C1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Yield: 11.1 %

Procedure:
2-(4-((4-(5-Amino-1H-benzo[d]imidazol-1-yl)piperidin-1-yl)methyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.212 mmol, 0.1 g) and phenyl pyridin-4-ylcarbamate (0.318 mmol, 0.068 g) were combined and heated in a Reactivial in dioxane (2 mL) for 2 days. The solvent was removed and the resulting residue purified by silica chromatography (eluting with a solvent gradient from dichloromethane to 8% methanol/dichloromethane) to afford the title compound (14 mg). MS (ESI) m/z 593.2 [M+H]+
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C@:7]23[CH2:15][O:14][C@@H:13]([CH3:16])[CH2:12][C@H:11]2[CH2:10][O:9][NH:8]3)[S:5][CH:6]=1.[C:17](=[O:24])([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[NH2:18].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[Pd].C1(C)C=CC=CC=1>[CH3:16][C@@H:13]1[O:14][CH2:15][C@:7]2([C:4]3[S:5][CH:6]=[C:2]([NH:18][C:17](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[N:3]=3)[NH:8][O:9][CH2:10][C@@H:11]2[CH2:12]1
Reactant: CC(C)(C)OC(N)=O
Reactant: C[C@H]1C[C@H]2CON[C@@]2(c2nc(Br)cs2)CO1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: C[C@H]1C[C@H]2CON[C@@]2(c2nc(NC(=O)OC(C)(C)C)cs2)CO1
Temperature: 100 °C

Procedure:
Degassed toluene (48 mL) was added to a mixture of C3 (6.01 g, 19.7 mmol), tert-butyl carbamate (3.45 g, 29.4 mmol), and powdered potassium phosphate (12.6 g, 59.4 mmol), and the mixture was degassed with a stream of nitrogen. In a separate vessel, tris(dibenzylideneacetone)dipalladium(0) (97%, 1.86 g, 1.97 mmol) and di-tert-butyl[2′,4′,6′-tri(propan-2-yl)biphenyl-2-yl]phosphane (98%, 428 mg, 0.99 mmol) were combined with degassed toluene (6 mL) and heated at 100° C. for 2 minutes with stirring; the dark purple mixture changed to a dark maroon color during this activation. The Pd-ligand complex was added via syringe into the mixture containing C3, and the vessel was rinsed with degassed toluene (6 mL), which was also was added to the reaction mixture. The reaction mixture was heated at 100° C. for 20 hours, whereupon it was allowed to cool to room temperature and then filtered through diatomaceous earth. The filter pad was washed with ethyl acetate (2×50 mL), and the combined filtrates were concentrated in vacuo. The resulting oil was purified by chromatography on silica gel (Gradient: 5% to 80% ethyl acetate in heptane), affording the product as a fluffy yellow solid. Yield: 5.16 g, 15.1 mmol, 77%. 1H NMR (500 MHz, CDCl3) δ 7.22-7.30 (br s, 1H, assumed; partially obscured by solvent peak), 7.12-7.21 (br s, 1H), 4.3-4.5 (v br s, 1H), 3.93 (AB quartet, downfield doublet is broadened, JAB=12.7 Hz, ΔνAB=27.2 Hz, 2H), 3.73 (br d, half of AB quartet, J=7.4 Hz, 1H), 3.68 (dd, half of ABX pattern, J=7.3, 4.7 Hz, 1H), 3.63-3.7 (m, 1H), 3.24 (ddd, J=11.6, 6.8, 4.9 Hz, 1H), 1.88 (ddd, J=14.2, 6.8, 2.0 Hz, 1H), 1.52 (s, 9H), 1.42 (ddd, J=14.1, 11.7, 11.7 Hz, 1H), 1.27 (d, J=6.1 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH3:10])[C:6]=2[CH:11]=1.[NH2:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:10][N:7]1[C:6]2[CH:11]=[C:2]([C:17]3[CH:18]=[C:13]([CH:14]=[CH:15][CH:16]=3)[NH2:12])[CH:3]=[CH:4][C:5]=2[N:9]=[CH:8]1
Reactant: Nc1cccc(B(O)O)c1
Reactant: Cn1cnc2ccc(Br)cc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cn1cnc2ccc(-c3cccc(N)c3)cc21
Temperature: 120 °C
Yield: 57.4 %

Procedure:
To a solution of 6-bromo-1-methyl-1H-benzo[d]imidazole (500 mg, 2.37 mmol) in dioxane (10 mL) was added (3-aminophenyl)boronic acid (320 mg, 2.34 mmol), 2N K2CO3 (2 mL, 4 mmol) and PdCl2(dppf) (50 mg, 0.063 mmol). The reaction mixture was heated at 120° C. under microwave conditions for 30 min. The cooled mixture was concentrated under reduced pressure and the residue dissolved in ethyl acetate, washed with water with the separated organic layers being dried and concentrated to afford the desired product as a brown solid (300 mg, 56.7%). LCMS (m/z): 224.1 [M+H]+
Reaction SMILES: [C:1](C1C([N+]([O-])=O)=CC(C(O)=O)=CC=1O)(=O)[C:2]1C=CC=CC=1.[Cl:22][C:23]1[CH:43]=[CH:42][C:26]([C:27]([C:29]2[C:37]([N+:38]([O-:40])=[O:39])=[CH:36][C:32]([C:33]([OH:35])=[O:34])=[CH:31][C:30]=2[OH:41])=[O:28])=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:43]=[CH:42][C:26]([C:27]([C:29]2[C:37]([N+:38]([O-:40])=[O:39])=[CH:36][C:32]([C:33]([O:35][CH2:1][CH3:2])=[O:34])=[CH:31][C:30]=2[OH:41])=[O:28])=[CH:25][CH:24]=1
Reactant: O=C(O)c1cc(O)c(C(=O)c2ccccc2)c([N+](=O)[O-])c1
Reactant: O=C(O)c1cc(O)c(C(=O)c2ccc(Cl)cc2)c([N+](=O)[O-])c1
Product: CCOC(=O)c1cc(O)c(C(=O)c2ccc(Cl)cc2)c([N+](=O)[O-])c1

Procedure:
By replacing in Example 6, step A, 4-benzoyl-3-hydroxy5-nitrobenzoic acid with 4-(4'-chlorobenzoyl)-3-hydroxy-5-nitrobenzoic acid and following the procedure described, ethyl 4-(4'-chlorobenzoyl)-3-hydroxy-5-nitrobenzoate is obtained with a melting point of 188°-191.5° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:2]1.Cl[C:34]([C@@H:36]([O:38]C(=O)C)[CH3:37])=[O:35]>>[OH:38][C@@H:36]([CH3:37])[C:34]([N:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:2]1)=[O:35]
Reactant: O=C(N[C@@H]1CCCNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Product: C[C@H](O)C(=O)N1CCC[C@@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-piperidin-3-ylamide (example A149) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][C:6](Br)=[CH:5][C:4]=2[N:3]=1.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].COCCOC>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.O>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: CCOCc1nc2c(N)nc3cc(Br)cnc3c2n1CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CCOCc1nc2c(N)nc3cc(-c4ccccc4)cnc3c2n1CC(C)(C)O
Temperature: 25 °C
Yield: 57.7 %

Procedure:
A suspension of 1-[4-amino-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol (1.55 g, 3.93 mmol), phenylboronic acid (0.575 g, 4.72 mmol), potassium carbonate (1.79 g, 13.0 mmol), dichlorobis(triphenylphosphine)palladium(II)(0.028 g, 0.039 mmol), DME (13 mL), and water (7 mL) was stirred under a nitrogen atmosphere and then heated at reflux for 61 hours and allowed to cool to room temperature. The volatiles were removed under reduced pressure. The residue was diluted with methanol, and silica gel was added. The mixture was concentrated under reduced pressure. The residue was purified by chromatography according to the method described in Example 59. The resulting foamy solid (1.55 g) was concentrated twice from acetonitrile and then triturated with acetonitrile (25 mL) to provide a solid. The solid was isolated by filtration, washed with acetonitrile, and dried in a vacuum oven at 65° C. to provide 887 mg of 1-[4-amino-2-(ethoxymethyl)-7-phenyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol as an off-white solid, mp 158-159° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH3:36])([CH3:35])[C@H:9]2[C@:22]([CH3:25])([CH2:23][CH:24]=1)[C@@H:21]1[C@:12]([CH3:34])([C@@:13]3([CH3:33])[C@H:18]([CH2:19][CH2:20]1)[C@H:17]1[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]1([NH2:32])[CH2:15][CH2:14]3)[CH2:11][CH2:10]2)(=O)=O.CC1(C)C(C)(C)OB([C:47]2[CH2:52][CH2:51][C:50]([C:53]([O:55][CH3:56])=[O:54])=[CH:49][CH:48]=2)O1>>[NH2:32][C@:16]12[CH2:28][CH2:27][C@@H:26]([C:29]([CH3:31])=[CH2:30])[C@@H:17]1[C@@H:18]1[C@@:13]([CH3:33])([CH2:14][CH2:15]2)[C@@:12]2([CH3:34])[C@@H:21]([C@:22]3([CH3:25])[C@@H:9]([CH2:10][CH2:11]2)[C:8]([CH3:35])([CH3:36])[C:7]([C:47]2[CH2:52][CH2:51][C:50]([C:53]([O:55][CH3:56])=[O:54])=[CH:49][CH:48]=2)=[CH:24][CH2:23]3)[CH2:20][CH2:19]1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: COC(=O)C1=CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Product: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC=C(C(=O)OC)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 60.8 %

Procedure:
The title compound was prepared following the method described in step 1 for the preparation of Example 1, using (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl trifluoromethanesulfonate and methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohexa-1,3-dienecarboxylate as the reactants. (60.8% yield). MS: m/e 529.5 (M−16)+, 2.816 min (method 8). 1H NMR (400 MHz, CHLOROFORM-d) δ 6.99 (d, J=5.8 Hz, 1H), 5.78 (d, J=5.8 Hz, 1H), 5.27 (dd, J=6.0, 1.8 Hz, 1H), 4.70 (d, J=2.0 Hz, 1H), 4.57 (d, J=1.3 Hz, 1H), 3.72 (s, 3H), 2.52 (td, J=10.8, 5.3 Hz, 1H), 2.48-2.39 (m, 1H), 2.36-2.29 (m, 1H), 2.09-1.95 (m, 2H), 1.76-1.20 (m, 22H), 1.66 (s, 3H), 1.05 (s, 3H), 0.98 (s, 3H), 0.94 (s, 6H), 0.86 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[CH:13]([NH:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[CH3:14].C(N(CC)CC)C.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1.ClCCl>O1CCOCC1.O>[CH3:29][O:30][C:31]1[CH:32]=[CH:33][C:34]([S:37]([N:19]2[CH2:20][CH2:21][CH:16]([NH:15][CH:13]([C:3]3[N:2]([CH3:1])[C:11](=[O:12])[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[N:4]=3)[CH3:14])[CH2:17][CH2:18]2)(=[O:39])=[O:38])=[CH:35][CH:36]=1
Reactant: CC(NC1CCNCC1)c1nc2ccccc2c(=O)n1C
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)N2CCC(NC(C)c3nc4ccccc4c(=O)n3C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Methyl-2-[1-(piperidin-4-ylamino)-ethyl]-3H-quinazolin-4-one (57.2 mg, 0.2 mmol) and triethylamine (167 μL, 0.4 mmol) were dissolved in dioxane (1 mL) and to this was added 4-methoxybenzenesulfonyl chloride (62 mg, 0.3 mmol). The reaction was shaken at room temperature overnight. Dichloromethane (2 mL) and water (2 mL) were added and the reaction tube was shaken. The top aqueous layer was aspirated off and the organic layer was concentrated in vacuo. The residue was dissolved in DMSO and purified by HPLC to yield the final product, 2-{1-[1-(4-Methoxy-benzenesulfonyl)-piperidin-4-ylamino]-ethyl}-3-methyl-3H-quinazolin-4-one. HPLC ret. time 2.23, 10-99% CH3CN, 5 min run; 1H NMR (CDCl3) δ 1.55 (d, 3H, J=6.6 Hz), 1.66 (q, 2H, J=12.1 Hz), 2.16 (m, 4H), 3.19 (m, 1H), 3.53 (s, 3H), 3.68 (m, 2H), 3.80 (s, 3H), 4.86 (q, 1H, J=5.7 Hz), 7.12 (d, 2H, J=9.0 Hz), 7.57 (t, 1H, J=8.1 Hz), 7.63 (d, 2H, J=8.9 Hz), 7.69 (d, 1H, J=7.7 Hz), 7.86 (t, 1H, J=8.4 Hz), 8.15 (dd, 1H, J=8.0, 1.2 Hz); ESI-MS m/z 457.4 (M+1)+.
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][CH2:4][C@@H:5]([O:7][C:8]1[CH:9]=[C:10]([CH:20]=[C:21]([OH:23])[CH:22]=1)[C:11]([NH:13][C:14]1[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=1)=[O:12])[CH3:6].[N:25]1([C:29]([C:31]2[CH:32]=[C:33]([Cl:38])[C:34](Cl)=[N:35][CH:36]=2)=[O:30])[CH2:28][CH2:27][CH2:26]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:25]1([C:29]([C:31]2[CH:32]=[C:33]([Cl:38])[C:34]([O:23][C:21]3[CH:20]=[C:10]([CH:9]=[C:8]([O:7][C@@H:5]([CH3:6])[CH2:4][O:3][CH:2]([F:1])[F:24])[CH:22]=3)[C:11]([NH:13][C:14]3[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=3)=[O:12])=[N:35][CH:36]=2)=[O:30])[CH2:28][CH2:27][CH2:26]1
Reactant: C[C@@H](COC(F)F)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Reactant: O=C(c1cnc(Cl)c(Cl)c1)N1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H](COC(F)F)Oc1cc(Oc2ncc(C(=O)N3CCC3)cc2Cl)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 160 °C
Reaction time: 3 h
Yield: 53.6 %

Procedure:
A mixture of 3-({(1S)-2-[(difluoromethyl)oxy]-1-methylethyl}oxy)-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide (110 mg, 0.32 mmol), 5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine (75 mg, 0.32 mmol) and potassium carbonate (89 mg, 0.64 mmol) in acetonitrile (5 mL) was stirred in a ‘Biotage initiator Microwave’ at 160° C. for 3 hours. The solvent was removed in vacuo and ethyl acetate (50 mL) added to the residue which was washed with water (20 mL), brine (50 mL), dried (MgSO4), filtered and the solvent removed in vacuo to give a yellow oil. The residue was chromatographed on silica, eluting with a gradient of 50-100% ethyl acetate in isohexane, to give the desired compound (92 mg). 1H NMR δ (CDCl3): 1.40 (d, 3H), 2.41 (quin, 2H), 3.81 (s, 3H), 4.01 (mult, 2H), 4.26 (t, 2H), 4.38 (t, 2H), 4.67 (sextet, 1H), 6.29 (t, 1H), 6.82 (d, 1H), 6.96 (t, 1H), 7.27 (t, 1H), 7.31 (d, 1H), 7.38 (t, 1H), 8.18 (d, 1H), 8.26 (d, 1H), 8.77 (s, 1H), m/z 536 (M+H)+
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:22](Cl)(=[O:24])[CH3:23].Cl>ClC(Cl)C>[OH:17][C:13]1[CH:14]=[CH:15][C:16]([C:22](=[O:24])[CH3:23])=[C:11]([NH:10][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:8])=[O:9])[CH:12]=1
Reactant: O=S(=O)(Nc1cccc(O)c1)c1ccccc1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CC(=O)c1ccc(O)cc1NS(=O)(=O)c1ccccc1

Procedure:
To 100 ml of dichloroethane were added 12.5 g of m-benzenesulfonamidophenol and 13.3 g of aluminum chloride and the resultant mixture was heated to 60° C. with stirring. To the mixture was added dropwise a solution of 3.6 ml of acetyl chloride dissolved in dichloroethane over a period of 2 hours followed by further heating to the same temperature for 2 hours. After allowing to cool, the mixture was placed in a hydrochloric acid acqueous solution and extracted with ethyl acetate. The extract was dried, concentrated and recrystallized from a mixture of hexane and ethyl acetate to provide 8.5 g of 4'-hydroxy-2'-benzenesulfonamidoacetophenone.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[N:5][NH:4][C:3]1=[O:7].[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=O)[CH:9]=1>Cl>[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=[N:1][N:2]2[CH:6]=[N:5][NH:4][C:3]2=[O:7])[CH:9]=1
Reactant: Nn1cn[nH]c1=O
Reactant: O=Cc1cccnc1
Agent: Cl
Product: O=c1[nH]ncn1N=Cc1cccnc1

Procedure:
A mixture of 4 g of 4-amino-1,2,4-triazol-3-one and 100 ml of alcohol is heated to the reflux temperature and 4.3 g of pyridine-3-carbaldehyde and 2 drops of 6N hydrochloric acid are added thereto. After 30 minutes under reflux the reaction mixture is cooled to 20°. The product that has precipitated is then filtered off with suction and dried under a high vacuum. 4.6 g of the title compound having a melting point of 264-265° are obtained.
Reaction SMILES: ClC(OCC(C)C)=O.CN1CCOCC1.[C:16]([Si:20]([CH3:29])([CH3:28])[O:21][CH2:22][C:23]#[C:24][C:25]([OH:27])=O)([CH3:19])([CH3:18])[CH3:17].[NH2:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[N:37]=[CH:36][C:35]([C:41]#[N:42])=[C:34]2[NH:43][C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([Br:50])[CH:45]=1>O1CCCC1.N1C=CC=CC=1.C(OCC)(=O)C>[Br:50][C:46]1[CH:45]=[C:44]([NH:43][C:34]2[C:33]3[C:38](=[CH:39][CH:40]=[C:31]([NH:30][C:25](=[O:27])[C:24]#[C:23][CH2:22][O:21][Si:20]([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:29])[CH3:28])[CH:32]=3)[N:37]=[CH:36][C:35]=2[C:41]#[N:42])[CH:49]=[CH:48][CH:47]=1
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Reactant: CC(C)(C)[Si](C)(C)OCC#CC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OCC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 34.8 %

Procedure:
Isobutyl chloroformate(0.214 g, 1.57 mmol) and N-methylmorpholine(0.190 g, 1.88 mmol) were added to an ice cold solution of 0.336 g (1.57 mmol) of 4(tert-butyl-dimethyl-silanyloxy)-2-butynoic acid in 15 mL of tetrahydrofuran under N2. After stirring for 30 min, it was transferred to an additional funnel plugged with a glass wool and added dropwise to a solution of 0.4 g (1.18 mmol) of 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile in 3 mL of tetrahydrofuran and 1.5 ml of pyridine. The mixture was stirred at 25° C. for 1 h. The reaction solution was poured into ethyl acetate and washed with saturated sodium bicarbonate and brine. The product was collected and purified by flash column chromatography (60% ethyl acetate in hexane) to give 0.220 g of N-[4-[(3-Bromophenyl)amino]-3-cyano-6-quinolinyl]-4-(tert-butyl-dimethyl-silanyloxy)-2-butynamide as a yellow solid (35%); ESMS m/z 535.1 (M+H+); mp ° C.(dec).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C@@H:17]1[O:28][C@:18]1([C:24]([O:26]C)=[O:25])[CH2:19][C:20]([O:22]C)=[O:21].CC1C=CC(S(N(N=O)C)(=O)=O)=CC=1.[OH-].[K+].CCOCC>OS(O)(=O)=O.O.CO.CCOCC>[C:24]([C@:18]1([OH:28])[C@@H:17]([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[O:22][C:20](=[O:21])[CH2:19]1)([OH:26])=[O:25]
Reactant: COC(=O)C[C@@]1(C(=O)OC)O[C@H]1CCCCCCCCc1ccc(Cl)cc1Cl
Agent: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CCOCC
Product: O=C1C[C@](O)(C(=O)O)[C@@H](CCCCCCCCc2ccc(Cl)cc2Cl)O1
Yield: 67.4 %

Procedure:
±(3R*,4S*) Methyl 12-(2,4-dichlorophenyl)-3,4-epoxy-3-methoxycarbonyldodecanoate (314 mg, 0.728 mmol) was heated at reflux in aqueous H2SO4 (7.5M) for 3.5 h. The solution was diluted with water, and extracted with ether. The extracts were washed with water, saturated aqueous NaCl, and dried (MgSO4). The solvent was removed under vacuum. Diazomethane, generated from diazald (450 mg, 2.10 mmol) and aqueous KOH (10.7M), was passed in a stream of ether saturated nitrogen through a solution of the crude acid in 10% methanol/ether (10 ml) until a yellow colouration was seen in the reaction flask. Excess diazomethane was quenched with acetic acid, then the solvent removed under vacuum. The residue was purified by chromatography on silica gel (50-80% ether/petroleum ether 40°-60° C.) to give the title compound (198 mg, 65%) as an oil.