Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][O:8][C:9]2[C:10](=[O:17])[CH:11]=[C:12]([CH2:15]Cl)[O:13][CH:14]=2)=[CH:5][CH:4]=1.[I-].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]2[C:10](=[O:17])[CH:11]=[C:12]([CH3:15])[O:13][CH:14]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(COc2coc(CCl)cc2=O)cc1
Agent: [I-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)=O
Product: COc1ccc(COc2coc(C)cc2=O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5-p-Methoxybenzyloxy-2-chloromethyl-4-pyrone, 10 g, was dissolved in 100 ml of acetone and, 5.5 g of sodium iodide and 11.6 g of triphenylphosphine were added to the solution followed by stirring at room temperature for 3 hours. After completion of the reaction, the reaction liquid was concentrated to dryness and the residue was added to 50 ml of water and 100 ml of dichloromethane. Under ice cooling, the pH was adjusted to 7.0 with saturated sodium hydrogencarbonate aqueous solution and the mixture was stirred at the same temperature for 30 minutes. The organic phase was washed with 20 ml of water. After drying over anhydrous magnesium sulfate, the organic phase was concentrated under reduced pressure and purified by flash column chromatography (eluting solution; chloroform: methanol=20:1) using Wako Gel C-300 (500 g) to give 8.2 g of the title compound.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3[CH2:20][C@H:19]([N:21]4[N:25]=[N:24][C:23]([CH2:26][CH3:27])=[N:22]4)[C@@H:18]([OH:28])[C@H:17]3[OH:29])=[C:9]([NH:30][CH2:31][CH:32]([C:40]3[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=3)[C:33]3[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=3)[N:8]=2)[CH2:3]1.C1(C(C2C=CC=CC=2)CNC2N=C(N3CC[C@@H](N[C:71]([NH:73][C:74]4[CH:75]=[N:76][CH:77]=[CH:78][CH:79]=4)=[O:72])C3)N=C3C=2N=CN3[C@@H]2C[C@H](N3N=NC(CC)=N3)[C@@H](O)[C@H]2O)C=CC=CC=1>>[OH:46][C:43]1[CH:44]=[CH:45][C:40]([CH:32]([C:33]2[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=2)[CH2:31][NH:30][C:9]2[N:8]=[C:7]([N:4]3[CH2:5][CH2:6][C@@H:2]([NH:1][C:71]([NH:73][C:74]4[CH:75]=[N:76][CH:77]=[CH:78][CH:79]=4)=[O:72])[CH2:3]3)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[C@@H:16]2[CH2:20][C@H:19]([N:21]3[N:25]=[N:24][C:23]([CH2:26][CH3:27])=[N:22]3)[C@@H:18]([OH:28])[C@H:17]2[OH:29])=[CH:41][CH:42]=1
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccc(O)cc5)c5ccc(O)cc5)nc(N5CC[C@@H](N)C5)nc43)[C@H](O)[C@@H]2O)n1
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)Nc6cccnc6)C5)nc43)[C@H](O)[C@@H]2O)n1
Product: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccc(O)cc5)c5ccc(O)cc5)nc(N5CC[C@@H](NC(=O)Nc6cccnc6)C5)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
This compound is prepared from (1R,2S,3R,5S)-3-{2-((R)-3-amino-pyrrolidin-1-yl)-6-[2,2-bis-(4-hydroxy-phenyl)-ethylamino]-purin-9-yl}-5-(5-ethyl-tetrazol-2-yl)-cyclopentane-1,2-diol (Example 106) using a procedure analogous to that of 1-((R)-1-{6-(2,2-diphenyl-ethylamino)-9-[(1R,2S,3R,4S)-4-(5-ethyl-tetrazol-2-yl)-2,3-dihydroxy-cyclopentyl]-9H-purin-2-yl}-pyrrolidin-3-yl)-3-pyridin-3-yl-urea (Example 105). MS (ES+) m/e 748.41 (MH+).
Reaction SMILES: [F:1][C:2]([F:28])([C:5]([F:27])([F:26])[C:6]([F:25])([F:24])[C:7]([F:23])([F:22])[C:8]([F:21])([F:20])[C:9]([F:19])([F:18])[C:10]([F:17])([F:16])[C:11]([F:15])([F:14])[CH2:12][OH:13])[CH2:3][OH:4].[OH-].[K+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C>[CH2:31]([O:13][CH2:12][C:11]([F:15])([F:14])[C:10]([F:16])([F:17])[C:9]([F:18])([F:19])[C:8]([F:20])([F:21])[C:7]([F:22])([F:23])[C:6]([F:25])([F:24])[C:5]([F:26])([F:27])[C:2]([F:28])([F:1])[CH2:3][OH:4])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CO
Reactant: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)COCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A dry 5 mL round bottom flask was charged with 2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9-hexadecafluorodecane-1,10-diol (2.2 mmol, 1.0 g), dry DMF (2.5 mL), and crushed potassium hydroxide (2.2 mmol, 121 mg). The mixture was flushed with argon and benzyl bromide (0.7 mmol, 123 mg) was added dropwise over 15 minutes. The solution was allowed to stir overnight at room temperature under argon. The reaction mixture was concentrated in vacuo, and the residue was partitioned between aqueous saturated ammonium chloride and ethyl acetate. The aqueous layer was extracted twice with EtOAc. The organic layers were combined, washed with water then brine, dried over MgSO4, and concentrated in vacuo. The residue was purified via flash column chromatography on silica gel using 5% EtOAc in petroleum ether as the eluent. The product was isolated as colorless oil; upon drying under high vacuum for 12 h, the oil solidified (90%). 1H NMR (CDCl3): δ7.36 (m, 5H), 4.68 (s, 2H), 4.10 (td, 2H, J=14, 6), 3.94 (t, 2H, J=14), 1.96 (t, 1H, J=7); 13C NMR (CDCl3): δ136.6, 128.8, 128.5, 128.0, 74.7, 66.9, 60.9; 19F NMR (CDCl3): δ −119.8, −122.3, −122.8, −123.7, −123.9.
Reaction SMILES: [CH3:1][O:2][CH2:3]OCOC.[C:8]([C:12]1[CH:17]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])C=[C:14]([Br:22])[CH:13]=1)([CH3:11])([CH3:10])[CH3:9].C(Cl)OC.COS(OC)(=O)=O.C(C1C=C(C(C)(C)C)C=CC=1O)(C)(C)C>>[CH3:1][O:2][C:3]1[C:14]([Br:22])=[CH:13][C:12]([C:8]([CH3:10])([CH3:9])[CH3:11])=[CH:17][C:16]=1[C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: COCOCOC
Reactant: CC(C)(C)c1cc(Br)cc(C(C)(C)C)c1
Agent: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Agent: COCCl
Solvent: COS(=O)(=O)OC
Product: COc1c(Br)cc(C(C)(C)C)cc1C(C)(C)C
Yield: 92 %

Procedure:
A procedure analogous the synthesis of 1-methoxymethylether-2,4-di-t-butyl-6-bromobenzene was employed. The MOMCl was replaced with Me2SO4 as alkylating agent. Starting from 20 g of 2,4-di-t-butyl-phenol, 26.8 g (92% yield over two steps) of 1-methoxy-2,4-di-t-butyl-6-bromobenzene were obtained. 1H NMR (300 MHz, CDCl3) δ: 1.30 (s, 9H, C(CH3)3), 1.41 (s, 9H, C(CH3)3), 3.92 (s, 3H, OCH3), 7.29 (d, 2H, aryl-H, 4J=2.3 Hz), 7.42 (d, 2H, aryl-H, 4J=2.3 Hz). 13C NMR (75 MHz, CDCl3) δ: 31.1 (C(CH3)3), 31.6 (C(CH3)3), 34.8 (C(CH3)3), 35.9 (C(CH3)3), 61.5 (OCH3), 117.8, 123.8, 129.0, 144.2, 147.4, 154.3 (aryl). GC-MS: M+=298.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH2:9]([C@:11]12[CH2:35][CH2:34][C:33](=[O:36])[CH2:32][C@H:12]1[CH2:13][CH2:14][O:15][C:16]1[C:17]2=[CH:18][C:19]2[CH:20]=[N:21][N:22]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([CH3:31])[CH:26]=3)[C:23]=2[CH:24]=1)[CH3:10]>CS(C)=O.C1COCC1>[CH2:9]([C:11]12[CH2:35][CH2:34][C:33]3([CH2:4][O:36]3)[CH2:32][CH:12]1[CH2:13][CH2:14][O:15][C:16]1[C:17]2=[CH:18][C:19]2[CH:20]=[N:21][N:22]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([CH3:31])[CH:26]=3)[C:23]=2[CH:24]=1)[CH3:10]
Reactant: CC[C@]12CCC(=O)C[C@H]1CCOc1cc3c(cnn3-c3ccnc(C)c3)cc12
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCC12CCC3(CO3)CC1CCOc1cc3c(cnn3-c3ccnc(C)c3)cc12
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 82.1 %

Procedure:
A 100 mL round-bottom flask equipped with rubber septum and nitrogen inlet needle was charged with sodium hydride (60 wt % in oil, 0.212 g, 5.29 mmol) in DMSO (13 mL) and then the mixture was heated at about 60° C. in a heating block for about 30 min. The mixture was allowed to cool to rt, at which point trimethylsulfoxonium iodide (1.16 g, 5.29 mmol) was added in one portion and the reaction mixture was stirred for about 15 min. A solution of rac-(4aR,12bS)-12b-ethyl-9-(2-methylpyridin-4-yl)-4,4a,5,6,9,12b-hexahydro-1H-benzo[4,5]oxepino[3,2-f]indazol-3 (2H)-one (92, R1=2-methylpyridin-4-yl, R2=Ethyl) (0.993 g, 2.64 mmol) in THF (13 mL) was added in one portion. After about 30 min the reaction was concentrated under reduced pressure and the residue was partitioned between EtOAc (50 mL) and water (50 mL). The layers were separated and the aqueous phase was extracted with EtOAc (2×10 mL). The combined organic phases were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was purified on silica gel (40 g, EtOAc). Collection and concentration of the appropriate fractions gave rac-(2′R,4aS,12bR)-12b-ethyl-9-(2-methylpyridin-4-yl)-1,2,4,4a,5,6,9,12b-octahydrospiro[benzo[4,5]oxepino[3,2-f]indazole-3,2′-oxirane] (93, R1=2-methylpyridin-4-yl, R2=Ethyl) (0.844 g, 82%). LC/MS, method 3, Rt=2.40 min, MS m/z 390 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.61-8.55 (m, 1H), 8.23 (s, 1H), 7.91-7.76 (m, 2H), 7.69 (s, 1H), 7.56 (s, 1H), 4.43-4.31 (m, 1H), 3.84-3.71 (m, 1H), 2.98-2.70 (m, 3H), 2.71-2.56 (m 2H), 2.56-2.16 (m, 4H), 2.07-1.93 (m, 1H), 1.93-1.77 (m, 1H), 1.73-1.33 (m, 4H), 0.97-0.83 (m, 1H), 0.74-0.56 (t, J=7.5 Hz, 3H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8]/[N:9]=[CH:10]/[C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[C:14]([N:21]4[CH2:26][CH2:25][CH:24]([CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:23][CH2:22]4)[CH:15]=[CH:16][CH:17]=3)[N:12]=2)[CH:3]=1.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>>[I:1][C:2]1[CH:7]=[CH:6][N:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:18]4[C:13](=[C:14]([N:21]5[CH2:22][CH2:23][CH:24]([CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:34])[CH3:33])[CH2:25][CH2:26]5)[CH:15]=[CH:16][CH:17]=4)[N:12]=3)=[N:9][N:8]=[C:4]2[CH:3]=1
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2cccc3ccc(/C=N/Nc4cc(I)ccn4)nc23)CC1
Solvent: Ic1ccccc1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCC1CCN(c2cccc3ccc(-c4nnc5cc(I)ccn45)nc23)CC1
Reaction time: 2 h

Procedure:
To (E)-tert-butyl (1-(2-((2-(4-iodopyridin-2-yl)hydrazono)methyl)quinolin-8-yl)piperidin-4-yl)methylcarbamate (178 mg, 0.304 mmol) was added iodobenzene diacetate (IBD) (127 mg, 0.395 mmol). The reaction was stirred for 2 hours. Additional IBD (0.5 eq) was added and the reaction was stirred for another 2 hours and then quenched with saturated Na2S2O3 (5 mL). The organic layer was extracted with DCM, dried (Na2SO4) and concentrated. The crude material was purified by silica gel chromatography (EtOAc/Hexane/MeOH 2:1:0.1) to provide the final product.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:10]([CH2:11][OH:12])=[CH:9][N:8]=[C:7]([S:13][CH3:14])[N:6]=1)([CH3:3])[CH3:2]>C(Cl)Cl.[O-2].[Mn+4].[O-2]>[CH:1]([NH:4][C:5]1[C:10]([CH:11]=[O:12])=[CH:9][N:8]=[C:7]([S:13][CH3:14])[N:6]=1)([CH3:3])[CH3:2]
Reactant: CSc1ncc(CO)c(NC(C)C)n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CSc1ncc(C=O)c(NC(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
To a solution of (4-(isopropylamino)-2-(methylthio)pyrimidin-5-yl)methanol (13.5 g, 63.4 mmol) in DCM (100 mL) was added manganese(IV) oxide (45 g, 0.5 mol), and the mixture was stirred at RT overnight. The reaction mixture was filtered and the filtrate was concentrated to give the 4-(isopropylamino)-2-(methylthio)pyrimidine-5-carbaldehyde (12.2 g, 91% yield), which was used in the next step without further purification. 1HNMR (400 MHz, DMSO-d6): δ 9.71 (s, 1 H), 8.50 (s, 1 H), 8.41 (d, J=7.2 Hz, 1 H), 4.33 (m, 1 H), 2.47 (s, 3 H), 1.21 (d, J=6.4 Hz, 6 H).
Reaction SMILES: [F:1][C:2]1([F:8])[CH2:4][CH:3]1[C:5](O)=[O:6].C(N1C=CN=C1)(N1C=CN=C1)=O.O[N:22]=[C:23]([C:25]1[CH:26]=[CH:27][C:28]([CH3:43])=[C:29]([NH:31][C:32]([C:34]2[N:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]3=[N:36][CH:35]=2)=[O:33])[CH:30]=1)[NH2:24]>CN1C(=O)CCC1>[F:1][C:2]1([F:8])[CH2:4][CH:3]1[C:5]1[O:6][N:22]=[C:23]([C:25]2[CH:26]=[CH:27][C:28]([CH3:43])=[C:29]([NH:31][C:32]([C:34]3[N:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]4=[N:36][CH:35]=3)=[O:33])[CH:30]=2)[N:24]=1
Reactant: Cc1ccc(C(N)=NO)cc1NC(=O)c1cnc2ccccn12
Reactant: O=C(O)C1CC1(F)F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN1CCCC1=O
Product: Cc1ccc(-c2noc(C3CC3(F)F)n2)cc1NC(=O)c1cnc2ccccn12
Temperature: 120 °C
Reaction time: 0.05 h

Procedure:
To a stirring solution of 2,2-difluorocyclopropanecarboxylic acid (325 mg, 2.66 mmol) in anhydrous NMP (7 mL) was added 1,1′-carbonyldiimidazole (CDI) (432 mg, 2.66 mmol). The reaction was stirred for 3 minutes. N-(5-(N′-hydroxycarbamimidoyl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (9) (825 mg, 2.66 mmol) was added and the reaction was stirred for 25 minutes. Then, the reaction was heated at 120° C. for minutes. The crude product was purified on silica gel using 10% MeOH in dichloromethane to give N-(5-(5-(2,2-difluorocyclopropyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (F64). 1H NMR (400 MHz, d6-DMSO) δ 9.60 (d, J=7.2 Hz, 1H), 8.56 (d, J=1.6 Hz, 1H), 8.51 (s, 1H), 8.12 (bs, 1H), 7.87 (dd, J=2.0, 7.8 Hz, 1H), 7.82 (d, J=9.2 Hz, 1H), 7.58-7.53 (m, 1H), 7.44 (d, J=8.0 Hz, 1H), 7.16 (td, J=0.8, 6.8 Hz, 1H), 3.19-3.12 (m, 1H), 2.48 (s, 3H), 2.45-2.36 (m, 1H), 2.27-2.18 (m, 1H). MS m/z 396.1 (M+1)+.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([O:13]C(=O)C)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[N:7]=1)=[N+:2]=[N-:3].C([O-])([O-])=O.[K+].[K+]>CO>[N:1]([CH2:4][C@H:5]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[N:7]=1)[OH:13])=[N+:2]=[N-:3]
Reactant: CC(=O)O[C@H](CN=[N+]=[N-])c1cccc(C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1cccc([C@H](O)CN=[N+]=[N-])n1
Reaction time: 2 h
Yield: 100.9 %

Procedure:
Dissolved acetic acid (R)-2-azido-1-(6-methyl-pyridin-2-yl)-ethyl ester (2.20 g, 9.90 mmol) into 50 mL of MeOH. To this was added K2CO3 (1.50 g) and the heterogenous mixture stirred for 2 h. LC-MS analysis indicated completion of the reaction. The mixture was concentrated and 100 mL of H2O was added. The mixture was extracted with 2×100 mL of CH2Cl2, dried with MgSO4, filtered and concentrated to give 1.78 g of (R)-2-azido-1-(6-methyl-pyridin-2-yl)-ethanol. ee % >99.
Reaction SMILES: [C:1]1([CH2:7][S:8](Cl)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:19])[NH:13]1.C(N(CC)CC)C>C(Cl)Cl>[CH2:7]([S:8]([N:13]1[CH:14]([C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:19])[CH2:15][CH2:16][CH2:17][NH:12]1)(=[O:10])=[O:9])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(OCCCCc1ccccc1)C1CCCNN1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCCCCc1ccccc1)C1CCCNN1S(=O)(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
A solution of α-toluene sulfonyl chloride (1.12 g, 5.77 mmol) in CH2Cl2 was added to a CH2Cl2 solution containing 4-phenylbutyl perhydropyridazinecarboxylate (1.37 g, 5.2 mmol) and triethylamine (0.83 ml, 6 mmol). The reaction was stirred overnight at room temperature under nitrogen atmosphere, and then diluted to 50 ml CH2Cl2. The organic layer was washed with water, dried, and concentrated. The crude material was purified by silica gel column to yield 1.4 g (64%) final product as clear oil. Rf=0.60 (2:1 hexane:EtOAc). 1H NMR (CDCl3, 400 MHz): δ 1.68 (m, 8H); 2.67 (m, 2H); 2.90 (m, 1H); 3.38 (m, 2H); 4.22 (m, 5H); 7.32 (m, 10H). Anal. Calcd. for C22H28N2S1O4: C, 63.44; H, 6.78; N, 6.73, S, 7.70. Found: C, 63.86; H, 6.83; N, 6.41, S, 7.58.
Reaction SMILES: C(O)C.[Cl:4][C:5]1[C:10]([CH3:11])=[C:9](Br)[CH:8]=[C:7]([S:13]([CH3:16])(=[O:15])=[O:14])[C:6]=1[CH3:17].C([O-])(=O)C.[Na+].[H][H]>[Pd].O>[Cl:4][C:5]1[C:6]([CH3:17])=[C:7]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:8]=[CH:9][C:10]=1[CH3:11]
Reactant: Cc1c(Br)cc(S(C)(=O)=O)c(C)c1Cl
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(S(C)(=O)=O)c(C)c1Cl
Temperature: 25 °C
Reaction time: 7 h

Procedure:
30 ml of ethanol was added to 1.0 g of the crude 2-chloro-4-bromo-6-methylsulfonyl-m-xylene obtained in Example 2, and 0.1 g of 5% palladium active carbon and 1.0 g of anhydrous sodium acetate were further added thereto. The reactor was sealed, and was substituted with hydrogen, then stirring at room temperature for 7 hours. 30 ml of water was added to the reaction liquor, and was concentrated under reduced pressure. 30 ml of EDC was further added thereto, and the resultant mixture was filtered. The EDC layer was taken out from the filtrate, and was washed with 20 ml of water and then with 10 ml of a saturated aqueous solution of common salt, and was dried over anhydrous sodium sulfate. The EDC layer thus obtained was concentrated under reduced pressure and was dried to a solid to obtain 0.7 g of a crude product of the above-identified aimed compound (purity measured by gas chromatography: 75.6%). The crude product thus obtained was recrystallized by methanol to obtain the above-identified aimed compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][C:19]([CH3:22])([OH:21])[CH3:20])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[Li+].CCC[CH2-].C(N(CC)CC)C.[CH2:35]([O:37][P:38](Cl)([O:40][CH2:41][CH3:42])=[O:39])[CH3:36]>C1COCC1.CCCCCC.O>[CH2:35]([O:37][P:38](=[O:39])([O:40][CH2:41][CH3:42])[O:21][C:19]([CH3:22])([CH3:20])[C:18]#[C:17][C:15]1[CH:14]=[CH:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)=[N:9][S:10][C:11]=2[CH:16]=1)[CH3:36]
Reactant: CCOP(=O)(Cl)OCC
Reactant: CC(C)(O)C#Cc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CCOP(=O)(OCC)OC(C)(C)C#Cc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 32.8 %

Procedure:
200 mg (0.54 mmol) 4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-2-methyl-but-3-yn-2-ol in 2 ml THF were treated with 36 μl (5.6 mmol) 1.6 M N-Butyllithium in hexane at −78° C. for 30 min. 112 μl (0.81 mmol, 1.5 eq) Triethylamine in 0.5 ml THF and 117 μl (0.8 mmol, 1.5 eq) Diethylchlorophosphate in 0.5 ml THF were added and the solution was stirred at −78° C. over night and at 0° C. for 4 h. Water was added, and the inorganic phase was extracted with EtOAc, the combined organic phases were washed with brine and dried over Na2SO4. Column chromatography on silica gel with hexane:EtOAc 3:1 gave 90 mg (33%) Phosphoric acid 3-[3-(4-bromo-phenyl)-benzo[d]isothiazol-6-yl]-1,1-dimethyl-prop-2-ynyl ester diethyl ester as yellow semisolid, MS: 508 (MH+, 1Br).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:31]=[C:30]([CH3:32])[C:29]([O:33]C(OC)=O)=[CH:28][C:5]=1[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18](=[O:27])[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:14][CH:15]=2)[N:10]=[CH:9][N:8]=1.Cl>CO.O>[F:3][C:4]1[CH:31]=[C:30]([CH3:32])[C:29]([OH:33])=[CH:28][C:5]=1[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18](=[O:27])[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:14][CH:15]=2)[N:10]=[CH:9][N:8]=1
Reactant: COC(=O)Oc1cc(Nc2ncnc3cc(NC(=O)CCN4CCOCC4)ccc23)c(F)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(F)c(Nc2ncnc3cc(NC(=O)CCN4CCOCC4)ccc23)cc1O
Reaction time: 1 h
Yield: 80 %

Procedure:
2M Aqueous sodium hydroxide solution (453 μl, 0.9 mmol) was added to a suspension of 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-(3-morpholinopropionamido)quinazoline (219 mg, 0.45 mmol) in methanol (6 ml) and the mixture stirred for 1 hour. The reaction mixture was diluted with water and then adjusted to pH6 with 2M hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and ethanol, and dried. The solid was dissolved in methylene chloride/methanol and a 5M solution of hydrogen chloride in isopropanol (0.3 ml) added. The volatiles were removed by evaporation, the resulting solid was washed with ether, and dried under vacuum to give 4-(2-fluoro-5-hydroxy-4-methylanilino)-7-(3-morpholinopropionamido)quinazoline (1-86 mg, 80%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[C:21]([OH:22])=[CH:20][C:19]3[C:18]([CH3:24])([CH3:23])[CH2:17][CH2:16][C:15]([CH3:26])([CH3:25])[C:14]=3[CH:13]=2)=[O:11])=[CH:6][CH:5]=1.[Br:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1>>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[C:21]([O:22][CH2:33][C:32]3[CH:35]=[CH:36][C:29]([Br:28])=[CH:30][CH:31]=3)=[CH:20][C:19]3[C:18]([CH3:23])([CH3:24])[CH2:17][CH2:16][C:15]([CH3:26])([CH3:25])[C:14]=3[CH:13]=2)=[O:11])=[CH:6][CH:5]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: COC(=O)c1ccc(C(=O)c2cc3c(cc2O)C(C)(C)CCC3(C)C)cc1
Product: COC(=O)c1ccc(C(=O)c2cc3c(cc2OCc2ccc(Br)cc2)C(C)(C)CCC3(C)C)cc1
Yield: 60 %

Procedure:
The 4-[(3-hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid methyl ester (from Example 7) was alkylated with 4-bromobenzylbromide as described for Example 60 to give 4-[(3-(4-bromobenzyloxy)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid methyl ester (60%): 1H NMR (400 MHz, CDCl3) δ 8.03 (1/2ABq, 2H, J=8.4 Hz, ArH), 7.80 (1/2ABq, 2H, J=8.4 Hz, ArH), 7.46 (s, 1H, ArH), 7.29 (1/2ABq, 2H, J=8.4 Hz, ArH), 6.87 (s, 1H, ArH), 6.81 (1/2ABq, 2H, J=8.4 Hz, ArH), 4.87 (s, 2H, OCH2), 3.97 (s, 3H, OCH3), 1.70 (m, 4H, 2CH2), 1.30 (s, 6H, 2CH3), 1.27 (s, 6H, 2CH3).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]2[C:9]([C:12]3[CH:13]=[C:14]([NH:18][C:19]([NH:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[O:20])[CH:15]=[CH:16][CH:17]=3)=[CH:10][N:11]=[C:5]2[CH:4]=1)#[N:2].[N-:27]=[N+:28]=[N-:29].[Na+].[Cl-].[NH4+]>CN(C=O)C>[N:2]1[NH:27][N:28]=[N:29][C:1]=1[C:3]1[CH:8]=[CH:7][N:6]2[C:9]([C:12]3[CH:13]=[C:14]([NH:18][C:19]([NH:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[O:20])[CH:15]=[CH:16][CH:17]=3)=[CH:10][N:11]=[C:5]2[CH:4]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccn2c(-c3cccc(NC(=O)NCC(F)(F)F)c3)cnc2c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4nn[nH]n4)ccn23)c1
Temperature: 90 °C
Yield: 19.3 %

Procedure:
1-[3-(7-Cyano-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea (65 mg, 0.18 mmol), sodium azide (14 mg, 0.19 mmol) and ammonium chloride (11 mg, 0.20 mmol) were dissolved in DMF (2 ml) and heated at 90° C. for 18 h. The reaction mixture was cooled, the solvent removed in vacuo and the crude reaction mixture purified using reverse phase HPLC. This afforded the title compound as a white solid (14 mg). MS: [M+H]+ 403.
Reaction SMILES: N#N.[N+:3]([CH2:6][CH2:7][CH2:8][C:9](=[O:11])[CH3:10])([O-:5])=[O:4].[CH2:12](O)[CH2:13][OH:14].CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[CH3:10][C:9]1([CH2:8][CH2:7][CH2:6][N+:3]([O-:5])=[O:4])[O:14][CH2:13][CH2:12][O:11]1
Reactant: OCCO
Reactant: CC(=O)CCC[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N#N
Agent: O=C([O-])O
Solvent: Cc1ccccc1
Product: CC1(CCC[N+](=O)[O-])OCCO1
Temperature: 120 °C
Reaction time: 5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and a Dean-Stark apparatus and under inert atmosphere (N2), crude 5-nitro-pentan-2-one (28.53 mmol) was dissolved in dry toluene (28 mL). Ethylene glycol (10.2 mL, 183.02 mmol) and p-TsOH (696 mg, 3.66 mmol) were added and the reaction mixture stirred at 120° C. for 5 h. The reaction mixture was then cooled down to rt and sat. aq. NaHCO3 was added. The layers were separated and the org. layer washed with brine (2×), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by FC (hept-EA, 4:1) to give the title compound as a pale brown oil. TLC:rf (4:1 hept-EA)=0.21.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:14][C:15]([CH3:19])=[N:16]2)=[CH:11][C:10]=1[Br:25])C1C=CC=CC=1.[Na]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[Br:25][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:9]=1[OH:8])[N:16]=[C:15]([CH3:19])[CH:14]=[C:13]2[N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Cc1cc(N2CCCC2)c2cc(Br)c(OCc3ccccc3)cc2n1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na]
Solvent: ClCCl
Product: Cc1cc(N2CCCC2)c2cc(Br)c(O)cc2n1
Reaction time: 1 h
Yield: 63.5 %

Procedure:
To a cooled (0° C.) solution of 7-benzyloxy-6-bromo-2-methyl-4-pyrrolidin-1-yl-quinoline (2.3 g, 5.79 mmol) in dichloromethane (70 mL) was added a 1M solution of titanium tetrachloride in dichloromethane (48.6 mL, 48.6 mmol) within 20 min. After 1 h, the reaction mixture was poured onto an aqueous solution of sodium hydrogenocarbonate, extracted with dichloromethane and evaporated. 1.13 g of the title compound was obtained. Yellow solid, ISP-MS: m/e=308.1 ([M+H]+).