Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:15]3[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:8][CH:7]=1.[OH-].[K+]>C1COCC1.CO>[CH2:21]([N:17]1[C:18]2[C:14](=[CH:13][C:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:39])=[O:2])=[CH:7][CH:8]=3)=[CH:20][CH:19]=2)[C:15]([CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[C:16]1[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCCCCc1c(-c2ccccc2)n(Cc2ccccc2)c2ccc(-c3ccc(OCC(=O)OC)cc3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCc1c(-c2ccccc2)n(Cc2ccccc2)c2ccc(-c3ccc(OCC(=O)O)cc3)cc12

Procedure:
The desired product was prepared using a procedure similar to step 2 of example 4. Thus, [4-(1-benzyl-3-pentyl-2-phenyl-1H-indol-5-yl)-phenoxy]-acetic acid methyl ester (0.281 g, 0.543 mmol) was reacted with 1N KOH (1.1 ml) in THF/MeOH (6 ml/4 ml) to give the product (0.177 g, 0.351 mmol, 65%) as a white solid, mp 141-143° C. 1H NMR (DMSO-d6) δ 0.76 (t, J=6.7 Hz, 3H), 1.13-1.22 (m, 4H), 1.53-1.59 (m, 2H), 2.68 (t, J=7.6 Hz, 2H), 4.69 (s, 2H), 5.27 (s, 2H), 6.84 (d, J=7.5 Hz, 2H), 6.98 (d, J=8.7 Hz, 2H), 7.14 (t, J=7.2 Hz, 1H), 7.20 (t, J=7.0 Hz, 2H), 7.33-7.38 (m, 4H), 7.43 (t, J=7.2 Hz, 1H), 7.48 (t, J=6.9 Hz, 2H), 7.59 (d, J=8.6 Hz, 2H), 7.75 (s, 1H), 13.00 (broad s, 1H); IR (solid) 3030, 2910, 2860, 1750, 1605, 1520, 1470, 1440, and 1230 cm−1; [ESI(−)], m/z 503 (M−H)−; Anal. Calcd. for C34H33NO3.0.25H2O: C, 80.37; H, 6.64; N, 2.76; Found: C, 80.55, H, 6.58; N, 2.70.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Br:13])C>ClC1C=CC=CC=1>[Br:13][C:8]1[C:7]2[S:6][CH:5]=[CH:4][C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(CSc1ccccc1Br)OCC
Solvent: Clc1ccccc1
Product: Brc1cccc2ccsc12
Yield: 93.2 %

Procedure:
Chlorobenzene (100 mL) and polyphosphoric acid (30.4 g, PPA) were combined and heated to reflux. The 2-(2-bromophenylthio) acetaldehyde diethyl acetal (13.7 g, 44.88 mmol, Scheme I, step A above) dissolved in chlorobenzene (20 mL) was added dropwise to the refluxing mixture over 20 minutes. The reaction was refluxed for 4 hours and then cooled. The solvent was decanted from the residue and toluene (2×50 mL) was added to the residue, stirred and decanted. The chlorobenzene/toluene extracts were concentrated under vacuum and the residue taken up in ethyl acetate and water. The organic phase was washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated to provide 7-bromobenzo(b)thiophene (8.91 g, 93%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:5][CH:4]=1.N1C(C)=CC=CC=1C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[CH3:21][S:22]([O:1][CH2:2][C:3]1[O:7][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:5][CH:4]=1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1ccc(CO)o1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(COS(C)(=O)=O)o1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 93.1 %

Procedure:
To a 0° C. solution of 5-hydroxymethyl-2-carboethoxyfuran (2.94 g, 17.3 mmol), prepared as in step 1, in CH2Cl2 (50 mL) was added 2,6-lutidine (2.50 mL, 21.5 mmol) and methanesulfonyl chloride (1.50 mL, 19.0 mmol). The reaction mixture was stirred for 40 min at 0° C., then the cold bath was removed and stirring was continued for 2 hours. The reaction mixture was extracted with 1N aqueous HCl and saturated aqueous NaHCO3, and the organic phase was dried over MgSO4, filtered, and concentrated in vacuo to give 5-methanesulfonyloxymethyl-2-carboethoxyfuran (4.0 g) as a yellow oil which was used without further purification.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].[NH2:30][CH2:31][CH:32]1[CH2:36][CH2:35][CH2:34][N:33]1[CH2:37][CH2:38][CH3:39]>C(Cl)(Cl)Cl.O>[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([S:20]([NH:30][CH2:31][CH:32]4[CH2:36][CH2:35][CH2:34][N:33]4[CH2:37][CH2:38][CH3:39])(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(Nc2ccnc3cc(Cl)ccc23)cc1
Reactant: CCCN1CCCC1CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCN1CCCC1CNS(=O)(=O)c1ccc(Nc2ccnc3cc(Cl)ccc23)cc1
Temperature: 25 °C
Yield: 28 %

Procedure:
4-(7-Chloro-4-quinolinylamino)benzenesulphonyl chloride hydrochloride (5.4 g, 0.014 mol) was added portionwise to a well-stirred two phase mixture of chloroform/water (140 ml/140 ml) containing sodium carbonate (14.8 g) and 2-aminomethyl-1-propylpyrrolidine (2.0 g, 0.014 mol) at about 10° C. The mixture was allowed to warm to room temperature, then stirred for 11/2 hours. The chloroform layer was separated, dried (MgSO4) and evaporated under reduced pressure to give a gum. The gum was crystallised from ethanol/water to give a pale yellow solid (1.8 g). A further recrystallisation from ethanol gave the title compound (0.5 g), melting point 192.5°-194° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14][O:15][CH3:16].[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[Sn](CCCC)(CCCC)CCCC>CN(C)C=O.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:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14][O:15][CH3:16]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: COC=C1C(=O)NC(=O)c2ccc(-c3ccco3)cc21
Temperature: 100 °C
Yield: 67.5 %

Procedure:
6-Bromo-4-methoxymethylene-4H-isoquinoline-1,3-dione (1.24 g, 4.4 mmol) and PdCl2(PPh3)2 (200 mg, 0.28 mmol) and 2-furyltributyltin (2 g, 5.6 mmol) in N,N-dimethylformamide (20 mL) is degassed and heated at 100° C. for 1 hour. Upon cooling to room temperature, the product precipitated out. After filtration, the precipitate is washed with Et2O and dried to provide the desired product (800 mg, 68%). MS (ESI): 270.1 (M+1)+1.
Reaction SMILES: Cl.[CH2:2]([C:4]1[N:5]=[C:6]([CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[S:18][C:14]=3[C:13](=[O:25])[N:12]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:11]2=[O:32])[O:7][CH:8]=1)[CH3:3].[CH2:33]([O:35][C:36]1[C:45]([O:46][CH3:47])=[CH:44][C:43]2[C:42]([C:48]3[CH:56]=[CH:55][C:51]([C:52](O)=[O:53])=[CH:50][CH:49]=3)=[N:41][C@@H:40]3[CH2:57][CH2:58][S:59][CH2:60][C@@H:39]3[C:38]=2[CH:37]=1)[CH3:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:33]([O:35][C:36]1[C:45]([O:46][CH3:47])=[CH:44][C:43]2[C:42]([C:48]3[CH:49]=[CH:50][C:51]([C:52]([N:29]4[CH2:30][CH2:31][CH:26]([N:12]5[C:13](=[O:25])[C:14]6[S:18][C:17]([C:19]7[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=7)=[CH:16][C:15]=6[N:10]([CH2:9][C:6]6[O:7][CH:8]=[C:4]([CH2:2][CH3:3])[N:5]=6)[C:11]5=[O:32])[CH2:27][CH2:28]4)=[O:53])=[CH:55][CH:56]=3)=[N:41][C@@H:40]3[CH2:57][CH2:58][S:59][CH2:60][C@@H:39]3[C:38]=2[CH:37]=1)[CH3:34]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Reactant: CCc1coc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5nc(CC)co5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
1-[(4-ethyl-1,3-oxazol-2-yl)methyl]-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (200 mg; compound B30) is reacted with 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (168 mg; compound C10) and HBTU (191 mg) in DCM (10 ml) in the presence of DIPEA (0.29 ml) according to the procedure described in example 2 to afford the title compound after purification by twofold flash column chromatography [silica gel, eluation gradient: cyclohexane/EtOAc, 3/1 to 0/1 (v/v) and DCM/MeOH, 1/0 to 1/1 (v/v)] as a solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]2[C:4]=1[N:5]=[C:6]([O:18][CH3:19])[C:7]([O:16][CH3:17])=[N:8]2.[NH2:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24]([OH:26])=[O:25].C(N(CC)CC)C>C(#N)C>[CH3:17][O:16][C:7]1[C:6]([O:18][CH3:19])=[N:5][C:4]2[C:9](=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:3]=2[CH2:2][NH:20][C:21]2[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=2)[C:24]([OH:26])=[O:25])[N:8]=1
Reactant: COc1nc2cc([N+](=O)[O-])cc(CBr)c2nc1OC
Reactant: Nc1cccc(C(=O)O)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1nc2cc([N+](=O)[O-])cc(CNc3cccc(C(=O)O)c3)c2nc1OC

Procedure:
350 mg (1.06 mmol) of 5-bromomethyl-2,3-dimethoxy-7-nitro-quinoxaline, 153 mg (1.05 equiv.) of 3-aminobenzoic acid and 0.165 ml (1.1 equiv.) of triethylamine are combined in 10 ml of acetonitrile, and heated at boiling at reflux for 24 hours. The reacton mixture is concentrated by evaporation, extracted with ethyl acetate and 1 N HCl and washed once with brine. The organic phases are combined, dried over magnesium sulfate and concentrated by evaporation.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([B:8]2[O:12][CH2:11][CH2:10]O2)[CH:5]=[CH:6][CH:7]=1.Br[C:14]1[CH:19]=[CH:18]C=[CH:16][C:15]=1COCOC>>[Cl:1][C:2]1[CH:3]=[C:4]([B:8]2[C:16]3[CH:15]=[CH:14][CH:19]=[CH:18][C:10]=3[CH2:11][O:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COCOCc1ccccc1Br
Reactant: Clc1cccc(B2OCCO2)c1
Product: Clc1cccc(B2OCc3ccccc32)c1

Procedure:
This was prepared as per the procedure in Example 11, from 2-(3-chlorophenyl)-[1,3,2]-dioxaborolane and 1-bromo-2-((methoxymethoxy)methyl)benzene to afford white crystalline product.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[C:17]([Cl:18])[N:11]2[N:10]=[C:9]1[CH:19]([CH:21]1[CH2:23][CH2:22]1)O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([NH:31][CH2:32][CH2:33][CH2:34][NH2:35])([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>C1(C)C(C)=CC=CC=1>[C:27]([O:26][C:24](=[O:25])[NH:31][CH2:32][CH2:33][CH2:34][NH:35][CH:19]([C:9]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[C:17]([Cl:18])[N:11]2[N:10]=1)[CH:21]1[CH2:23][CH2:22]1)([CH3:30])([CH3:28])[CH3:29]
Reactant: O=c1c2ccc(Cl)n2nc(C(O)C2CC2)n1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCN
Solvent: Cc1ccccc1C
Product: CC(C)(C)OC(=O)NCCCNC(c1nn2c(Cl)ccc2c(=O)n1Cc1ccccc1)C1CC1
Yield: 69.3 %

Procedure:
A solution of 3-benzyl-7-chloro-2-(cyclopropyl-hydroxy-methyl)-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (0.32 g, 0.92 mmol) and N-BOC-1,3-diaminopropane (Fluka, 1.0 g, 5.7 mmol) in xylene (12 mL) was heated at 110° C. under nitrogen for 4 days. The solvent was removed under reduced pressure. Purification of the residue by flash column chromatography (SiO2, EtOAc/hexane 1:3 to 3:2) gave the title compound as a light yellow oil (0.31 g, 62%): 1H NMR (CDCl3) δ 7.25 (m, 3H), 7.20 (m, 1H), 7.07 (d, 2H, J=7.15 Hz), 7.00 (d, 1H, J=4.95 Hz), 6.44 (d, 1H, J=4.95 Hz), 5.41 (m, 1H), 4.82 (m, 1H), 3.33 (m 1H), 3.03 (m, 2H), 2.40 (m, 2H), 1.52 (m, 2H), 1.35 (s, 9H), 1.30 (m, 2H), 1.19 (m, 2H), 0.52 (m, 1H), 0.35 (m, 1H), 0.13 (m, 1H); MS (ESI+) 486.17, 488.17 (M++H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([C:11]1[CH:31]=[CH:30][C:14]([C:15]([NH:17][C@H:18]([C:20]2[NH:24][C:23]3[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:22]=3[N:21]=2)[CH3:19])=[O:16])=[CH:13][C:12]=1[Cl:32])=[O:10].[C:33](OC(=O)C)(=[O:35])[CH3:34].[Cl-].[Na+].ClCl>C(O)(=O)C.CO>[C:33]([NH:1][CH2:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([C:11]1[CH:31]=[CH:30][C:14]([C:15]([NH:17][C@H:18]([C:20]2[NH:24][C:23]3[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:22]=3[N:21]=2)[CH3:19])=[O:16])=[CH:13][C:12]=1[Cl:32])=[O:10])(=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H](NC(=O)c1ccc(C(=O)N2CCC[C@H]2CCN)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(=O)NCC[C@@H]1CCCN1C(=O)c1ccc(C(=O)N[C@@H](C)c2nc3cc(Cl)ccc3[nH]2)cc1Cl
Yield: 67 %

Procedure:
Prepared analogously to Example 124 from 4-[(2S)-2-(2-aminoethyl)pyrrolidin-1-ylcarbonyl]-3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethyl]benzamide and acetic anhydride in glacial acetic acid. Yield: 67%; Rf value: 0.32 (Reversed phase RP 8; methanol:5% sodium chloride solution=6:4); C25H27Cl2N5O3 (516.43); mass spectrum: (M+H)+=516/518/520 (chlorine isotope).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([F:9])[C:3]=1[F:10].C(O[B:15]1[O:19][C:18]([CH3:21])([CH3:20])[C:17]([CH3:23])([CH3:22])[O:16]1)(C)C>O1CCCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([B:15]2[O:19][C:18]([CH3:21])([CH3:20])[C:17]([CH3:23])([CH3:22])[O:16]2)=[C:3]([F:10])[C:4]=1[F:9]
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Fc1c(Cl)ccc(Br)c1F
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(Cl)c(F)c2F)OC1(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 1-bromo-4-chloro-2,3-difluorobenzene (720 mg, 3.17 mmol) in tetrahydrofuran (10 mL) was added i-propylmagesiumchloride (1.90 mL, 3.80 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h. Then 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxa-borolane (0.98 mL, 4.75 mmol) in tetrahydrofuran (5.0 mL) was added. The reaction mixture was allowed to warm up to room temperature and stirred at RT for 1 h. The mixture was used directly in the next step.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:10]=1[C:11]([O:13]CC1C=CC=CC=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.CO>[CH2:1]([O:8][C:9]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:10]=1[C:11]([OH:13])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(=O)OCc2ccccc2)c(OCc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)O)c(OCc2ccccc2)c1
Yield: 53.4 %

Procedure:
A solution of benzyl 2-benzyloxy-4-methylbenzoate acid (25 g) in a mixture of THF and methanol was treated with aqueous 2N NaOH (188 ml) and heated under reflux for 12 hours. The reaction mixture was concentrated to half its volume and was diluted with water, extracted once with EtOAc and the aqueous layer was acidified with HCl to pH4. The solid which precipitated was filtered and dried to give 2-benzyloxy-4-methylbenzoic acid (yield 9.73 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([OH:11])[CH:6]([S:12]([CH3:15])(=[O:14])=[O:13])[CH2:5]2.N1C=CC=CC=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>ClCCl>[C:22]([O:11][CH:7]1[C:8]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)[CH2:5][CH:6]1[S:12]([CH3:15])(=[O:14])=[O:13])(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: CS(=O)(=O)C1Cc2cc(Cl)ccc2C1O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC1c2ccc(Cl)cc2CC1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
0.247 g (1 mmol) of 5-chloro-2-methylsulfonylindan-1-ol is dissolved in 5 ml of dichloromethane. 1 ml of pyridine and 1 ml of acetic anhydride are added to the solution, and the reaction mixture is then stirred at room temperature for 2 days. The reaction solution is evaporated completely and the residue is taken up in dichloromethane and extracted with dilute citric acid. The organic phase is separated off, concentrated and purified chromatographically (silica gel; dichloromethane/methanol 20/1). This gives 1-acetoxy-5-chloro-2-methylsulfonylindane of melting point 136° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[CH2:8][O:9][C:10](=[O:11])[C:5]2=[CH:4][CH:3]=1.[Se](=O)=[O:13]>O1CCOCC1>[O:11]=[C:10]1[C:5]2[C:6](=[N:7][C:2]([CH:1]=[O:13])=[CH:3][CH:4]=2)[CH2:8][O:9]1
Reactant: O=[Se]=O
Reactant: Cc1ccc2c(n1)COC2=O
Solvent: C1COCCO1
Product: O=Cc1ccc2c(n1)COC2=O
Temperature: 100 °C
Yield: 79.7 %

Procedure:
A solution of 2-methyl-7H-furo[3,4-b]pyridin-5-one (1.41 g, 9.46 mmol) in dioxane (50 mL) is treated with selenium dioxide (1.2 g, 10.8 mmol) and the reaction mixture is heated at 100° C. for 3 h. Additional selenium dioxide (1.2 g, 10.8 mmol) is added at 3 and 6 hours and the reaction mixture is heated at 100° C. The reaction is heated at 100° C. for an additional 42 h. The reaction mixture is filtered through celite and washed with dioxane. The filtrate is concentrated under reduced pressure and subject to chromatography (silica gel, EtOAc/hexane). The high Rf product containing fractions are concentrated to give 5-Oxo-5,7-dihydro-furo[3,4-b]pyridine-2-carbaldehyde (1.23 g, 80%). The low Rf containing fractions are concentrated to give 5-Oxo-5,7-dihydro-furo[3,4-b]pyridine-2-carboxylic acid (159 mg, 9%).
Reaction SMILES: [CH:1]([C:4]1[N:5]([CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14])[CH:6]=[CH:7][N:8]=1)([CH3:3])[CH3:2].[Li]CCCC.[CH3:20][Sn:21](Cl)([CH3:23])[CH3:22]>C1COCC1.CCOC(C)=O>[CH:1]([C:4]1[N:5]([CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14])[C:6]([Sn:21]([CH3:23])([CH3:22])[CH3:20])=[CH:7][N:8]=1)([CH3:3])[CH3:2]
Reactant: COCCOCn1ccnc1C(C)C
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCCOCn1c([Sn](C)(C)C)cnc1C(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 94.4 %

Procedure:
A −78° C. solution of 2-isopropyl-1-((2-methoxyethoxy)methyl)-1H-imidazole (1.50 g, 7.57 mmol) in THF (30 mL) was treated drop-wise with n-BuLi (2.5N, 4.24 mL, 10.59 mmol), stirred for 10 min, then warmed to 0° C. for 45 min. The solution was re-cooled to −78° C., treated drop-wise, with trimethyltin chloride (1.0 N, 7.19 mL, 7.19 mmol), over 5 min, warmed to RT and stirred overnight. The mixture was diluted with EtOAc, washed with brine, dried over Na2SO4 and concentrated to dryness to afford 2-isopropyl-1-((2-methoxyethoxy)methyl)-5-(trimethylstannyl)-1H-imidazole (2.45 g, 90%). MS (ESI) m/z: 363.1 (M+H+).
Reaction SMILES: [ClH:1].[C:2]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][N:10]=[C:9]2[Cl:16])(=[O:4])[CH3:3].[CH3:17][N:18]1[CH:22]=[CH:21][N:20]=[C:19]1[S:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][C:25]=1[F:31]>>[ClH:16].[ClH:1].[C:2]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][N:10]=[C:9]2[NH:30][C:27]1[CH:28]=[CH:29][C:24]([S:23][C:19]2[N:18]([CH3:17])[CH:22]=[CH:21][N:20]=2)=[C:25]([F:31])[CH:26]=1)(=[O:4])[CH3:3]
Reactant: CC(=O)Oc1ccc2ncnc(Cl)c2c1
Reactant: Cn1ccnc1Sc1ccc(N)cc1F
Agent: Cl
Product: CC(=O)Oc1ccc2ncnc(Nc3ccc(Sc4nccn4C)c(F)c3)c2c1
Yield: 58 %

Procedure:
Using an analogous procedure to that described in Example 1, 6-acetoxy-4-chloroquinazoline hydrochloride was reacted with 4-amino-2-fluorophenyl 1-methylimidazol-2-yl sulphide to give 6-acetoxy-4-[3-fluoro-4-(1-methylimidazol-2-ylthio)anilino]quinazoline dihydrochloride salt in 58% yield, m.p. 245-248 (decomposes);
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[CH2:9]1)(OC(C)(C)C)=O.[CH2:15](O)[CH2:16][OH:17].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[O:14]1[C:10]2([CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)[O:17][CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: C1CNCC2(C1)OCCO2

Procedure:
To a solution of 1-Boc-3-piperidone (700 mg, 3.51 mmol) in toluene (20 mL) was added ethylene glycol (588 μL, 10.54 mmol) followed by p-toluene sulfonic acid hydrate (1.0 g, 5.27 mmol) and the reaction heated to reflux using Dean-Stark apparatus for 7 h. To the mixture was added NaHCO3 solution, and the organic layer was removed. The aqueous phase was evaporated to dryness and the resulting residue dissolved in THF. Filtration through celite and removal of the solvent in vacuo gave the desired product as light brown oil. δH (CD3OD): 3.99 (2H, s), 3.73-3.57 (2H, m), 3.63 (4H, m), 2.77 (1H, m), 2.73 (1H, m), 1.76 (2H, m).
Reaction SMILES: [OH-].[Na+].[CH2:3]1[C:10](=[O:11])[NH:9][C:7](=[S:8])[NH:6][C:4]1=[O:5].[F:12][C:13]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15]Br>C(O)C.O.C(O)C.O>[F:12][C:13]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][S:8][C:7]1[NH:6][C:4](=[O:5])[CH2:3][C:10](=[O:11])[N:9]=1
Reactant: Fc1cccc(CBr)c1F
Reactant: O=C1CC(=O)NC(=S)N1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C1CC(=O)NC(SCc2cccc(F)c2F)=N1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
Sodium hydroxide (6.1 g) in ethanol (20 ml) and water (20 ml) was added to a suspension of 4,6-dihydroxy-2-thiopyrimidine in ethanol/water (120 ml/120 ml). 2,3-difluorobenzyl bromide (28.4 g) was added dropwise to this solution. The mixture was heated at 60° C. for 2 h and stirred at room temperature for 20 h. The solids were filtered and washed with water (200 ml), isopropanol (20 ml) and dried in vacuo at 40° C. for 24 h to yield the subtitle compound. Yield 31.0 g.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:48][CH2:49][CH2:50][O:51][C:52]([CH3:73])([CH3:72])[CH2:53][N:54]1[C:66]2[C:65]3[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=3[N:59]=[C:58]([NH2:67])[C:57]=2[N:56]=[C:55]1[CH2:68][O:69][CH2:70][CH3:71]>CN(C=O)C>[NH2:67][C:58]1[C:57]2[N:56]=[C:55]([CH2:68][O:69][CH2:70][CH3:71])[N:54]([CH2:53][C:52]([CH3:73])([O:51][CH2:50][CH2:49][NH:48][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:72])[C:66]=2[C:65]2[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=2[N:59]=1
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)O
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)OCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)OCCNC(=O)CCCCCNC(=O)OC(C)(C)C
Yield: 27.8 %

Procedure:
6-(tert-Butoxycarbonylamino)hexanoic acid (197 mg, 850 μmol) was combined with DMF (10.9 mL) to give a colorless solution. O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU, 300 mg, 936 μmol) and N,N-diisopropylethylamine (DIEA, 728 μl, 4.25 mmol) were added with stirring in an inert atmosphere. Then 1-(2-(2-aminoethoxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine (Example 1c, 304 mg, 850 μmol) was added and the mixture was stirred for 2 hours at room temperature. The mixture was concentrated in vacuo, dissolved in ethyl acetate (5 mL), stirred for 1 min with cold sodium hydroxide solution (1 N) and dried by passing through ChemElut® (10 g). The organic phase was concentrated in vacuo again and the residue was purified by flash chromatography (silica gel, 10% methanol in dichloromethane) to give the title compound (0.135 g, 23%) as light brown oil; LC-MS (UV peak area, ESI) 83%, 571.5 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8](O)(=O)[CH:9](C(C(O)=O)O)[OH:10]>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:9](=[O:10])[CH3:8])[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: O=C(O)C(O)C(O)C(=O)O
Product: CC(=O)N1CCN(C)CC1
Yield: 38 %

Procedure:
2-(2,3-Dihydro-2-oxo-3-phenyl-5-benzofuranyl)-1-(4-methylpiperazinyl-1-oxoethane was prepared according to the process described in Example 3, but using 4-methylpiperazine in Stage C. The latter compound was dissolved in a solution of DL-tartaric acid to form the corresponding salt, and then recrystallized in ethyl ether.