Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:47])=[C:4]([CH:44]=[CH:45][CH:46]=1)[C:5]([N:7]([CH2:30][CH2:31][CH2:32][NH:33]C(=O)OCC1C=CC=CC=1)[C@@H:8]([C:12]1[N:13]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:14](=[O:22])[C:15]2[N:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)[CH2:9][C:10]#[CH:11])=[O:6].I[Si](C)(C)C.C([O-])(O)=O.[Na+].ClCCl>C(#N)C>[NH2:33][CH2:32][CH2:31][CH2:30][N:7]([C@@H:8]([C:12]1[N:13]([NH:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:14](=[O:22])[C:15]2[N:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)[CH2:9][C:10]#[CH:11])[C:5](=[O:6])[C:4]1[CH:44]=[CH:45][CH:46]=[C:2]([Cl:1])[C:3]=1[F:47]
Reactant: C#CC[C@H](c1nc2cccnc2c(=O)n1Nc1ccccc1)N(CCCNC(=O)OCc1ccccc1)C(=O)c1cccc(Cl)c1F
Agent: C[Si](C)(C)I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: C#CC[C@H](c1nc2cccnc2c(=O)n1Nc1ccccc1)N(CCCN)C(=O)c1cccc(Cl)c1F
Reaction time: 0.17 h
Yield: 50.4 %

Procedure:
To a solution of (R)-benzyl 3-(3-chloro-2-fluoro-N-(1-(4-oxo-3-(phenylamino)-3,4-dihydropyrido[3,2-d]pyrimidin-2-yl)but-3-ynyl)benzamido)propylcarbamate (100 mg, 0.153 mmol) in acetonitrile (2 ml) was slowly added iodotrimethylsilane (83 μl, 0.613 mmol) at 0° C. After stirring for 10 minutes, 0.5 ml of sat.NaHCO3 solution was added to quench the reaction. 100 ml of dichloromethane was added to the reaction mixture, then washed with water (30 ml), brine (30 ml), dried over Na2SO4 and concentrated to dryness under reduced pressure. The crude product was purified by preparative HPLC. The resulted product (TFA salt) was dissolved in dichloromethane (100 ml) and washed with sat.NaHCO3 solution (20 ml), sat.NaCl solution (20 ml), dried over Na2SO4 and concentrated to dryness under reduced pressure. To a solution of the residue in EtOAc (2 ml) was added HCl:EtOAc (3.0 M, 1.0 ml). The mixture was stirred at room temperature for 30 minutes and concentrated to afford (R)-N-(3-aminopropyl)-3-chloro-2-fluoro-N-(1-(4-oxo-3-(phenylamino)-3,4 dihydropyrido[3,2-d]pyrimidin-2-yl)but-3-ynyl)benzamide (40 mg, 44%, 2HCl) as a pale yellow solid, M.p. 198-200° C. LCMS: m/e 519 [M+H]. 1H NMR (CD3OD): δ 8.93 (s. 1H), 8.59 (d, J=8.0 Hz, 1H), 8.12 (s, 1H), 7.52 (s, 1H), 7.27 (d, J=6.4 Hz, 2H), 7.10 (s, 2H), 7.00 (m, 1H), 6.85 (s, 1H), 6.53 (s, 1H), 6.38 (s, 1H), 5.51 (s, 1H), 5.26 (s, 1H), 3.73-3.59 (m, 2H), 2.65-2.29 (m, 2H), 2.01-1.59 (m, 2H), 1.19 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C:12](=O)[C:13](Cl)=[O:14])=[CH:5][N:6]2[CH3:11].Cl.C([O:21][C:22](=[NH:37])[CH2:23][C:24]1[C:32]2[C:27](=[CH:28][C:29]([N+:33]([O-:35])=[O:34])=[CH:30][CH:31]=2)[N:26]([CH3:36])[CH:25]=1)(C)C>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C:12]1[C:13](=[O:14])[NH:37][C:22](=[O:21])[C:23]=1[C:24]1[C:32]3[C:27](=[CH:28][C:29]([N+:33]([O-:35])=[O:34])=[CH:30][CH:31]=3)[N:26]([CH3:36])[CH:25]=1)=[CH:5][N:6]2[CH3:11]
Reactant: CC(C)OC(=N)Cc1cn(C)c2cc([N+](=O)[O-])ccc12
Reactant: Cn1cc(C(=O)C(=O)Cl)c2c(F)cccc21
Agent: Cl
Product: Cn1cc(C2=C(c3cn(C)c4cccc(F)c34)C(=O)NC2=O)c2ccc([N+](=O)[O-])cc21

Procedure:
3-(4-Fluoro-1-methyl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)-pyrrole-2,5-dione was prepared from (4-fluoro-1-methyl-1H-indol-3-yl)-oxo-acetyl chloride and 2-(1-methyl-6-nitro-1H-indol-3-yl)-acetimidic acid isopropyl ester hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].N1C=CC=CC=1.[N+:17]([C:20]1[CH:32]=[CH:31][C:23]([O:24][CH:25]([CH2:29][CH3:30])[C:26](Cl)=[O:27])=[CH:22][CH:21]=1)([O-:19])=[O:18]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH:6][C:26](=[O:27])[CH:25]([O:24][C:23]1[CH:31]=[CH:32][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=1)[CH2:29][CH3:30]
Reactant: COc1ccccc1CN
Reactant: CCC(Oc1ccc([N+](=O)[O-])cc1)C(=O)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCC(Oc1ccc([N+](=O)[O-])cc1)C(=O)NCc1ccccc1OC
Yield: 58.1 %

Procedure:
In 50 ml of toluene were dissolved 1.9 g (0.014 mole) of 2-methoxybenzylamine and 1.2 g (0.015 mole) of pyridine. Then, was added dropwise thereto a solution of 2.8 g (0.012 mole) of 2-(4-nitrophenoxy)-butyroyl chloride in 30 ml of toluene and the mixture was treated according to the same procedure as in Synthesis Example 7. The resultant crude crystals were recrystallized from ethanol to give 2.4 g of N-(2-methoxybenzyl)-2-(4-nitrophenoxy)-butyramide melting at 109°~112° C. as colorless needles.
Reaction SMILES: C(#N)C.N(OC(C)(C)C)=O.N[C:12]1[C:13]2[N:14]([N:19]=[C:20]([S:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:21]=2)[C:15]([Cl:18])=[CH:16][CH:17]=1.[Cl:30]CCl>Cl.[Cu]Cl>[CH2:23]([S:22][C:20]1[N:21]=[C:13]2[C:12]([Cl:30])=[CH:17][CH:16]=[C:15]([Cl:18])[N:14]2[N:19]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Nc1ccc(Cl)n2nc(SCc3ccccc3)nc12
Reactant: ClCCl
Agent: Cl[Cu]
Agent: CC(C)(C)ON=O
Agent: Cl
Solvent: CC#N
Product: Clc1ccc(Cl)n2nc(SCc3ccccc3)nc12

Procedure:
A mixture of 9.9 g (0.10 mol) of copper(I) chloride with 300 mL of acetonitrile was prepared and 8.7 mL (6.8 g, 0.066 mol) of 90 percent t-butyl nitrite was added with stirring. After 10 minutes 9.5 g (0.033 mol) of 8-amino-2-benzylthio-5-chloro[1,2,4]triazolo[1,5-a]pyridine was added and the reaction mixture was allowed to react with stirring for 3 days. The mixture was then diluted with dichloromethane and 2N aqueous hydrochloric acid, and after mixing this well, the phases were separated. The organic layer was washed with 2N aqueous hydrochloric acid and concentrated by evaporation under reduced pressure. The residue was chromatographed on silica gel eluting with dichloromethane to obtain 6.5 g (63 percent of theory) of the title compound as a yellow powder melting at 103°-104° C.
Reaction SMILES: CO[C:3]1[CH:8]=[C:7](C)[C:6]([S:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]2[CH2:19][O:20][CH2:21][C:22]([OH:24])=[O:23])(=[O:12])=[O:11])=[C:5]([CH3:25])[CH:4]=1.[Cl:26]C1C=CC=C(C)C=1S(Cl)(=O)=O>>[Cl:26][C:7]1[CH:8]=[CH:3][CH:4]=[C:5]([CH3:25])[C:6]=1[S:10]([N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1[CH2:19][O:20][CH2:21][C:22]([OH:24])=[O:23])(=[O:12])=[O:11]
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCC[C@H]2COCC(=O)O)c(C)c1
Reactant: Cc1cccc(Cl)c1S(=O)(=O)Cl
Product: Cc1cccc(Cl)c1S(=O)(=O)N1CCCC[C@H]1COCC(=O)O

Procedure:
Synthesis of this acid unit was carried out in analogy to (S)-2-((1-(4-Methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetic acid (AC28) employing 2-chloro-6-methylbenzene-1-sulfonyl chloride in step (ii).
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([OH:21])[CH:14]=[C:15]([F:20])[CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.CS(O[CH2:27][C:28]([C@@H:31]1[CH2:35][O:34][C:33]([CH3:37])([CH3:36])[O:32]1)([CH3:30])[CH3:29])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O>[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:21][CH2:30][C:28]([C@@H:31]4[CH2:35][O:34][C:33]([CH3:37])([CH3:36])[O:32]4)([CH3:27])[CH3:29])[CH:14]=[C:15]([F:20])[CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: Oc1cc(F)cc2ccc(-c3nnc4ccccn34)nc12
Reactant: CC1(C)OC[C@@H](C(C)(C)COS(C)(=O)=O)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CC1(C)OC[C@@H](C(C)(C)COc2cc(F)cc3ccc(-c4nnc5ccccn45)nc23)O1
Temperature: 85 °C
Yield: 134.8 %

Procedure:
2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-ol (0.09 g, 0.34 mmol), (R)-2-(2,2-dimethyl-1,3-dioxolan-4-yl)-2-methylpropyl methanesulfonate (0.11 g, 0.45 mmol) and cesium carbonate (0.22 g, 0.69 mmol) were added to 1 to 2 mL of DMA and heated to 85° C. for 4-5 hours. The reaction was concentrated and treated with water and ethyl acetate. The reaction was extracted several times with ethyl acetate. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified on Silica gel using 2% NH4OH in isopropyl acetate and DCM to provide 200 mgs of the desired product (85% pure).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:23]1(CN)CCCC[CH2:24]1>>[CH:5]1([CH2:1][NH:6][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)[CH2:4][CH2:3][CH2:2][CH2:24][CH2:23]1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Reactant: NCC1CCCCC1
Product: Cc1nc(NCc2ccccn2)nc(NCC2CCCCC2)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using 1-cyclohexylmethanamine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.66-0.73 (m, 2H), 1.00 (bs, 3H), 1.35 (bs, 1H), 1.42-1.58 (m, 5H), 1.86 (s, 3H), 2.18 (s, 3H), 3.06 (bs, 2H), 4.58 (bs, 2H), 7.26 (bs, 2H), 7.40-7.46 (m, 1H), 7.68-7.74 (m, 1H), 8.49 (bs, 1H); MS (ESI) m/z 326.5 (M+1)+.
Reaction SMILES: C(O[C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)C.ClC1C=CC(C2[C:25]([C:26]3[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:33]4[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][N:42]([CH2:45][CH3:46])[CH2:43][CH3:44])=[CH:35][CH:34]=4)[N:27]=3)=[CH:24][NH:23][N:22]=2)=CC=1>>[CH2:45]([N:42]([CH2:43][CH3:44])[CH2:41][CH2:40][O:39][C:36]1[CH:37]=[CH:38][C:33]([NH:32][C:28]2[N:27]=[C:26]([C:25]3[C:4]([C:5]4[CH:6]=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=4)=[N:22][NH:23][CH:24]=3)[CH:31]=[CH:30][N:29]=2)=[CH:34][CH:35]=1)[CH3:46]
Reactant: CCOC(=O)c1ccc(OC)cc1
Reactant: CCN(CC)CCOc1ccc(Nc2nccc(-c3c[nH]nc3-c3ccc(Cl)cc3)n2)cc1
Product: CCN(CC)CCOc1ccc(Nc2nccc(-c3c[nH]nc3-c3ccc(OC)cc3)n2)cc1

Procedure:
The title compound is prepared as described in Example 1 using 4-methoxy-benzoic acid ethyl ester (Aldrich W24,200-4) and 4-(2-diethylamino-ethoxy)-phenylamine (see Example 3).
Reaction SMILES: [CH3:1][C:2](=[N:5][OH:6])[CH2:3][CH3:4].[CH:7]1([N:13]=[C:14]=[N:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>C1COCC1.[OH-].[Na+]>[CH:16]1([NH:15][C:14](=[N:13][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[O:6][N:5]=[C:2]([CH2:3][CH3:4])[CH3:1])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CCC(C)=NO
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCC(C)=NOC(=NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 76.6 %

Procedure:
To a solution of methylethylketone oxime (4.6 g, 0.053 mol) in dry THF (30 ml) is added finely powdered NaOH (0.15 g) and dicyclohexylcarbodiimide (10.3 g, 0.05 mol). The mixture is then stirred 5 h at room temperature under argon. The turbid mixture is thereafter filtered and evaporated under reduced pressure. The residue is stirred 10 minutes with acetonitrile (30 ml), the acetonitrile phase is then discarded, the oily residue is dissolved in dichloromethane (30 ml), filtered and evaporated to afford 11.24 g of the title compound as a slightly yellow liquid.
Reaction SMILES: [C:1]1([CH2:7][OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[C:12]1[C:13]2[N:14]([CH:19]=[CH:20][N:21]=2)[N:15]=[C:16]([Cl:18])[CH:17]=1.O>C1COCC1>[CH2:7]([O:8][C:12]1[C:13]2[N:14]([CH:19]=[CH:20][N:21]=2)[N:15]=[C:16]([Cl:18])[CH:17]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCc1ccccc1
Reactant: Clc1cc(Br)c2nccn2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Clc1cc(OCc2ccccc2)c2nccn2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of phenylmethanol (3.35 g, 31 mmol, 1.2 eq) in THF (80 mL), NaH (60% dispersion in mineral oil, 1.34 g, 33.5 mmol, 1.3 eq) is added in portions. The resulting mixture is stirred at RT for 30 min and then 8-bromo-6-chloroimidazo[1,2-b]pyridazine (D-3) (6 g, 25.8 mmol, 1.0 eq) is added. The resulting mixture is stirred at RT for an additional 2 h and then poured into water (30 mL). The mixture is extracted with ethyl acetate (2×100 mL). The combined organic layers are washed with brine, dried over Na2SO4 and filtered. The filtrate is concentrated in vacuo to afford the product, 8-(benzyloxy)-6-chloroimidazo[1,2-b]pyridazine (D-4).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:11])=[CH:8][C:9]=1[OH:10])=[O:3].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>CN(C=O)C>[OH:10][C:9]1[CH:8]=[C:7]([O:11][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:6]=[CH:5][C:4]=1[C:2](=[O:3])[CH3:1]
Reactant: CCCCCCCCBr
Reactant: CC(=O)c1ccc(O)cc1O
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(C(C)=O)c(O)c1
Temperature: 55 °C
Reaction time: 168 h

Procedure:
A slurry of 2,4-dihydroxy actophenone (3.8 g; 25 mmol) and KHCO3 (2.75 g; 27.5 mmol) in DMF (50 mL) was stirred at 50° C. for 1 hour and then added 1-bromooctane (4.75 mL; 27.5 mmol). The reaction mixture was stirred at 50-60° C. for 7 days, poured onto H2O (100 mL) and the aqueous phase extracted with diethyl ether (3×). The combined organic fractions was dried (MgSO4), filtered, evaporated to dryness and purified by column chromatography (SiO2; EtOAc/PE80-100° C.=1:10) to yield 4.39 g (66%) as yellow oil. MS (direct; Cl): 265 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:22])=[C:4]([NH:8][CH2:9][C:10]2[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[S:12][C:11]=2[C:19](O)=[O:20])[CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O>C(Cl)Cl>[Br:1][C:2]1[C:3]([CH3:22])=[C:4]([N:8]2[C:19](=[O:20])[C:11]3[S:12][C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:14][C:10]=3[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Br)cccc1NCc1cc(C(C)(C)C)sc1C(=O)O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Cc1c(Br)cccc1N1Cc2cc(C(C)(C)C)sc2C1=O
Temperature: 25 °C
Yield: 70.9 %

Procedure:
A 250-mL single-necked round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 101e (1.12 g, 2.93 mmol) and anhydrous methylene chloride (50 mL). Thionyl chloride (1.25 g, 10.5 mmol) was added and the reaction was stirred at ambient temperature. After 16 h the reaction was concentrated under reduced pressure. Purification of the resulting residue by column chromatography afforded a 65% yield (757 mg) of 101f as a white solid: mp 185-186° C.; 1H NMR (300 MHz, CDCl3) δ 7.56 (dd, 1H, J=6.6, 1.2 Hz), 7.20 (dd, 1H, J=6.3, 1.5 Hz), 7.11 (t, 1H, 7.8 Hz), 6.87 (s, 1H), 4.56 (s, 2H), 2.33 (s, 3H), 1.45 (s, 9H); MS (ESI+) m/z 364.2 (M+H).
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][C:11]2[CH:21]=[CH:20][C:14]3[N:15]=[C:16]([S:18][CH3:19])[S:17][C:13]=3[CH:12]=2)[CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:30])C=1>C(Cl)Cl>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][C:11]2[CH:21]=[CH:20][C:14]3[N:15]=[C:16]([S:18]([CH3:19])=[O:30])[S:17][C:13]=3[CH:12]=2)[CH:2]=1
Reactant: CSc1nc2ccc(Cn3cnc4cccnc43)cc2s1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1nc2ccc(Cn3cnc4cccnc43)cc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a solution of 6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]thiazole (2.5 g, 8 mmol) in CH2Cl2 (150 mL) was added mCPBA (70%, 2.36 g, 9.6 mmol) slowly at 0° C. The mixture was stirred at rt overnight. The resulting solution was diluted with 150 mL CH2Cl2 and washed sequentially with saturated aq Na2S2O3, saturated aq NaHCO3 and brine. The organic layer was dried over MgSO4, and concentrated under reduced pressure to give 6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole as a white solid (2.6 g, 99%). 1H NMR (300 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.37 (dd, J=1.3, 4.7 Hz, 1H), 8.23 (d, J=0.9 Hz, 1H), 7.99-8.18 (m, 2H), 7.63 (dd, J=1.7, 8.5 Hz, 1H), 7.30 (dd, J=4.7, 8.1 Hz, 1H), 5.70 (s, 2H), 3.06 (s, 3H). LCMS (ESI) m/z 339 (M+H)+.
Reaction SMILES: [O:1]=[O+][O-].[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[CH2:9][N:10]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH:21]=C)[CH:17]=2)[N:12]([CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:11]1=[O:29]>C(Cl)Cl>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[CH2:9][N:10]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH:21]=[O:1])[CH:17]=2)[N:12]([CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:11]1=[O:29]
Reactant: O=[O+][O-]
Reactant: C=Cc1ccc2c(c1)c(=O)n(Cc1ccc(OC)c(OC)c1)c(=O)n2C1CCOCC1
Solvent: ClCCl
Product: COc1ccc(Cn2c(=O)c3cc(C=O)ccc3n(C3CCOCC3)c2=O)cc1OC
Temperature: -78 °C
Reaction time: 8 h

Procedure:
A stream of ozone is passed for 10 minutes through a solution of 1.4 g of the compound obtained in Step 14.1 in 100 ml of DCM cooled to −78° C. The reaction medium is degassed with nitrogen, 40 ml of dimethyl sulfide are added and the resulting mixture is stirred overnight at room temperature. The reaction medium is evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with a DCM/EtOAc mixture from (100/0, v/v) to (60/40, v/v) to give 0.58 g of the expected product.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[C:13](I)[C:12]([Cl:16])=[CH:11][N:10]=1.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]#[CH:31])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>CN(C)C=O.[Cu]I.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>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]#[C:31][C:13]2[C:12]([Cl:16])=[CH:11][N:10]=[C:9]([Cl:8])[CH:14]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Clc1cc(I)c(Cl)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(C#Cc2cc(Cl)ncc2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Copper(I) iodide (0.50 g), bis-(triphenylphosphine)-palladium(II) chloride (0.50 g), and triethylamine (3.4 mL) are added successively to a solution of 2,5-dichloro-4-iodo-pyridine (6.54 g) in N,N-dimethylformamide (45 mL) under Ar atmosphere at room temperature. The resulting mixture is stirred at room temperature for 1 h prior to the addition of 4-ethynyl-piperidine-1-carboxylic acid tert-butyl ester (5.15 g). The mixture is stirred at 55° C. for 2 h. The solvent is evaporated and the residue is diluted with ethyl acetate. The resulting mixture is washed with water and brine, dried (Na2SO4), and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 85:15→50:50) to give the title compound. LC (method 3): tR=1.66 min; Mass spectrum (ESI+): m/z=355/357/359 (2 Cl) [M+H]+.
Reaction SMILES: [Cl-].[NH4+].[N+:3]([C:6]1[C:11]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:20][C:21]([O:23]CC)=O)([O-])=O>C(O)C.O.[Fe]>[O:23]=[C:21]1[CH2:20][C:7]2[C:6](=[C:11]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[CH:10]=[CH:9][CH:8]=2)[NH:3]1
Reactant: CCOC(=O)Cc1cccc(Oc2ccccc2Cl)c1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: O=C1Cc2cccc(Oc3ccccc3Cl)c2N1

Procedure:
A mixture of iron powder and ammonium chloride in ethanol and water and ethyl 2-[2-nitro-3-(2-chlorophenoxy)phenyl]acetate were treated in a similar manner to that of Preparation 28-(1) to give 2-oxo-7-(2-chlorophenoxy)indoline
Reaction SMILES: OS(O)(=O)=O.[N+:6]([O-:9])(O)=[O:7].[CH2:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N+:13]=1[O-:18])[CH3:11]>>[CH2:10]([C:12]1[CH:17]=[C:16]([N+:6]([O-:9])=[O:7])[CH:15]=[CH:14][N+:13]=1[O-:18])[CH3:11]
Reactant: O=[N+]([O-])O
Reactant: CCc1cccc[n+]1[O-]
Agent: O=S(=O)(O)O
Product: CCc1cc([N+](=O)[O-])cc[n+]1[O-]
Temperature: 80 °C

Procedure:
Concentrated H2SO4 (1826.0 g, 18.660 mol) and fuming HNO3 (1174.0 g, 18.640 mol) are mixed at 0° C. Then 573.8 g (4.7 mol) 2-ethyl-pyridine-1-oxide are added to the mixture over 1 h. The resulting mixture is heated to 80° C. for 3 h. After cooling to RT, the mixture is slowly poured into the crushed ice with fierce stirring. The aqueous layer is extracted with DCM (6×1.0 L), the combined layer is dried over anhydrous Na2SO4. The solvent is removed in vaccuo to afford the title compound. Yield: 700.0 g (89%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:4][C:5]([CH3:8])=[CH:6][N:7]=1.[H-].[Na+].Cl[CH2:20][N:21]1[C:25]([Cl:26])=[C:24]([Cl:27])[N:23]=[CH:22]1.C(OCC)(=O)C>CN(C)C=O>[CH3:1][C:2]1[C:3]([O:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:20][N:21]3[C:25]([Cl:26])=[C:24]([Cl:27])[N:23]=[CH:22]3)=[CH:12][CH:11]=2)=[N:4][C:5]([CH3:8])=[CH:6][N:7]=1
Reactant: Cc1cnc(C)c(Oc2ccc(O)cc2)n1
Reactant: ClCn1cnc(Cl)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cnc(C)c(Oc2ccc(OCn3cnc(Cl)c3Cl)cc2)n1
Temperature: 70 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
At room temperature (about 20° C.), 7.8 g of 4-(3,6-dimethyl-2-pyrazinyloxy)-phenol in 20 ml of anhydrous dimethylformamide is dripped into 1.3 g of 80% strength sodium hydride in 30 ml of anhydrous dimethylformamide. The mixture is stirred for one hour at 70° C., and then 6.68 g of 1-chloromethyl- 4,5-dichloroimidazole in 30 ml of anhydrous dimethylformamide is dripped in. The mixture is stirred for 8 hours at 70° C. and overnight at room temperature. It is then stirred into 200 ml of ethyl acetate, and this mixture is washed twice with water, four times with 5% strength sodium hydroxide solution and twice with saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and the solvent is evaporated off under reduced pressure. The crude product obtained is crystallized with n-hexane. There is obtained 8.9 g of 1-[4-(3,6-dimethyl-2-pyrazinyloxy)-phenoxymethyl]-4,5-dichloroimidazole: m.p.: 84°-85° C.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([O:17][CH3:18])=[C:6]2[C:16]=1[CH2:15][C@H:9]1[O:10][CH2:11][CH2:12][N:13]([CH3:14])[C@@H:8]1[CH2:7]2.[CH3:19][S:20][Li]>CN(C=O)C>[CH3:18][O:17][C:5]1[CH:4]=[CH:3][C:2]([S:20][CH3:19])=[C:16]2[C:6]=1[CH2:7][C@H:8]1[N:13]([CH3:14])[CH2:12][CH2:11][O:10][C@@H:9]1[CH2:15]2
Reactant: COc1ccc(I)c2c1C[C@@H]1[C@@H](C2)OCCN1C
Reactant: [Li]SC
Solvent: CN(C)C=O
Product: COc1ccc(SC)c2c1C[C@@H]1[C@@H](C2)OCCN1C
Reaction time: 5 h

Procedure:
0.44 g (1.2 mM) of trans-3,4,4a,5,10,10a-hexahydro-9-iodo-6-methoxy-4-methyl-2H-naphth[2,3-b]-1,4-oxazine (for production see example 1), dissolved in 5 ml of DMF, as well as 2.34 g (16.3 mM) of copper-I-oxide, are added to a suspension of 0.53 g (9.8 mM) of methylthiolithium in 10 ml of dimethylformamide. The reaction mixture is subsequently stirred for 5 hours at 80° under an argon atmosphere. The preparation is then filtered through Hyflo, washed with 20 ml of methylene chloride, and the filtrate is concentrated by evaporation. The residue is taken up in 30 ml of methylene chloride/30 ml of ice water, the organic phase is separated, and the aqueous phase is extracted three times, each with 10 ml of methylene chloride. The combined organic phases are dried and concentrated by evaporation. Trans-3,4,4a,5,10,10a-hexahydro-6-methoxy-4-methyl-9-methylthio-2H-naphth[2,3-b]-1,4-oxazine is obtained as an oil. The oil is purified by chromatography (silica gel, methylene chloride, 5% methanol). 1-H-NMR 90 MHz (CDCl3): δ=2.36 (s; 3H, N--CH3), 2.42 (s; 3H, S--CH3), 3.81 (s; 3H, O--CH3).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](O)=[O:10])=[C:4]([N+:12]([O-])=O)[CH:3]=1.S(=O)(=O)(O)O>C(O)C.[Zn]>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH2:8][C:9](=[O:10])[NH:12]2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Br)cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Zn]
Solvent: CCO
Product: O=C1Cc2ccc(Br)cc2N1
Yield: 89.6 %

Procedure:
4-Bromo-2-nitrophenylacetic acid (0.26 g), 0.26 g zinc powder and 3 mL 50% sulfuric acid in 5 mL of ethanol were heated at 100° C. overnight. The reaction mixture was filtered, diluted with a little acetic acid, concentrated to remove ethanol, diluted with water and extracted twice with ethyl acetate. The combined extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated to give 0.19 g (90% yield) of 6-bromo-2-oxindole as a yellow solid.