Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[CH:20]=[C:19]3[C:14]([C:15]([N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:16][C:17]([CH3:21])=[N:18]3)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[ClH:2].[CH3:21][C:17]1[CH:16]=[C:15]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[C:14]2[C:19](=[CH:20][C:11]([O:10][CH2:9][C:6]3[CH:7]=[N:8][C:3]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[CH:4][CH:5]=3)=[CH:12][CH:13]=2)[N:18]=1
Reactant: Cc1cc(N2CCCC2)c2ccc(OCc3ccc(Cl)nc3)cc2n1
Reactant: C1COCCN1
Agent: Cl
Product: Cc1cc(N2CCCC2)c2ccc(OCc3ccc(N4CCOCC4)nc3)cc2n1
Temperature: 25 °C
Yield: 20.9 %

Procedure:
A suspension of 98.5 mg (0.25 mmol) of 7-(6-chloro-pyridin-3-ylmethoxy)-2-methyl-4-pyrrolidin-1-yl-quinoline hydrochloride, product of example 56, in 0.44 ml (5 mmol) of morpholine was heated under nitrogen at 60° C. (oil bath temperature) for 23 h and further 72 h at 100° C. The mixture was cooled to RT and partitioned between EtOAc and water. The organic layer was separated, washed with water, dried over magnesium acetate and concentrated in vacuo. The residue was taken up in ether (20 ml), insoluble material was removed by filtration and the filtrate treated with 0.1 ml of 3 N HCl in MeOH. The solid that precipitated was collected, triturated with ether (5 ml), filtered off by suction, dried in a high vacuum and then applied to a to silica gel column with CH2Cl2/MeOH/NH4OH (19:1:0.05) as eluent. The purified fractions were combined and concentrated in vacuo to a small volume then acidified by adding a few drops of 3 N HCl in MeOH. The solvent was taken off in vacuo to give 23 mg (18%) of the desired 2-methyl-7-(6-morpholin-4-yl-pyridin-3-ylmethoxy)-4-pyrrolidin-1-yl-quinoline hydrochloride as a light yellow solid. ISP mass spectrum, m/e: 405.5 (M+1 calculated for C24H28N4O2: 405).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.[C:22]([CH2:26][C:27](Cl)=O)([CH3:25])([CH3:24])[CH3:23].[OH-].[Na+].C(O)C>C(OCC)(=O)C>[CH3:23][C:22]([CH3:25])([CH3:24])[CH2:26][C:27]1[N:14]([CH2:15][CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:3]2[CH:4]=[CH:5][C:6]([S:8]([CH:11]([CH3:12])[CH3:13])(=[O:9])=[O:10])=[CH:7][C:2]=2[N:1]=1
Reactant: CC(C)S(=O)(=O)c1ccc(NCCN2CCCC2)c(N)c1
Reactant: CC(C)(C)CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)S(=O)(=O)c1ccc2c(c1)nc(CC(C)(C)C)n2CCN1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
To a solution of 2-amino-4-(isopropylsulfonyl)-1-(N-2-pyrrolidine-1-ylethylamino)benzene (122.9 mg, 0.39 mmol) in ethyl acetate (8 mL) was added tert-butylacetyl chloride (60 μL, 0.43 mmol) at room temperature, and the mixture was stirred for 1 h at room temperature. 2N—NaOH (1 mL) and ethanol (3 mL) were then added to the reaction mixture at room temperature, and stirred for 6 h at 80° C. The reaction was quenched with water, and extracted with three times with ethyl acetate. The combined organic layers were dried over MgSO4 and filtered. The filtrate was evaporated under reduced pressure. The residue was purified by amine coated silica gel column chromatography (hexane:ethyl acetate=3:1) to give the title compound as an orange solid (107.9 mg, 70%).
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[NH:4][CH2:3][CH2:2]2.Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=1.O1CCOCC1>O>[N+:17]([C:16]1[CH:15]=[CH:14][C:13]([CH:2]2[CH2:3][NH:4][CH:5]3[CH2:8][CH2:9][N:1]2[CH2:7][CH2:6]3)=[N:12][CH:11]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: C1CN2CCC(CC2)N1
Solvent: O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(C2CNC3CCN2CC3)nc1

Procedure:
1,4-diazabicyclo[3.2.2]nonane (6.3 g, 50 mmol) was added to a mixture of 2-chloro-nitropyridine (11.9, 75 mmol), and dioxane (250 ml) at 0° C. The reaction mixture was allowed to reach room temperature. Water (100 ml) was added. The mixture was extracted with dichloromethane (3×50 ml). Chromatography on silica gel with dichloromethane and 10% methanol as solvent gave the title compound as an oil. Yield 8.1 g (65%). Mp. 143-146° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16]CC3C=CC([N+]([O-])=O)=CC=3)=[C:12]([O:27][CH3:28])[CH:11]=2)S[C:6]=1[C:29]([O:31][CH3:32])=[O:30])(=[O:3])[CH3:2]>[Ni].CCOC(C)=O>[CH3:32][O:31][C:29](=[O:30])[CH2:6][CH:5]([CH2:9][CH2:8][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([O:27][CH3:28])[CH:11]=1)[NH:4][C:1](=[O:3])[CH3:2]
Reactant: COC(=O)c1sc(-c2ccc(OCc3ccc([N+](=O)[O-])cc3)c(OC)c2)cc1NC(C)=O
Agent: [Ni]
Solvent: CCOC(C)=O
Product: COC(=O)CC(CCc1ccc(O)c(OC)c1)NC(C)=O
Yield: 59.9 %

Procedure:
Methyl 3-acetamido-5-[3-methoxy-4-(4-nitrobenzyloxy) phenyl]thiophene-2-carboxylate (1.4481 g, 3.17 mmol) was reductively desulfurized using Raney nickel. The filtered solution was taken up in hot EtOAc then washed with 0.5 N HCl (2×30 mL) and H2O. The organic layer was dried (MgSO4), filtered and concentrated to yield the title compound as a yellow oil (0.5620 g, 1.90 mmol, 60.0%); TLC: Rf=0.80 (Solvent L); IR (cm−1): 3498 (OH), 2905 (CH aliphatic), 1743 (ester C═O), 1663 (amide C═O), 726 (═CH); 1H nmr (CDCl3): δ 6.82 (., 1H, J=7.9 Hz), 6.67 (m, 2H), 6.10 (br d, 1H, J=8.6 Hz), 5.56 (br s, 1H), 4.28 (m, 1H), 3.88 (s, 3H), 3.68 (s, 3H), 2.60 (d, 2H, J=8.4 Hz), 2.55 (t, 2H, J=2.2 Hz), 1.97 (s, 3H), 1.85 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12](=[O:21])[O:13][C@@H:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C@@H:7]1[CH2:6][CH2:5]2.Br[CH2:23][CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:15]1([C@H:14]2[C@@H:7]3[CH2:6][CH2:5][C:4]4[C:9]([N:8]3[C:12](=[O:21])[O:13]2)=[CH:10][CH:11]=[C:2]([O:1][CH2:23][CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27])[CH:3]=4)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C1O[C@@H](c2ccccc2)[C@@H]2CCc3cc(O)ccc3N12
Reactant: FC(F)(F)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1O[C@@H](c2ccccc2)[C@@H]2CCc3cc(OCCCC(F)(F)F)ccc3N12
Temperature: 90 °C
Yield: 66.7 %

Procedure:
To a solution of 0.65 g (2.3 mmol) of cis-(±)-7-hydroxy-3-phenyl-3,3a,4,5-tetrahydro-1H-oxazolo[3,4-a]quinolin-1-one in 15 ml of dimethylformamide are added 0.66 g (3.5 mmol) of 1-bromo-4,4,4-trifluorobutane and 0.64 g (4.6 mmol) of potassium carbonate. The mixture is heated for 4 hours at 90° C. and is then diluted with ethyl acetate and washed with water. The organic phase is then dried over sodium sulphate and concentrated under reduced pressure, and the residue is chromatographed on a column of silica, with cyclohexane containing 20% of ethyl acetate. After trituration in diisopropyl ether, 0.60 g of product is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH2:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:13][N:14]1[C:23]2[CH2:22][CH2:21][CH2:20][C:19](=O)[C:18]=2[CH:17]=[CH:16][C:15]1=[O:25].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:13][N:14]1[C:23]2[CH2:22][CH2:21][CH2:20][CH:19]([NH:12][CH2:11][CH2:10][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[C:18]=2[CH:17]=[CH:16][C:15]1=[O:25]
Reactant: Cn1c2c(ccc1=O)C(=O)CCC2
Reactant: NCCc1ccc([N+](=O)[O-])cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cn1c2c(ccc1=O)C(NCCc1ccc([N+](=O)[O-])cc1)CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.6 %

Procedure:
A mixture of 2-(4-nitrophenyl)ethylamine (3.4 g), 5,6,7,8-tetrahydro-1-methyl-5-oxo-2(1H)-quinolinone (3.0 g), and para-toluenesulfonic acid (256 mg) was heated in refluxing toluene (70 ml), with azeotropic removal of water, for a total of 72 hrs. An additional 1.0 g of the amine was added at 24 and 48 hrs. The resulting solution was cooled and concentrated in vacuo. Sodium borohydride (0.6 g) was added to a solution of the residue in ethyl alcohol (70 ml). The resulting mixture was stirred at room temperature for 1 hr, and the mixture was concentrated in vacuo. The residue was quenched with water, and the mixture was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate concentrated. The residue was purified by high performance liquid chromatography (silica gel, eluted with methanol/ethyl acetate) to provide 3.8 g (69%) of product. Recrystallization from ethyl acetate afforded the analytical sample, mp 138°-139° C.,
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH:5]([OH:12])[C:4]=2[N+:3]=1[O-:13].[O:14]=[C:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:24]#[N:25])[CH:21]=2)[NH:16]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>O1CCCC1>[C:24]([C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:14])[CH:23]2[C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH:5]([OH:12])[C:4]=2[N+:3]=1[O-:13])#[N:25]
Reactant: N#Cc1ccc2c(c1)CC(=O)N2
Reactant: [O-][n+]1c(Cl)ccc2c1C(O)CCC2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1ccc2c(c1)C(c1ccc3c([n+]1[O-])C(O)CCC3)C(=O)N2

Procedure:
The title compound was prepared as described for Example 3.3 using 2-chloro-8-hydroxy-5,6,7,8-tetrahydroquinoline 1-oxide (100 mg, 0.501 mmol), 2-oxoindoline-5-carbonitrile (83 mg, 0.526 mmol), tetrahydrofuran (2.5 mL), and a 1.0 M solution of sodium bis(trimethylsilyl)amide (1.668 μL, 1.668 mmol). The reaction was quenched by addition of methanol (2.5 mL). The resulting solution was evaporated to dryness. The crude was used in the following reaction step without further purification.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][CH2:20][CH3:21])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N+:28]([O-])([N+]([O-])=O)=[O:29]>O1CCCC1.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][N:4]([N:28]=[O:29])[C:5]([N:7]([CH2:19][CH2:20][CH3:21])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: CCCN(C(=O)NCCCl)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCN(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Yield: 72.4 %

Procedure:
3.3 g of 1-(2-chloroethyl)-3-n-propyl-3-D-glucopyranosylurea are dissolved in a mixture of 60 ml of tetrahydrofuran and 60 ml of methylene chloride, and 15 g of sodium carbonate anhydrate are added thereto. 5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under ice-cooling. The mixture is treated in the same manner as described in Example 2. 2.6 g of 1-(2-chloroethyl)-1-nitroso-3-n-propyl-3-D-glucopyranosylurea are thereby obtained as yellow caramel.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:3]=1.ClCCl.[Br:17]N1C(=O)CCC1=O>CCCCCC>[Br:17][C:7]1[C:2]([CH3:1])=[N:3][C:4]([N:8]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)=[N:5][CH:6]=1
Reactant: Cc1ccnc(N2CCOCC2)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCCCCC
Solvent: ClCCl
Product: Cc1nc(N2CCOCC2)ncc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
4-(4-Methylpyrimidin-2-yl)morpholine (300 mg) was mixed with dichloromethane (4 ml), and N-bromosuccinimide (357 mg) was added thereto at 0° C., followed by stirring at room temperature for 1 hour. Hexane was added to the reaction mixture, followed by purification by silica gel column chromatography (EtOAc/hexane), to obtain 4-(5-bromo-4-methylpyrimidin-2-yl) morpholine (372 mg).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8]([OH:10])=O)[N:6]=1.C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O.[O:28]=[C:29]1[N:36]2[C@H:31]([CH2:32][O:33][C:34]([CH:49]3[CH2:53][CH2:52][CH2:51][O:50]3)=[C:35]2[C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)=[O:38])[C@@H:30]1[NH:54]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8]([NH:54][C@@H:30]2[C:29](=[O:28])[N:36]3[C@@H:31]2[CH2:32][O:33][C:34]([CH:49]2[CH2:53][CH2:52][CH2:51][O:50]2)=[C:35]3[C:37]([O:39][CH2:40][C:41]2[CH:42]=[CH:43][C:44]([O:47][CH3:48])=[CH:45][CH:46]=2)=[O:38])=[O:10])[N:6]=1
Reactant: COc1ccc(COC(=O)C2=C(C3CCCO3)OC[C@@H]3[C@H](NC(c4ccccc4)(c4ccccc4)c4ccccc4)C(=O)N23)cc1
Reactant: CO/N=C(\C(=O)O)c1csc(N)n1
Agent: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc(OC)cc3)=C(C3CCCO3)OC[C@H]12)c1csc(N)n1
Reaction time: 0.5 h

Procedure:
A stirred mixture of 2-(Z)-methoxyimino-2-(2-aminothiazol-4-yl)acetic acid (III) (54 mg) and N,N-diisopropylethylamine (0.047 ml) in dimethylformamide (0.3 ml) was cooled to -55° to -60° C. and methanesulphonyl chloride (0.021 ml) was added. The mixture was stirred at the same temperature for 0.5 h and then a solution of 4-methoxybenzyl (6S,7S)-7-amino-8-oxo-3-(tetrahydrofuran-2-yl)-1-aza-4-oxabicyclo[4.2.0]oct-2-ene-2-carboxylate (II) (91 mg) in dimethylformamide (1 ml) was added, followed by p-ndine (0.022 ml). The mixture was then stirred at 0° C. for 1 h and then at room temperature for 0.5 h. The mixture was partitioned between ethyl acetate and aqueous citric acid solution and the organic phase was washed twice with water, then brine, dried over magnesium sulphate and evaporated. Column chromatography (silica gel, ethyl acetate as eluent) gave the title compound (88 mg. νmax (CHCl3) 1769, 1709, 1679 and 1613 cm-1 ; δ(CDCl3) 1.72-2.12 (4H, m), 3.35 (3H, s), 3.68-3.96 (4H, m), 3.76 (3H, s), 4.64 (1H, dd, J 9.19 and 15.89 Hz), 5.13 (3H, s), 5.20 (1H, t, J 6.77 Hz), 5.72 (1H, dd, J 4.14 and 8.91 Hz), 6.80 (1H, s), 6.93 (2H, d, J 8.68 Hz), 7.24 (2H, s), 7.37 (2H, d, J 8.66 Hz), 9.23 (1H, d, J 9 Hz).
Reaction SMILES: [I:1][C:2]1[N:3]=[CH:4][N:5]([CH3:8])[C:6]=1I.C([Mg]Br)C.[CH2:13]([Sn:17](Cl)([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].[NH4+].[Cl-]>C1COCC1.O>[CH2:22]([Sn:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:18][CH2:19][CH2:20][CH3:21])[C:6]1[N:5]([CH3:8])[CH:4]=[N:3][C:2]=1[I:1])[CH2:23][CH2:24][CH3:25]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cn1cnc(I)c1I
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)c1c(I)ncn1C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
4,5-Diiodo-1-methyl-1H-imidazole (40.0 g) was stirred in anhydrous THF (560 mL) at ambient temperature and ethylmagnesium bromide (3M in ether, 42.0 mL) was added over 20 minutes under an inert atmosphere. The resulting white precipitate was stirred for 30 minutes then tributyltin chloride (34.2 mL) added dropwise. The resulting clear solution was stirred for 1 hr, then saturated aqueous NH4Cl (50 mL) and water (300 mL) were added. The reaction mixture was extracted with DCM (500 mL), washed with water (3×300 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica eluting with hexane:EtOAc (1:1) to afford the title compound as a colourless oil (45.1 g, 76%);
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:19]3[C:10](=[CH:11][C:12]4[CH2:13][CH2:14][CH2:15][N:16]([C:20]([C:22]5[CH:27]=[CH:26][C:25]([C:28]6[CH:33]=[CH:32][C:31]([C:34]([NH:36][NH2:37])=[O:35])=[CH:30][C:29]=6[CH3:38])=[CH:24][CH:23]=5)=[O:21])[C:17]=4[CH:18]=3)[O:9][CH2:8]2)[CH2:4][CH2:3]1.[CH2:39](OC(OCC)OCC)C>>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:19]3[C:10](=[CH:11][C:12]4[CH2:13][CH2:14][CH2:15][N:16]([C:20]([C:22]5[CH:23]=[CH:24][C:25]([C:28]6[CH:33]=[CH:32][C:31]([C:34]7[O:35][CH:39]=[N:37][N:36]=7)=[CH:30][C:29]=6[CH3:38])=[CH:26][CH:27]=5)=[O:21])[C:17]=4[CH:18]=3)[O:9][CH2:8]2)[CH2:4][CH2:3]1
Reactant: Cc1cc(C(=O)NN)ccc1-c1ccc(C(=O)N2CCCc3cc4c(cc32)C2(CCN(C)CC2)CO4)cc1
Reactant: CCOC(OCC)OCC
Product: Cc1cc(-c2nnco2)ccc1-c1ccc(C(=O)N2CCCc3cc4c(cc32)C2(CCN(C)CC2)CO4)cc1
Yield: 58 %

Procedure:
A suspension of 2,3,5,6,7,8-hexahydro-1'-methyl-5-(4'-hydrazinocarbonyl-2'-methylbiphenyl-4-carbonyl)spiro[furo[2,3-g]quinoline-3,4'-piperidine] (E49) (794 mg) in triethylorthoformate (25 ml) was heated at reflux overnight. The mixture was concentrated in vacuo and the residue refluxed overnight in xylene (40 ml) to complete cyclisation. The xylene was evaporated under reduced pressure and the residue purified by chromatography on silica gel, eluting with chloroform and methanol, to afford the title compound (470 mg, 58%). The hydrochloride salt precipitated from acetone as a white solid.
Reaction SMILES: [F:1][C:2]1[C:14]([N:15]2[C:20](=[O:21])[C:19]([CH3:22])=[C:18]([C:23]([F:26])([F:25])[F:24])[NH:17][C:16]2=[O:27])=[CH:13][C:5]2[N:6]([CH2:10][C:11]#[CH:12])[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.[CH3:28]OS(OC)(=O)=O.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[F:1][C:2]1[C:14]([N:15]2[C:20](=[O:21])[C:19]([CH3:22])=[C:18]([C:23]([F:24])([F:25])[F:26])[N:17]([CH3:28])[C:16]2=[O:27])=[CH:13][C:5]2[N:6]([CH2:10][C:11]#[CH:12])[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1
Reactant: COS(=O)(=O)OC
Reactant: C#CCn1c(=O)sc2cc(F)c(-n3c(=O)[nH]c(C(F)(F)F)c(C)c3=O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: C#CCn1c(=O)sc2cc(F)c(-n3c(=O)c(C)c(C(F)(F)F)n(C)c3=O)cc21

Procedure:
29,6 g of 3-[6-fluoro-2-oxo-3-(2-propinyl)-5-benzothiazolinyl]-5-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidindion in 200 ml acetonitrile is stirred with 9,25 g dimethylsulfate and 10,14 g potassium carbonate at 40° C. for 90 minutes. Thereafter, the reaction mixture is poured into 200 ml of water and extracted two times with 200 ml ethyl acetate each time. The organic phase is subsequently concentrated. The thus-obtained residue is purified by chromatography with 400 g silica gel using hexane:ethyl acetate (7:3).
Reaction SMILES: [CH2:1]1COCC1.[C:6]1([CH:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CCN(CC)CC>C1(C)C=CC=CC=1>[C:6]1([CH:12]2[CH2:17][CH2:16][C:15](=[CH2:1])[CH2:14][CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C1CCC(c2ccccc2)CC1
Reactant: C1CCOC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=C1CCC(c2ccccc2)CC1
Reaction time: 0.17 h
Yield: 10 %

Procedure:
BDAM (2.83 grams) was suspended in 40 milliliters of toluene and 2.2 milliliters of THF were added dropwise. After 10 minutes of stirring, 2.10 grams of 4-phenylcyclohexanone were added. The reaction mixture was refluxed for 1 hour and hydrolyzed with hydrated Ca(OH)2 in the presence of Et3N. After the usual work up, 0.21 grams of 4-phenyl-1-methylenecyclohexane was isolated (10% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[F:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.N1C=CC=CC=1>O1CCOCC1>[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:5]2[C:6]([CH3:8])=[CH:7][C:2]([CH3:1])=[C:3]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:4]2=[O:9])=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1c(C)cc(C)[nH]c1=O
Reactant: OB(O)c1ccc(F)cc1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CCOC(=O)c1c(C)cc(C)n(-c2ccc(F)cc2)c1=O
Temperature: 80 °C
Yield: 16.6 %

Procedure:
A suspension of ethyl 4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carboxylate (5.0 g, 0.025 mol), 4-fluorophenylboronic acid (10.7 g, 0.077 mol), cupric acetate (1.33 g, 0.007 mol), pyridine (6.86 mL), and 4 A molecular sieves (5.0 g) in 1,4-dioxane (80 mL) is heated at 80° C. for 68 hours. The solids are filtered off and the filtrate is concentrated. The residue is partitioned with EtOAc (50 mL) and 2N HCl (70 mL). The precipitated solid is collected by filtration and washed with EtOAc to give the title product (1.2 g). The EtOAc filtrate is separated, dried and concentrated. The residue is purified by silica gel column chromatography eluting with PE:EtOAc:MeOH (40:20:1) to give another portion of product (0.12 g), (1.32 g total, 17.8% yield). MS (m/z): 290.1 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:13][CH2:12][CH2:11][CH2:10][C:9](=[O:14])[C:8]=2[CH:15]=1)([O-:3])=[O:2].[BH4-].[Na+]>CO>[OH:14][CH:9]1[C:8]2[CH:15]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=2[O:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=C1CCCOc2ccc([N+](=O)[O-])cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1ccc2c(c1)C(O)CCCO2
Temperature: 0 °C

Procedure:
32.1 g (0.155 mole) of 2,3-dihydro-7-nitro-1-benzoxepin-5(4H)-one are suspended in 220 ml of methanol and, while stirring at 0° C. under argon, 6.5 g (0.17 mole) of sodium borohydride are added in portions. The mixture is then stirred for about 30 minutes and stirred into ice/water, and the precipitated solid is filtered off with suction and thoroughly washed with water. The solid is taken up in the ethyl acetate, and the solution is separated from the water, dried over sodium sulfate, filtered and evaporated in vacuo. The residue is crystallized in diisopropyl ether/cyclohexane with the addition of active charcoal.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[C:9]([C:14]([OH:16])=O)[N:10]=[CH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].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.[NH:50]1[CH:54]=[CH:53][N:52]=[C:51]1[NH:55][C:56]([C:58]1[C:66]2[NH:65][C:64]([NH2:67])=[N:63][C:62]=2[CH:61]=[CH:60][CH:59]=1)=[O:57]>CN(C=O)C>[NH:52]1[CH:53]=[CH:54][N:50]=[C:51]1[NH:55][C:56]([C:58]1[C:66]2[NH:65][C:64]([NH:67][C:14]([C:9]3[N:10]=[CH:11][C:12]4[C:7]([CH:8]=3)=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=4)=[O:16])=[N:63][C:62]=2[CH:61]=[CH:60][CH:59]=1)=[O:57]
Reactant: O=C(O)c1cc2ccc([N+](=O)[O-])cc2cn1
Reactant: Nc1nc2cccc(C(=O)Nc3ncc[nH]3)c2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nc2cccc(C(=O)Nc3ncc[nH]3)c2[nH]1)c1cc2ccc([N+](=O)[O-])cc2cn1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 11.3 %

Procedure:
To a solution of 44 mg (0.2 mmol) of 7-nitro-isoquinoline-3-carboxylic acid in DMF (1 mL) was added 113 mg (0.3 mmol) of HBTU and DIEA (0.3 mL). The mixture was stirred for 10 min and then 40 mg (0.16 mmol) of 2-amino-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide (intermediate B) was added. The reaction was heated at 80° C. for 1 h. After the usual work up, the residue was purified by column chromatography eluting with DCM/methanol (v/v=10:1) to afford 8 mg (9%) of 7-nitro-isoquinoline-3-carboxylic acid [7-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide. LCMS: 443 (M+1)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.[Cl:16][C:17]1[CH:36]=[C:35]([OH:37])[CH:34]=[C:33]([Cl:38])[C:18]=1[CH2:19][C@@H:20]1[CH2:24][CH2:23][N:22]([N:25]2[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH2:26]2)[C:21]1=[O:32]>CS(C)=O.C(OCC)(=O)C>[Cl:16][C:17]1[CH:36]=[C:35]([CH:34]=[C:33]([Cl:38])[C:18]=1[CH2:19][C@@H:20]1[CH2:24][CH2:23][N:22]([N:25]2[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH2:26]2)[C:21]1=[O:32])[O:37][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: O=C1[C@H](Cc2c(Cl)cc(O)cc2Cl)CCN1N1CCC(O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Oc2cc(Cl)c(C[C@@H]3CCN(N4CCC(O)CC4)C3=O)c(Cl)c2)cc1
Yield: 49.7 %

Procedure:
Add potassium carbonate (0.385 g, 2.8 mmol) and 4-fluorobenzonitrile (0.253 g, 2.1 mmol) to a solution of (R)-3-(2,6-dichloro-4-hydroxy-benzyl)-1-(4-hydroxy-piperidin-1-yl)-pyrrolidin-2-one (0.5 g, 1.4 mmol) in DMSO. Stir the reaction at 80° C. for 3 hours. Cool the reaction, dilute with ethyl acetate, and wash three times with water and one time with brine. After drying the organic layer over sodium sulfate, filter and concentrate under vacuum. Purify the residue by silica gel chromatography with 50% ethyl acetate/hexane to 100% ethyl acetate gradient to afford 0.32 g (50%) of the title compound. MS (m/z): 460 (M+).