Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]12[CH2:20][C:19](=[O:21])[CH:18]=[C:6]1[C:7]1[CH:8]=[CH:9][C:10]([O:14][CH2:15][O:16][CH3:17])=[CH:11][C:12]=1[CH2:13]2)[CH2:2][CH2:3][CH3:4].[CH:22]([N-]C(C)C)([CH3:24])[CH3:23].[Li+].C(I)CC>O1CCCC1.CCOC(C)=O>[CH2:1]([C@@:5]12[C@H:20]([CH2:23][CH2:22][CH3:24])[C:19](=[O:21])[CH:18]=[C:6]1[C:7]1[CH:8]=[CH:9][C:10]([O:14][CH2:15][O:16][CH3:17])=[CH:11][C:12]=1[CH2:13]2)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)[N-]C(C)C
Reactant: CCCCC12CC(=O)C=C1c1ccc(OCOC)cc1C2
Agent: [Li+]
Solvent: CCCI
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC[C@]12Cc3cc(OCOC)ccc3C1=CC(=O)[C@H]2CCC
Temperature: 2.5 °C
Reaction time: 0.42 h

Procedure:
A solution of 8a-butyl-6-(methoxymethoxy)-8,8a-dihydrocyclopenta[a]inden-2(1H)-one (109 mg, 0.38 mmol) in anhydrous tetrahydrofuran (THF, 2 mL) was placed under a N2 atmosphere and cooled in an ice bath. Freshly prepared lithium diisopropylamide in THF (1.2 mL of a 0.4M solution, 0.48 mmol) was added and the resulting solution was stirred at 0-5° C. for 25 minutes. Propyl iodide (0.185 in L, 1.9 mmol) was then added and the mixture was stirred overnight with gradual warming to room temperature. The mixture was diluted with EtOAc, washed with 1N HCl, 5% NaHCO3, and brine, dried over MgSO4, filtered, and evaporated under vacuum. The residue (125 mg) was purified by Biotage™ (Charlottesville, Va.) flash chromatography on a 12S (1.2×7.5 cm) silica gel column, eluting with 19:1 hexane-EtOAc, to afford (rac)-(1S,8aR)-8a-butyl-6-(methoxymethoxy)-1-propyl-8,8a-dihydrocyclopenta[a]inden-2(1H)-one as an oil.
Reaction SMILES: C[Al](C)C.C[Si]([N:9]=[N+:10]=[N-:11])(C)C.[NH2:12][C:13]1[C:18]2[C:19](=[O:39])[N:20]([C:24]3[CH:29]=[CH:28][C:27]([C@H:30]4[CH2:35][CH2:34][C@H:33]([CH2:36][C:37]#[N:38])[CH2:32][CH2:31]4)=[CH:26][CH:25]=3)[CH2:21][CH2:22][O:23][C:17]=2[N:16]=[CH:15][N:14]=1>C1(C)C=CC=CC=1>[NH2:12][C:13]1[C:18]2[C:19](=[O:39])[N:20]([C:24]3[CH:25]=[CH:26][C:27]([CH:30]4[CH2:31][CH2:32][CH:33]([CH2:36][C:37]5[NH:38][N:11]=[N:10][N:9]=5)[CH2:34][CH2:35]4)=[CH:28][CH:29]=3)[CH2:21][CH2:22][O:23][C:17]=2[N:16]=[CH:15][N:14]=1
Reactant: N#CC[C@H]1CC[C@H](c2ccc(N3CCOc4ncnc(N)c4C3=O)cc2)CC1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Nc1ncnc2c1C(=O)N(c1ccc(C3CCC(Cc4nnn[nH]4)CC3)cc1)CCO2
Temperature: 80 °C

Procedure:
To a cooled 0° C., stirred solution of trimethylaluminum (2M in toluene, 0.33 mL) in toluene (0.66 mL) were added trimethylsilylazide (0.86 mL) and {trans-4-[4-(4-amino-5-oxo-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-6(5H)-yl)phenyl]cyclohexyl}acetonitrile (25 mg). This mixture was heated at 80° C. for 40 hours, cooled, concentrated in vacuo and chromatographed (4 g silica gel column, 0-10% methanol:chloroform) to afford the title compound as a white solid, 2.8 mg. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.96-1.28 (m, 2 H) 1.25-1.45 (m, 2H) 1.62-1.80 (m, 5H) 2.31-2.50 (m, 1H) 2.62-2.76 (m, 2H) 3.85-3.95 (m, 2H) 4.45-4.57 (m, 2H) 7.13-7.29 (m, 4H) 7.55 (br. s., 2H) 8.10 (s, 1H) m/z=421.3 (M+1). IC50 76.2 nM (range 47.5-163 nM).
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[F:19][C:20]1[CH:21]=[C:22]([N+:27]([O-:29])=[O:28])[CH:23]=[CH:24][C:25]=1F>CN(C=O)C>[F:19][C:20]1[CH:21]=[C:22]([N+:27]([O-:29])=[O:28])[CH:23]=[CH:24][C:25]=1[CH:4]([C:3]([O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: CCOC(=O)CC(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCc1ccccc1)c1ccc([N+](=O)[O-])cc1F
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 84.1 %

Procedure:
Sodium hydride (504 mg, 12.6 mmol) was added portionwise to an ice bath chilled solution of benzyl ethyl malonate (2.9 g, 12.6 mmol) in dry DMF (20 ml) and stirred for 10 minutes. At room temperature 3,4-difluoronitrobenzene (2 g, 12.6 mmol) was added and stirred under argon. Heated at 100° C. for 20 hours. The reaction mixture was cooled and partitioned between 2N Hydrochloric acid (75 ml) and ethyl acetate (75 ml). The aqueous layer was extracted with ethyl acetate (2×75 ml) and the combined organics were evaporated to a yellow oil. Purified by chromatography on silica gel eluting with ethyl acetate/hexane (1:4) to give the title compound as a yellow oil (3.86 g, 10.6 mmol). LC/MS: Rt=3.40, [MH]+ 362
Reaction SMILES: CO[C:3]1[CH:11]=[CH:10][C:9](S(=O)(=O)N)=[CH:8][C:4]=1[C:5](O)=[O:6].CC(C)=O.ClC(OCC(C)C)=O.C1(C[N:32]2CCCC2CN)CC1>O.C(N(CC)CC)C>[C:5]([NH2:32])(=[O:6])[C:4]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:3]=1
Reactant: COc1ccc(S(N)(=O)=O)cc1C(=O)O
Reactant: NCC1CCCN1CC1CC1
Agent: CC(C)COC(=O)Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: NC(=O)c1ccccc1

Procedure:
5.8 g of 2-methoxy-5-sulphamoyl benzoic acid, 50 ml of acetone, 10 ml of water and 3.6 ml of triethylamine (density 0.726) are placed in a 250 ml flask fitted with an agitator, a thermometer and a dropping funnel. The solution is cooled to about +10° C., then 3.6 g of isobutyl chloroformate is added drop by drop. The medium is reacted for 30 minutes at 0° C., after which 4.5 g of 1-cyclopropylmethyl-2-aminomethyl-pyrrolidine is poured in drop by drop. The medium is reacted for 1 hour at room temperature, 50 ml of water is added and the acetone is evaporated under vacuum. The reaction medium is further diluted with 50 ml of water and made alkaline with 10 ml of ammonia (density 0.91). The viscous product which is precipitated crystallises slowly. The solid is filtered off, washed with water and re-crystallised in 50 ml of ethanol. 3.8 g 841%) of benzamide is obtained, melting at 177° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18]Br>CN(C)C=O>[CH3:9][C:3]1[C:2]2[NH:1][CH2:17][CH2:18][O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: BrCCBr
Reactant: Cc1cccc(O)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc2c1NCCO2
Temperature: 130 °C
Reaction time: 4 h

Procedure:
To a solution of 2-amino-m-cresol (5.0 g) in N,N-dimethylformamide (50 ml), potassium carbonate (28.3 g) and 1,2-dibromoethane (5.3 ml) were added and stirred at 130° C. for 4 hours and then stirred overnight at room temperature. To the reaction mixture, 1,2-dibromoethane (5.3 ml) was added and stirred at 130° C. for 6 hours. After addition of additional 1,2-dibromoethane (3.5 ml), the reaction mixture was stirred at 130° C. for 5 hours and then stirred overnight at room temperature. After insoluble materials were filtered off, the filtrate was diluted with ethyl acetate and washed sequentially with water and brine. The organic layer was dried over anhydrous sodium sulfate and then filtered to remove the desiccant, followed by distilling off the solvent under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=20:1 to 10:1) to give the titled compound, i.e., 5-methyl-3,4-dihydro-2H-1,4-benzoxazine (2.69 g) as a brown oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:38])[O:6][CH:5]([C:7]([NH:9][C:10]2[C:11]([I:37])=[C:12]([CH2:32][O:33][C:34](=[O:36])[CH3:35])[C:13]([I:31])=[C:14]([C:29]=2[I:30])[C:15]([NH:17][CH2:18][CH:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:20][O:21][C:22](=[O:24])[CH3:23])=[O:16])=[O:8])[CH2:4][O:3]1.C(=O)([O-])[O-].[C:43]([O:46][CH2:47][CH2:48]Br)(=[O:45])[CH3:44].O>CS(C)=O>[C:43]([O:46][CH2:47][CH2:48][N:9]([C:10]1[C:11]([I:37])=[C:12]([CH2:32][O:33][C:34](=[O:36])[CH3:35])[C:13]([I:31])=[C:14]([C:29]=1[I:30])[C:15]([NH:17][CH2:18][CH:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:20][O:21][C:22](=[O:24])[CH3:23])=[O:16])[C:7]([CH:5]1[CH2:4][O:3][C:2]([CH3:38])([CH3:1])[O:6]1)=[O:8])(=[O:45])[CH3:44]
Reactant: CC(=O)OCCBr
Reactant: CC(=O)OCc1c(I)c(NC(=O)C2COC(C)(C)O2)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)OCCN(C(=O)C1COC(C)(C)O1)c1c(I)c(COC(C)=O)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I
Temperature: 45 °C
Reaction time: 17 h

Procedure:
5-(2,2-Dimethyl-1,3-dioxolane-4-carboxamido)-3-acetoxymethyl-N-(2,3-diacetoxypropyl)-2,4,6-triiodobenzamide (0.44 a, 0.50 mmol) was dissolved in dimethylsulfoxide (3 ml) and cesmium carbonate (0.33 g, 1.0 mmol) was added. 2-Bromoethyl acetate (0.25 g, 2.5 mmol) was added dropwise. The mixture was stirred at 45° C. for 17 h then added slowly into water (50 ml). A precipitate was formed, filtered off and the filtercake was dissolved in chloroform (60 ml). The organic phase was washed with water (2×30 ml), then dried (Na2SO4) and evaporated to a solid product. Yield: 0.46 g (93%).
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][S:11][C:5]=2[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:3]1.N1C=CC=CC=1.[C:24]12([CH2:34][C:35](Cl)=[O:36])[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH2:25]1)[CH2:31]2>C(Cl)Cl.CCOC(C)=O>[C:24]12([CH2:34][C:35]([NH:1][N:2]3[C:7](=[O:8])[C:6]4[CH:9]=[CH:10][S:11][C:5]=4[C:4]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[N:3]3)=[O:36])[CH2:31][CH:30]3[CH2:29][CH:28]([CH2:27][CH:26]([CH2:32]3)[CH2:25]1)[CH2:33]2
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reactant: Nn1nc(-c2ccccc2)c2sccc2c1=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nn1nc(-c2ccccc2)c2sccc2c1=O
Reaction time: 2 h
Yield: 51.8 %

Procedure:
A mixture of the product from Example 9B (31 mg), pyridine (0.012 mL, 0.15 mmol), and (adamantan-1-yl)acetyl chloride (31 mg, 0.15 mmol) in CH2Cl2 (0.4 mL) was stirred for 2 hours, diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine, dried (Na2SO4), and filtered. The residue was chromatographed on SiO2 (10% EtOAc/CH2Cl2) to give the title compound (27.7 mg, 0.066 mmol) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 11.31 (s, 1H), 8.23 (d, J=5.2 Hz, 1H), 7.86-7.78 (m, 3H), 7.65-7.55 (m, 3H), 2.07 (s, 2H), 1.95 (s, 3H), 1.76-1.53 (m, 12H); MS (ESI+) M/Z 420.3 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[C:4](F)=[C:5]([F:22])[CH:6]=[C:7]2[C:12]=1[N:11]([CH:13]1[CH2:15][CH2:14]1)[CH:10]=[C:9]([C:16]([O:18]CC)=[O:17])[C:8]2=[O:21])#[N:2].[C@H:24]12[CH2:32][NH:31][CH2:30][C@@H:29]1[NH:28][CH2:27][CH2:26][O:25]2.O.[OH-].[Li+].[ClH:36]>C(#N)C.O.C(N(CC)CC)C>[ClH:36].[C:1]([C:3]1[C:4]([N:31]2[CH2:32][C@H:24]3[C@@H:29]([NH:28][CH2:27][CH2:26][O:25]3)[CH2:30]2)=[C:5]([F:22])[CH:6]=[C:7]2[C:12]=1[N:11]([CH:13]1[CH2:14][CH2:15]1)[CH:10]=[C:9]([C:16]([OH:18])=[O:17])[C:8]2=[O:21])#[N:2]
Reactant: C1CO[C@H]2CNC[C@@H]2N1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(C#N)c(F)c(F)cc2c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1c(N2C[C@@H]3NCCO[C@H]3C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
200 mg (0.63 mmol) of ethyl 8-cyano-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate are stirred under argon at 40-45° C. for 2 hours with 97 mg (0.75 mmol) of (1S,6S)-2-oxa-5,8-diazabicyclo[4.3.0]nonane and 0.17 ml of triethylamine in 3 ml of acetonitrile. All volatile components are removed in vacuo, the residue is treated with water, insoluble material is filtered off and the filtrate is extracted with dichloromethane. The organic phase is dried over sodium sulphate and then concentrated in vacuo. The resulting residue is dissolved in 6 ml of tetrahydrofuran and 2 ml of water and treated with 30 mg (0.72 mmol) of lithium hydroxide monohydrate. After stirring at room temperature for 16 hours, the mixture is acidified with dil. hydrochloric acid and the resulting precipitate is filtered off with suction and dried.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]#[N:24])#[N:16].[Br:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28](Br)[CH:27]=1.[Cl-].[NH4+]>O1CCCC1>[Br:25][C:26]1[CH:27]=[C:28]([C:15]2([C:2]3[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=3)[C:17]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:23]([NH2:24])=[N:16]2)[CH:29]=[CH:30][CH:31]=1
Reactant: N#Cc1ccccc1C#N
Reactant: COc1ccc(Br)cc1
Reactant: Brc1cccc(Br)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C2(c3cccc(Br)c3)N=C(N)c3ccccc32)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 11.1 %

Procedure:
To a −78° C. cooled solution of 4-bromoanisol (489 uL, 3.90 mmol) in tetrahydrofuran (20 mL) was added 1.6 M n-butyllithium in hexanes (2.44 mL, 3.90 mmol) and the solution stirred 10 minutes. This was cannulated into a −78° C. solution of 1,2-dicyanobenzene (500 mg, 3.90 mmol) in tetrahydrofuran (20 mL). To a separate round bottom flask was added 1,3-dibromobenzene (471 uL, 3.90 mmol) and tetrahydrofuran (20 mL) and the solution cooled in a −78° C. bath. To this was added 1.6 M n-butyllithium in hexanes (2.44 mL, 3.90 mmol) and the solution stirred 10 minutes. This anion was cannulated into the 1,2-dicyanobenzene reaction and the mixture was stirred at −78° C. for 2 hours. The reaction was poured into saturated ammonium chloride (100 mL) and extracted with ethyl acetate twice. The combined organic layers were washed with aqueous saturated sodium chloride, dried over magnesium sulfate and removed of solvent under reduced pressure to give an amber oil. The amber oil was placed on a 40 g silica gel column eluted with dichloromethane/methanol (9:1) and the combined purified fractions were removed of solvent under reduced pressure to give the titled compound as a tan solid (170 mg, 11%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2[CH:15]=[C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][CH:4]=1.[C:30](Cl)(=[O:33])[CH:31]=[CH2:32]>CN1C(=O)CCC1.ClCCl>[CH3:1][N:2]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([NH:9][C:10]2[CH:15]=[C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)[N:13]=[CH:12][N:11]=2)[N:8]=1)[C:30](=[O:33])[CH:31]=[CH2:32]
Reactant: CNc1cccc(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)n1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: C=CC(=O)N(C)c1cccc(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N4-(6-(methylamino)pyridine-2-yl)-N6-(4-phenoxyphenyl)pyrimidine-4,6-diamine (0.07 g, 0.18 mmol) in NMP (1 mL) was added acryloyl chloride (0.032 g, 0.36 mmol) at 0° C. and the reaction mixture was stirred at rt for 1 h. The reaction mixture was diluted with dichloromethane (2 mL), was washed with NaHCO3 (I mL), water (1 mL), and brine (1 mL). The dichloromethane solution was dried over Na2SO4 and was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 60-120, chloroform/methanol, 9/1) to give N-methyl-N-(6-(6-(4-phenoxyphenylamino)pyrimidin-4-ylamino)pyridin-2-yl)acrylamide (I-78) as a yellow solid. 1H NMR (DMSO-d6) δ ppm: 3.22 (s, 3H), 5.60 (dd, J=2.56 & 9.76 Hz, 1H), 6.12-6.16 (m, 2H), 6.79 (d, J=7.56 Hz, 1H), 6.96 (d, J=8.64 Hz, 5H), 7.09 (t, J=7.32 Hz, 1H), 7.23 (s, 1H), 7.33-7.37 (m, 4H), 7.45 (d, J=8.2 Hz, 2H), 7.32 (t, J=7.8 Hz, 1H), 8.24 (s, 1H); LCMS: m/e 439.3 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[C:18]([F:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=1O.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>CCOCC.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][O:11][C:14]2[C:13]([Cl:12])=[C:18]([F:19])[CH:17]=[CH:16][C:15]=2[F:20])=[CH:6][CH:7]=1
Reactant: Oc1c(F)ccc(F)c1Cl
Reactant: OCCCc1ccc(Br)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Fc1ccc(F)c(OCCCc2ccc(Br)cc2)c1Cl
Temperature: 80 °C

Procedure:
3-(4-Bromophenyl)propan-1-ol from the previous step (1 eq.) and 2-chloro-3,6-difluorophenol (1 eq.) were taken up in freshly deoxygenated toluene (0.3 M). To this solution was then added 1,1′-(azodicarbonyl)-dipiperidine (1.2 eq.) and finally tributylphosphine (1.2 eq.). The resulting yellow solution was heated at 80° C. for 2 h. The reaction mixture was cooled to RT, diluted with ether, and washed with 1 N aq. NaOH. The aqueous wash was back extracted with ether and the combined organic extracts were dried over MgSO4. Filtration and concentration of the filtrate in vacuo afforded a yellow semi-solid. Purification of the crude product thus obtained by way of flash chromatography (SiO2, Hex→15:1 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]2[N:19]3[C:20]4[N:11]([C:12](=[O:22])[CH:13]=[CH:14][C:15]=4[CH:16]=[CH:17][C:18]3=[O:21])[CH2:10]2)[CH2:4][CH2:3]1.COC1N=C2C(CCC(=O)N2C[C@@H]2CO2)=CC=1.[S:40]1[C:49]2[CH:48]=[C:47]([CH:50]=O)[N:46]=[CH:45][C:44]=2[O:43][CH2:42]C1>>[S:40]1[C:49]2[CH:48]=[C:47]([CH2:50][NH:1][CH:2]3[CH2:3][CH2:4][N:5]([CH2:8][CH:9]4[N:19]5[C:20]6[N:11]([C:12](=[O:22])[CH:13]=[CH:14][C:15]=6[CH:16]=[CH:17][C:18]5=[O:21])[CH2:10]4)[CH2:6][CH2:7]3)[N:46]=[CH:45][C:44]=2[O:43][CH2:42]1
Reactant: NC1CCN(CC2Cn3c(=O)ccc4ccc(=O)n2c43)CC1
Reactant: O=Cc1cc2c(cn1)OCCS2
Agent: COc1ccc2c(n1)N(C[C@@H]1CO1)C(=O)CC2
Product: O=c1ccc2ccc(=O)n3c2n1CC3CN1CCC(NCc2cc3c(cn2)OCS3)CC1

Procedure:
The title compound was prepared from 1-[(4-amino-1-piperidinyl)methyl]-1,2-dihydro-4H,9H-imidazo[1,2,3-ij]-1,8-naphthyridine-4,9-dione (2:1 mixture of S:R prepared analogously to Example 11(a-d)) but using 7-(methyloxy)-1-[(2R)-2-oxiranylmethyl]-3,4-dihydro-1,8-naphthyridin-2(1H)-one (for a synthesis see example 5(f)) and 2,3-dihydro[1,4]oxathiino[2,3-c]pyridine-7-carbaldehyde (for a synthesis see WO2004058144, Example 60) according to the general method of Example 12.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][C:12]3[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=3)[C:4]=2[O:3]1.[CH3:20][O:21][N:22]([CH3:26])[C:23](Cl)=[O:24]>CN(C)C=O>[CH3:1][C:2]1([CH3:19])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][C:12]3[CH:18]=[CH:17][C:15]([NH:16][C:23]([N:22]([O:21][CH3:20])[CH3:26])=[O:24])=[CH:14][CH:13]=3)[C:4]=2[O:3]1
Reactant: CC1(C)Cc2cccc(Oc3ccc(N)cc3)c2O1
Reactant: CON(C)C(=O)Cl
Solvent: CN(C)C=O
Product: CON(C)C(=O)Nc1ccc(Oc2cccc3c2OC(C)(C)C3)cc1
Reaction time: 1.5 h
Yield: 69.6 %

Procedure:
1.5 g of 4-(2,3-dihydro-2,2-dimethyl-7-benzofuranyloxy)aniline was dissolved in 20 ml of N,N-dimethylformamide, and 0.8 g of N-methoxy-N-methylcarbamoyl chloride was gradually added to this solution at room temperature. After 1.5 hours, N,N-dimethylformamide was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, washed with water and dried over magnesium sulfate. After distilling off the solvent, the residual oily substance was purified by silica gel column chromatography by using a solvent mixture of ethyl acetate/n-hexane=1/4 as the developer, to obtain 1.4 g of compound No. 2 as identified in Table 1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([CH2:14][NH:15][CH2:16][C@@H:17]([OH:32])[C@@H:18]([NH:28][C:29](=[O:31])[CH3:30])[CH2:19][C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=2)[CH:3]=1.C([Sn](CCCC)(CCCC)[C:38]([O:40]CC)=[CH2:39])CCC.[ClH:51]>C1(C)C=CC=CC=1.CCOCC>[ClH:51].[C:38]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([CH2:14][NH:15][CH2:16][C@@H:17]([OH:32])[C@@H:18]([NH:28][C:29](=[O:31])[CH3:30])[CH2:19][C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=2)[CH:3]=1)(=[O:40])[CH3:39]
Reactant: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNCc1cc(Br)ccc1-c1ccccc1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNCc1cc(C(C)=O)ccc1-c1ccccc1
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
To N-[(1S,2R)-3-{[(4-bromo-1,1′-biphenyl-2-yl)methyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]acetamide (120 mg, 0.24 mmol) in toluene (1 mL) was added tributyl(1-ethoxyvinyl)tin (100 μL, 0.28 mmol) and bis-triphenylphoshine palladium(II) dichloride (10 mg, 0.012 mmol), and the reaction was heated at 100° C. 3 h under N2. The solution was cooled to room temperature, 1 N hydrochloric acid (1 mL) was added, and the mixture was stirred 20 min. The mixture was partitioned, and the organics were washed with saturated potassium fluoride (aq). The reaction mixture was dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 8% methanol/methylene chloride) provided an oil. The residue was dissolved in ether, precipitated with excess 1N HCl in ether, and concentrated to provide the title compound (11 mg). ESI MS m/z 467.28 [M+H]+.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C=O)C>[CH2:14]([N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: O=C1Nc2ccccc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1C(=O)N(Cc2ccccc2)c2ccccc21
Reaction time: 0.33 h
Yield: 84.9 %

Procedure:
Prepared according to literature procedure (C. Martin and E. M. Carreira, J. Am. Chem. Soc., 2005, 127, 11505-11515). A stirred solution of isatin (10.0 g, 68 mmol) in dry DMF (125 mL) was cooled in an ice bath before addition of sodium hydride (60 wt % in mineral oil, 2.86 g, 71.5 mmol) in 10 portions, the orange solution turning quickly purple. When no further evolution of gas was observed, benzyl bromide (13.4 g, 78.0 mmol) was added by syringe. A colour change back to orange was observed within 20 min. Water (300 mL) was added with stirring, and the resulting orange-red precipitate collected by filtration and washed with water and a little cold ethanol. The solid was then recrystallized from boiling ethanol (300 mL) to afford N-benzylisatin (13.7 g, 85%) as long, red needles.
Reaction SMILES: O=[O+][O-].C(C[O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][C@H:14]3[N:26]([CH3:27])[CH2:25][CH2:24][C@:20]45[C:21]=2[C:22]=1[O:23][C@H:19]4[C@@H:18]([OH:28])[CH:17]=[CH:16][C@@H:15]35)(O)=O.C([O-])(=O)C(CC([O-])=O)O>>[CH:11]1[C:12]2[CH2:13][C@H:14]3[N:26]([CH2:25][CH2:24][C@@:20]45[C@H:15]3[CH:16]=[CH:17][C@H:18]([OH:28])[C@@H:19]4[O:23][C:22]([C:21]=25)=[C:9]([OH:8])[CH:10]=1)[CH3:27]
Reactant: CN1CC[C@]23c4c5ccc(OCC(=O)O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Agent: O=C([O-])CC(O)C(=O)[O-]
Agent: O=[O+][O-]
Product: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5

Procedure:
1.4 O3 -Carboxymethyl morphine conjugate to malate dehydrogenase.