Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]2[CH:15]=[N:14][CH:13]=[CH:12][N:11]=2)=[CH:4][CH:3]=1.Cl.[NH2:18][OH:19].C(=O)([O-])[O-].[Na+].[Na+].O>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:18][OH:19])[CH2:9][C:10]2[CH:15]=[N:14][CH:13]=[CH:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cc1cnccn1)c1ccc(Cl)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=C(Cc1cnccn1)c1ccc(Cl)cc1

Procedure:
10 g of 4'-chloro-2-(2-pyrazinyl)-acetophenone, 10 g of hydroxylamine hydrochloride and 12 g of anhydrous sodium carbonate are stirred at 60° in 100 ml of ethanol for 2 hours. The mixture is then treated with water and extracted with ethyl acetate, and the organic phase is dried over sodium sulfate and subsequently concentrated. The residue is crystallized from acetone/n-hexane to yield 4'-chloro-2-(2-pyrazinyl)-acetophenone oxime, m.p. 134°.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[S:8][C:9]([C:11]([O:13]C)=[O:12])=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[C:7]2[S:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc2cccc(Cl)c2s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc2cccc(Cl)c2s1

Procedure:
Methyl 7-chlorobenzo[b]thiophene-2-carboxylate (3 g, 13 mmol) was dissolved is ethanol (15 mL) and treated 5 N sodium hydroxide (5 mL). The reaction was heated at reflux overnight. The volatiles were removed in vacuo and the aqueous residue was acidified to pH 2 using 5 N HCl. The resulting white solid was filtered off, washed well with water and dried in a vacuum oven at 60° C. Yield=2.6 g. MS (M−H)− 210.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[O:12][C:13]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[CH:22]=[C:21]([O:26][CH2:27][C:28]#[N:29])[CH:20]=[CH:19]4)=[CH:14][N:15]=2)=[CH:3]1.[N-:30]=[N+:31]=[N-:32].[Na+].[Cl-].[NH4+].Cl>CN(C=O)C.O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[O:12][C:13]([C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[C:21]([O:26][CH2:27][C:28]5[NH:32][N:31]=[N:30][N:29]=5)[CH:22]=4)[CH:17]=3)=[CH:14][N:15]=2)=[CH:3]1
Reactant: [N-]=[N+]=[N-]
Reactant: Cn1cc(-c2ncc(-c3ccc4cc(OCC#N)ccc4c3)o2)c2ccccc21
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(-c2ncc(-c3ccc4cc(OCc5nnn[nH]5)ccc4c3)o2)c2ccccc21
Temperature: 100 °C
Reaction time: 5 h
Yield: 82.3 %

Procedure:
A mixture of ({6-[2-(1-methyl-1H-indol-3-yl)-1,3-oxazol-5-yl]-2-naphthyl}oxy)acetonitrile (313 mg, 0.826 mmol), prepared in the previous step, sodium azide (163 mg, 2.5 mmol) and ammonium chloride (134 mg, 2.5 mmol) in 20 mL of DMF was stirred under nitrogen at 100° C. for 5 h. Following the reaction by MS, starting material remained. Additional sodium azide (165 mg, 2.6 mmol) and ammonium chloride(134 mg, 2.5 mmol) were added and the reaction stirred at 100° C. for two more hours. This procedure was repeated three additional times until the MS showed that the reaction had gone to completion. The reaction was acidified with 25 mL of 1N HCl and then diluted with 25 mL of H2O. The solid that formed was collected by filtration and dried under reduced pressure to give the title compound (287 mg, 82%) as a brown solid, mp 254-256° C. Elemental Analysis for C24H18N6O2+0.71 H2O Calc'd: C, 66.23; H, 4.50; N, 19.31. Found: C, 63.15; H, 4.17; N, 18.00.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2[NH:8][C:9]3[C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=[C:12]([O:20][CH3:21])[C:10]=3[N:11]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].C(B(CC)[C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1)C>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:21][O:20][C:12]1[C:10]2[N:11]=[C:7]([CH2:6][C:5]3[CH:22]=[CH:23][C:2]([C:33]4[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=4)=[CH:3][CH:4]=3)[NH:8][C:9]=2[C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1
Reactant: CCB(CC)c1cccnc1
Reactant: COC(=O)c1ccc(OC)c2nc(Cc3ccc(Br)cc3)[nH]c12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(OC)c2nc(Cc3ccc(-c4cccnc4)cc3)[nH]c12
Temperature: 25 °C
Yield: 59.3 %

Procedure:
A solution of methyl 2-(4-bromobenzyl)-7-methoxy-3H-benzimidazole-4-carboxylate [0.268 g, Reference Example 3(1)] in toluene (8 ml) was treated with tetrakis(triphenylphosphine) palladium (0) (0.266 g), aqueous sodium carbonate solution (0.5 ml, 2M) and diethyl (3-pyridyl)borane (0.085 g). The mixture was heated at reflux for 12 hours then cooled to room temperature. Aqueous work-up and subjected to flash chromatography on silica to give the title compound (0.128 g). NMR {(CD3)2SO}: δ 3.90(s, 3H), 4.10(s, 3H), 4.40(s, 2H), 6.70(d, 1H), 7.45(d, 3H), 7.60(d, 3H), 7.90 (dd, 1H), 8.60(d, 1H), 8.85(d, 1H), 10.10(s, 1H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11]([N:13]1[CH2:17][CH2:16][C@H:15]([OH:18])[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].N1C=CC=CC=1.C(OCC)(=O)C>ClCCl.O>[C:6]([O:10][C:11]([N:13]1[CH2:17][CH2:16][C@@H:15]([O:18][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:14]1)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CC[C@@H](OS(C)(=O)=O)C1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
Methanesulfonyl chloride was added to a mixture of (S)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (40 g) and pyridine (17.4 g) in dichloromethane (400 mL) at 0° C. The reaction mixture was stirred at this temperature for 15 min and then heated at 50° C. for 8 h. The reaction mixture was subsequently mixed with ethyl acetate and water, and the ethyl acetate phase was washed with dil. HCl solution. The ethyl acetate phase was dried over sodium sulfate and the solvent was removed in vacuo. The (R)-3-methanesulfonyloxypyrrolidine-1-carboxylic acid tert-butyl ester obtained in this way was dissolved in pyrrolidine (18.2 mL), and the reaction mixture was heated to 100° C. The reaction mixture was then mixed with ethyl acetate and water. The ethyl acetate phase was washed several times with water. The organic phase was dried over sodium sulfate and the solvent was removed in vacuo.
Reaction SMILES: CN1CCCCC1.[CH3:8][C:9]1[CH:10]=[C:11]([S:15](Cl)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=1.[NH2:19][CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([CH2:30][C:31]([NH:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)=[O:32])[CH:28]=2)[O:23][C:22]([CH3:43])([CH3:42])[CH:21]1[OH:44]>ClCCl>[Cl:41][C:38]1[CH:39]=[CH:40][C:35]([CH2:34][NH:33][C:31](=[O:32])[CH2:30][C:27]2[CH:28]=[C:29]3[C:24](=[CH:25][CH:26]=2)[O:23][C:22]([CH3:43])([CH3:42])[CH:21]([OH:44])[CH:20]3[NH:19][S:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([CH3:8])[CH:10]=2)(=[O:17])=[O:16])=[CH:36][CH:37]=1
Reactant: CC1(C)Oc2ccc(CC(=O)NCc3ccc(Cl)cc3)cc2C(N)C1O
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Solvent: CN1CCCCC1
Solvent: ClCCl
Product: Cc1cccc(S(=O)(=O)NC2c3cc(CC(=O)NCc4ccc(Cl)cc4)ccc3OC(C)(C)C2O)c1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
15 mg PS-methylpiperidine and a solution of 6.0 mg 3-methylbenzenesulfonyl chloride in 0.5 ml dichloromethane were added in succession in a sample well of a sample plate for automatic parallel synthesis to a solution of 9 mg of the 2-(4-amino-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-N-4-chlorobenzyl acetamide obtained above in 0.5 ml dichloromethane. The sample plate was shaken for 40 hours at room temperature, and then 20 mg AMPS was added to the well. The plate was shaken for a further 16 hours at room temperature before the liquid reaction phase was separated from the resin, and the resin was washed twice with 1 ml portions of dichloromethane. The solvent of the combined organic phases was evaporated at reduced pressure, and the title compound was obtained in a purity of 95% (determination by HPLC-MS), [M+H]+ 529.
Reaction SMILES: [Li+].[C:2]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:18][CH2:17][CH2:16][N:15]([CH2:19][CH2:20][CH2:21][C:22]([O-:24])=O)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].F[P-](F)(F)(F)(F)F.CN(C)C(ON1C2C=CC=CC=2N=N1)=[N+](C)C.Cl.[N+:50]([C:53]1[CH:58]=[CH:57][C:56]([NH:59][CH:60]2[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]2)=[CH:55][C:54]=1[C:66]([F:69])([F:68])[F:67])([O-:52])=[O:51].C(N(C(C)C)CC)(C)C.[O-2].[Al+3].[O-2].[O-2].[Al+3]>O1CCCC1.CN(C)C=O>[C:2]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:18][CH2:17][CH2:16][N:15]([CH2:19][CH2:20][CH2:21][C:22]([N:63]3[CH2:64][CH2:65][CH:60]([NH:59][C:56]4[CH:57]=[CH:58][C:53]([N+:50]([O-:52])=[O:51])=[C:54]([C:66]([F:67])([F:68])[F:69])[CH:55]=4)[CH2:61][CH2:62]3)=[O:24])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)([CH3:3])([CH3:5])[CH3:4]
Reactant: O=[N+]([O-])c1ccc(NC2CCNCC2)cc1C(F)(F)F
Reactant: CC(C)(C)c1ccc(N2CCCN(CCCC(=O)[O-])CC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(N2CCCN(CCCC(=O)N3CCC(Nc4ccc([N+](=O)[O-])c(C(F)(F)F)c4)CC3)CC2)cc1
Reaction time: 3 h
Yield: 18 %

Procedure:
To a solution of 4-[4-(4-tert-butyl-phenyl)-[1,4]diazepan-1-yl]-butyric acid lithium salt (16 mg; 0.05 mmol, prepared in accordance with Example 162) in tetrahydrofuran (0.5 mL) is added tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (19 mg; 0.05 mmol) in dimethylformamide (0.25 mL). A solution of (4-nitro-3-trifluoromethyl-phenyl)-piperidin-4-yl-amine hydrochloride (16 mg; 0.05 mmol, prepared in accordance with Example 8) in dimethylformamide (0.25 mL) and diisopropylethyl amine (25 μL; 0.15 mmol) are then added and the reaction is stirred. After 3 hours at room temperature, aluminium oxide (90 active basic) is added and stiffing is continued for 40 minutes. The solids are removed by filtration and the filtrate is concentrated under high vacuum. The obtained residue is purified by preparative HPLC to afford the desired compound (5 mg; 0.009 mmol). The structure was confirmed using Protocol I-D. Calculated mass=590; observed mass=590; HPLC retention time=1.66 min.
Reaction SMILES: [CH3:1][CH:2]([CH3:47])[C@H:3]([NH:42][C:43](=[O:46])[O:44][CH3:45])[C:4]([N:6]1[CH2:10][C@@H:9]([CH3:11])[CH2:8][C@H:7]1[C:12]1[NH:16][C:15]2[C:17]3[C:22]([CH:23]=[CH:24][C:14]=2[N:13]=1)=[CH:21][C:20]1[C:25]2[C:30]([CH2:31][O:32][C:19]=1[CH:18]=3)=[CH:29][C:28](B1OC(C)(C)C(C)(C)O1)=[CH:27][CH:26]=2)=[O:5].Br[C:49]1[NH:53][C:52]([C@@H:54]2[CH2:58][CH2:57][CH2:56][N:55]2[C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])=[N:51][CH:50]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:45][O:44][C:43]([NH:42][C@H:3]([C:4]([N:6]1[CH2:10][C@@H:9]([CH3:11])[CH2:8][C@H:7]1[C:12]1[NH:16][C:15]2[C:17]3[C:22]([CH:23]=[CH:24][C:14]=2[N:13]=1)=[CH:21][C:20]1[C:25]2[C:30]([CH2:31][O:32][C:19]=1[CH:18]=3)=[CH:29][C:28]([C:49]1[NH:53][C:52]([C@@H:54]3[CH2:58][CH2:57][CH2:56][N:55]3[C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])=[N:51][CH:50]=1)=[CH:27][CH:26]=2)=[O:5])[CH:2]([CH3:1])[CH3:47])=[O:46]
Reactant: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc2ccc3cc4c(cc3c2[nH]1)OCc1cc(B2OC(C)(C)C(C)(C)O2)ccc1-4)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(Br)[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc2ccc3cc4c(cc3c2[nH]1)OCc1cc(-c2cnc([C@@H]3CCCN3C(=O)OC(C)(C)C)[nH]2)ccc1-4)C(C)C
Temperature: 85 °C
Yield: 23.9 %

Procedure:
Methyl [(2S)-3-methyl-1-{(2S,4S)-4-methyl-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]pyrrolidin-1-yl}-1-oxobutan-2-yl]carbamate (298 mg, 0.47 mmol), (S)-tert-butyl 2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (443 mg, 1.4 mmol), Pd(PPh3)4 (54 mg, 0.05 mmol), PdCl2(dppf)2 (36 mg, 0.05 mmol), and K2CO3 (2M in H2O, 0.78 mL, 1.55 mmol) were combined in DME (5 mL). The mixture was degassed with bubbling N2 for 10 min then heated to 85° C. for 16 h. After cooling, the reaction mixture was diluted with EtOAc, and washed successively with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (0% to 30% MeOH/EtOAc) to afford tert-butyl (2S)-2-[5-(2-{(2S,4S)-1-[N-(methoxycarbonyl)-L-valyl]-4-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]pyrrolidine-1-carboxylate (84 mg, 24%).
Reaction SMILES: [CH2:1]([N:4]([CH2:10][CH:11]=O)[C:5](=[O:9])[O:6][CH2:7][CH3:8])[CH:2]=[CH2:3].O.[NH:14]1[CH2:17][CH2:16][CH:15]1C(O)=O>C1(C)C=CC=CC=1>[N:14]12[CH2:17][CH2:16][CH:15]1[CH2:3][CH:2]1[CH:11]2[CH2:10][N:4]([C:5]([O:6][CH2:7][CH3:8])=[O:9])[CH2:1]1
Reactant: O=C(O)C1CCN1
Reactant: C=CCN(CC=O)C(=O)OCC
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)N1CC2CC3CCN3C2C1

Procedure:
17.1 g (0.1 mol) of ethyl N-allyl-N-(2-oxoethyl) -carbamate are heated under reflux overnight in a water separator with 10 g (0.1 mol) of azetidine-2-carboxylic acid in 200 ml of toluene. Unreacted amino acid is filtered off with suction, the filtrate is concentrated and the residue is distilled.
Reaction SMILES: C(O[CH2:5][C:6]1[C@H:7]2[CH2:20][CH2:19][C@@H:18]([CH3:21])[C@H:8]2[C@H:9]([O:12][CH:13]([O:15][CH2:16][CH3:17])[CH3:14])[O:10][CH:11]=1)(=O)C.[H][H]>C(OCC)(=O)C.N1C=CC=CC=1.[C].[Pd]>[CH2:16]([O:15][CH:13]([O:12][C@H:9]1[C@@H:8]2[C@H:18]([CH3:21])[CH2:19][CH2:20][C@@H:7]2[C:6]([CH3:5])=[CH:11][O:10]1)[CH3:14])[CH3:17]
Reactant: CCOC(C)O[C@@H]1OC=C(COC(C)=O)[C@H]2CC[C@@H](C)[C@@H]12
Reactant: [H][H]
Agent: [Pd]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(C)O[C@@H]1OC=C(C)[C@H]2CC[C@@H](C)[C@@H]12
Yield: 74.5 %

Procedure:
(1S, 4aS, 7R, 7aR)-4-(acetoxymethyl)-1-[1-(ethoxy)ethoxy]-1, 4a, 5, 6, 7, 7a-hexahydro-7-methylcyclopenta[ c]pyran (65 mg, 0.00024 mol) obtained in Example 26 was dissolved in 3 mι of ethyl acetate, and 0.05 mι of pyridine and 10% palladium carbon (3 mg) were added. The reaction mixture was stirred for 24 hours in a hydrogen gas atmosphere of 1 atm. After the catalyst was removed by celite filtration, concentration was effected. The residual matter was purified by chromatography using silica gel, and the solvent of the fraction obtained from hexane:ether=8:2 eluent was distilled off. A colorless oily substance was thus obtained, i.e., (1S, 4aS, 7R, 7aR)-1-[1-(ethoxy)ethoxy]-1, 4a, 5, 6, 7, 7a-hexahydro-4, 7-dimethylcyclopenta[c]pyran (43 mg, yield=82%). This (1S, 4aS, 7R, 7aR)-1-[1-(ethoxy)ethoxy]-1, 4a, 5, 6, 7, 7a-hexahydro-4, 7-dimethylcyclopenta[c]pyran had the following physicochemical properties:
Reaction SMILES: [C:1](O)(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[CH2:13]1[C@H:22]2[C@H:17]([CH2:18][CH2:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=32)[NH:16][CH2:15][CH2:14]1>>[CH2:13]1[C@H:22]2[C@H:17]([CH2:18][CH2:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=32)[N:16]([C:1]([C:2]2[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=2)=[O:11])[CH2:15][CH2:14]1
Reactant: NC(=O)c1ccc(C(=O)O)cc1
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Product: NC(=O)c1ccc(C(=O)N2CCC[C@@H]3c4ccccc4CC[C@@H]32)cc1
Yield: 58 %

Procedure:
The title compound is prepared from terephthalamic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 58% of theory; LC (method 1): tR=3.16 min; Mass spectrum (ESI+): m/z=335 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][C:9]([OH:11])=O.Cl.[CH3:13][NH:14][O:15][CH3:16].C(Cl)CCl.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl.O>[CH3:16][O:15][N:14]([CH3:13])[C:9](=[O:11])[CH2:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: O=C(O)CCc1ccccn1
Reactant: CNOC
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)CCc1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
A solution of 3-pyridin-2-yl-propionic acid (1.0 g, 6.62 mmol), DMAP (10 mg), and N,O-dimethylhydroxylamine hydrochloride (679 g, 7.0 mmol) and EDC (1.34 g, 7.0 mmol) in dichloromethane (40 mL) was treated with triethylamine (2.8 mL, 20.0 mmol). After stirring at room temperature overnight, the solution was poured into water, extracted with ethyl acetate (3×) and the combined organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated. Purification by column chromatography (silica gel, 30-100% ethyl acetate in heptane) gave N-methoxy-N-methyl-3-(pyridin-2-yl)propanamide (1.02 g, 78%) as a colorless oil. ESI MS found for C10H14N2O2 m/z [195.1 (M+1)].
Reaction SMILES: [C:1]([Si:5]([CH3:36])([CH3:35])[O:6][CH:7]([CH2:11][CH2:12][CH:13]1[CH:22]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[C:21]2[C:16](=[C:17]([F:34])[CH:18]=[CH:19][C:20]=2[F:33])[O:15][CH2:14]1)[CH2:8][CH2:9]O)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.CS(Cl)(=O)=O.CC([O-])(C)C.[K+]>C(Cl)Cl.C1COCC1>[C:1]([Si:5]([O:6][CH:7]1[CH2:11][CH2:12][CH:13]2[CH2:14][O:15][C:16]3[C:21]([C:22]2([S:23]([C:26]2[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=2)(=[O:24])=[O:25])[CH2:9][CH2:8]1)=[C:20]([F:33])[CH:19]=[CH:18][C:17]=3[F:34])([CH3:36])[CH3:35])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OC(CCO)CCC1COc2c(F)ccc(F)c2C1S(=O)(=O)c1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: CS(=O)(=O)Cl
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC1CCC2COc3c(F)ccc(F)c3C2(S(=O)(=O)c2ccc(Cl)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
A solution of 3-(tert-butyl-dimethyl-silanyloxy)-5-[4-(4-chloro-benzenesulfonyl)-5,8-difluoro-chroman-3-yl]-pentan-1-ol (730 mg, 1.30 mmol) in CH2Cl2 (10 mL) at 0° C. was treated with Et3N (360 μL, 2.6 mmol) followed by MsCl (150 μL, 1.95 mmol). After 30 min, the reaction mixture was quenched with saturated aqueous NH4Cl and extracted with CH2Cl2 (2×). The combined organic extracts were washed with saturated aqueous NaHCO3, dried over MgSO4 and concentrated in vacuo to provide the crude product. The residue was dissolved in THF (13 mL), cooled to 0° C. and treated with KOt-Bu (1 M in THF, 3.0 mL, 3.0 mmol). After 1 h, the reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc (2×). The combined organic extracts were washed with saturated aqueous NaHCO3, brine, dried over MgSO4 and concentrated in vacuo to give the title compound (700 mg, 99% over 2 steps): 1H NMR (CDCl3 400 MHz) δ 7.63 (dd, J=8.8, 1.5 Hz, 2H), 7.49 (dd, J=8.8, 1.5 Hz, 2H), 7.04 (m, 1H), 6.43 (m, 1H), 5.07 (dd, J=10.9, 2.2 Hz, 1H), 4.23 (m, 1H), 4.04 (m, 0.5H), 3.58 (m, 0.5H), 2.97 (m, 1H), 2.71-2.26 (m, 2H), 2.10 (m, 1H), 1.83-1.43 (m, 5H), 0.90 (s, 4.5H), 0.77 (s, 4.5H), 0.03 (s, 3H), −0.01 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([N:9]1[CH:12]([S:13][N:14]2[C:18](=[O:19])[CH2:17][CH2:16][C:15]2=[O:20])[CH:11]([NH:21][C:22](=[O:30])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:10]1=[O:31])[C:6]([CH3:8])=[CH2:7])=[O:4].C1OC1C.[Br:36]N1C(=O)CCC1=O.ClCCCl>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([CH:5]([N:9]1[CH:12]([S:13][N:14]2[C:18](=[O:19])[CH2:17][CH2:16][C:15]2=[O:20])[CH:11]([NH:21][C:22](=[O:30])[CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:10]1=[O:31])[C:6]([CH2:8][Br:36])=[CH2:7])=[O:4]
Reactant: C=C(C)C(C(=O)OC)N1C(=O)C(NC(=O)Cc2ccccc2)C1SN1C(=O)CCC1=O
Reactant: O=C1CCC(=O)N1Br
Agent: CC1CO1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCCl
Product: C=C(CBr)C(C(=O)OC)N1C(=O)C(NC(=O)Cc2ccccc2)C1SN1C(=O)CCC1=O
Temperature: 76 °C

Procedure:
A mixture of 4.45 g (10 mmoles) of 1-(1-methoxycarbonyl-2-methylprop-2-enyl)-3-phenylacetamido-4-succinimidothio-azetidin-2-one, 10 ml of propylene oxide, 3.6 g (20 mmoles) of N-bromosuccinimide, 50 mg of azo-isobutyronitrile, 100 ml of 1,2dichloroethane and 200 ml of carbon tetrachloride was heated for 5 hours at 76° C under nitrogen. After washing with sodium metabisulfite and water, the reaction mixture was concentrated and purified by column chromatography [silica gel; toluene-ethyl acetate 3:1 (v/v)] to obtain 1-(1-methoxycarbonyl-2-bromomethylprop-2-enyl)-3-phenylacetamido-4-succinimidothio-azetidin-2-one. The structure was confirmed by PMR and IR spectroscopy.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.Cl[CH2:59][C:60]1[CH:65]=[C:64]([C:66]([F:69])([F:68])[F:67])[CH:63]=[C:62]([C:70]([F:73])([F:72])[F:71])[CH:61]=1.[Mg].[Cl-].[Li+]>O1CCCC1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Zn].[Cl-].[Zn+2].[Cl-]>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([CH2:59][C:60]2[CH:61]=[C:62]([C:70]([F:72])([F:73])[F:71])[CH:63]=[C:64]([C:66]([F:67])([F:68])[F:69])[CH:65]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1cc(CCl)cc(C(F)(F)F)c1
Reactant: Clc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: FC(F)(F)c1cc(Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc(C(F)(F)F)c1
Temperature: 65 °C
Reaction time: 1 h
Yield: 32.8 %

Procedure:
To a solution of 3,4-bis(benzyloxy)-6-chloropyridazine (Intermediate 1) (1 g, 3.06 mmol)dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.143 g, 0.3 mmol) and palladium (II) acetate (0.034 g, 0.15 mmol) in tetrahydrofuran (10 ml) under nitrogen was added the supernatant zinc reagent [generated from the addition of 1-(chloromethyl)-3,5-bis(trifluoromethyl)benzene (3 g, 11.43 mmol) to a suspension of magnesium (0.694 g, 28.6 mmol) in lithium chloride (28.6 ml, 14.28 mmol) in tetrahydrofuran (1M) and zinc(II) chloride (12.57 ml, 12.57 mmol) in tetrahydrofuran, warmed to 30° C. to initiate and stirred for one hour to complete] and the resulting red/brown mixture was heated at 65° C. for 16 hours. The reaction mixture was cooled, diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution, saturated aqueous ammonium chloride solution and brine. The organics were dried (MgSO4), filtered and solvent removed in vacuo to give a brown oil. The oil was purified by silica chromatography eluting with 0-40% ethyl acetate in petrol to yield the title compound (520 mg 33%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4](Cl)[N:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>CC(N(C)C)=O.CCOC(C)=O>[O:13]1[CH2:14][CH2:15][N:10]([C:4]2[CH:5]=[C:6]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[N:7]=[C:2]([NH2:1])[N:3]=2)[CH2:11][CH2:12]1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: C1COCCN1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Nc1nc(N2CCOCC2)cc(N2CCOCC2)n1
Temperature: 150 °C
Yield: 71.1 %

Procedure:
4,6-dimorpholinopyrimidin-2-amine was prepared using the following procedure: 2-amino-4,6-dichloropyrimidine (1 g, 6.10 mmol) and morpholine (5.33 ml, 60.9 mmol) were dissolved in DMA (1.1 ml) and sealed into a microwave tube. The mixture was heated to 150° C. over a period of 20 minutes in the microwave reactor. The reaction mixture was diluted with AcOEt, filtered and the filtrate concentrated to give an oil. The crude product was purified by flash chromatography on silica gel eluting with 0 to 4% methanol in dichloromethane. The solvent was evaporated to dryness to afford 4,6-dimorpholinopyrimidin-2-amine (1.15 g, 71%) as a white foam.