Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10]2[C:15]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:13]=[CH:12][N:11]=2)[S:7][CH:8]=1.C(N(CC)CC)C.[C:31]([Cl:34])(=[O:33])[CH3:32]>CN(C=O)C>[ClH:34].[CH2:17]([O:16][C:15]1[C:10]([NH:9][C:6]2[S:7][CH:8]=[C:4]([CH2:3][CH2:2][NH:1][C:31](=[O:33])[CH3:32])[N:5]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCCc1csc(Nc2ncccc2OCc2ccccc2)n1
Reactant: CC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)NCCc1csc(Nc2ncccc2OCc2ccccc2)n1
Product: Cl
Reaction time: 2 h
Yield: 46.8 %

Procedure:
Crude 4-(2-aminoethyl)-N-(3-(benzyloxy)pyridin-2-yl)thiazol-2-amine (0.50 g, 1.53 mmol) was dissolved in DMF (20 mL), and triethylamine (0.854 ml, 6.13 mmol) was added, followed by the addition of acetyl chloride (0.240 g, 3.06 mmol). The reaction mixture was stirred for 2 hours, then partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried, and concentrated. The residue was dissolved in THF (10 mL) and 1N HCl in ether (2 mL) was added. The mixture was diluted in ether (15 mL) and triturated for 15 minutes, and the solids were filtered, washed with ether and hexanes, and dried to afford the title compound (0.290 g, 46.8% yield) as a light yellow powder. 1H NMR (DMSO-d6) δ 1.80 (s, 3H), 2.80 (m, 2H), 3.37 (m, 2H), 5.34 (s, 2H), 6.96 (s, 1H), 7.15 (m, 1H), 7.32-7.43 (m, 3H), 7.57-7.66 (m, 3H), 8.00 (d, 1H), 8.05 (t, 1H), 8.20 (bs, 1H), 11.35 (bs, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:46])[C:7]1[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](=[O:45])[NH:31][C@H:32]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH:17]=[C:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)F.CN(C(O[N:60]1[C:65](=[O:66])[CH2:64][CH2:63][C:61]1=[O:62])=[N+](C)C)C.CCN(C(C)C)C(C)C>C1COCC1>[C:13]([O:12][C:10](=[O:11])[C:9]1[CH:17]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](=[O:45])[NH:31][C@H:32]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:33][CH2:34][C:35]([O:37][N:60]2[C:65](=[O:66])[CH2:64][CH2:63][C:61]2=[O:62])=[O:36])[CH:19]=[C:7]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:46])[CH:8]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)c1cc(OCCCCCCCCCC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C)cc(C(=O)OC(C)(C)C)c1
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cc(OCCCCCCCCCC(=O)N[C@@H](CCC(=O)ON2C(=O)CCC2=O)C(=O)OC(C)(C)C)cc(C(=O)OC(C)(C)C)c1
Temperature: 25 °C

Procedure:
5-[9-((S)-1-tert-Butoxycarbonyl-3-carboxy-propylcarbamoyl)-nonyloxy]-isophthalic acid di-tert-butyl ester (70 mg, 0.11 mmol) was dissolved in dry THF (1 ml). TSTU (40 mg, 0.13 mmol) and DIPEA (0.05 ml) was added. The mixture was stirred at room temperature under nitrogen over the weekend. The mixture was concentrated. The residue was redissolved in EtOAc and filtered. The filtrate was washed with 0.1N HCl (2×), washed with brine (1×), dried (Na2SO4) and concentrated to give a clear syrup. There was still starting material present and the TSTU-treatment was repeated followed by work up to give the title compound as a clear syrup.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:22][CH3:23])=[C:4]([C:8]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2F)(=[O:14])=[O:13])=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].C(N(CC)CC)C.[CH3:31][N:32]([CH3:39])[CH2:33][C:34]([CH3:38])([CH3:37])[CH2:35][NH2:36]>C(#N)C>[Br:1][C:2]1[C:3]([O:22][CH3:23])=[C:4]([C:8]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH:36][CH2:35][C:34]([CH3:38])([CH3:37])[CH2:33][N:32]([CH3:39])[CH3:31])(=[O:14])=[O:13])=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: COc1c(Br)ccc(NS(=O)(=O)c2ccccc2F)c1C(=O)O
Reactant: CN(C)CC(C)(C)CN
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1c(Br)ccc(NS(=O)(=O)c2ccccc2NCC(C)(C)CN(C)C)c1C(=O)O
Temperature: 65 °C
Reaction time: 144 h

Procedure:
A mixture of Example 371A (150 mg, 0.37 mmol), acetonitrile (2.5 mL), triethylamine (0.26 mL, 1.86 mmol), and N,N,2,2-tetramethyl-1,3-propanediamine (381 mg, 3.0 mmol) was sealed in a vial and shaken at 65° C. for 144 hours and heated to 80° C. for 18 hours. The mixture was concentrated and the residue was purified by preparative HPLC on a; Waters Symmetry C8 column (25 mm×100 mm, 7 μm particle size) using a gradient of 10% to 100% acetonitrile/10 mmol aqueous ammonium acetate over 8 minutes (10 minute run time) at a flow rate of 40 mL/min to provide the desired product. MS (ESI(+)) m/e 514, 516 (M+H)+; (ESI(−)) m/e 512, 514 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 12.07 (br s, 1H), 7.61 (d, 1H), 7.38 (d, 1H), 7.31 (t, 1H), 7.01 (d, 1H), 6.85 (t, 1H), 6.63 (t, 1H), 5.75 (s, 1H), 3.68 (s, 3H), 3.26 (br s, 1H), 3.09 (m, 4H), 2.79 (br s, 6H), 1.07 (s, 6H).
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5])#[N:2].Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].[C:17](=[O:20])(O)[O-].[Na+]>C(O)C>[C:17]([N:5]([C:4]1[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=1[C:1]#[N:2])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:20])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:4]=1
Reactant: CCOC(=O)CBr
Reactant: O=C([O-])O
Reactant: N#Cc1ccccc1N
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CN(C(=O)c1ccccc1)c1ccccc1C#N
Reaction time: 42 h

Procedure:
2-cyanoaniline (59g), ethyl bromoacetate (90g) and sodium bicarbonate (50g) were refluxed in ethanol (500ml), with stirring, for 42 hours. The reaction mixture was cooled slightly, filtered, and the filtrate cooled. The solid which formed was removed by filtration. Evaporation left an oil, containing unreacted starting material and the desired product, N-(2-cyanophenyl) glycine, ethyl ester. Trituration with ethanol and cooling gave the required product which after filtering was crystallized from ethanol.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[CH2:9]([O:11][C:12]([C:14]1([CH2:27][CH:28]=O)[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)=[O:13])[CH3:10].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.C(Cl)Cl>[CH2:9]([O:11][C:12]([C:14]1([CH2:27][CH2:28][NH:8][C:5]2[CH:4]=[N:3][C:2]([Br:1])=[CH:7][N:6]=2)[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)=[O:13])[CH3:10]
Reactant: CCOC(=O)C1(CC=O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: Nc1cnc(Br)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)C1(CCNc2cnc(Br)cn2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 92.5 %

Procedure:
To a solution of 5-bromo-2-pyrazinamine (0.35 g, 2.01 mmol) in 1-2 dichloroethane (DCE, 5.0 mL) was added a solution of 4-(2-oxo-ethyl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (0.722 g, 2.41 mmol) in DCE (2.0 mL), acetic acid (3.1 eq) and allowed to stir at room temperature for an hour. NaBH(OAc)3 (3.0 eq.) was then added in one portion and reaction mixture was allowed to stir at room temperature for 16 hours. The reaction mixture was then diluted with DCM (5 mL), quenched with 2 M of NH4OH in water. The layers were separated, and the aqueous layer was extracted with DCM (5.0 mL×2). The combined organic layers were washed with aqueous NaHCO3 (15 mL), brine (30 mL), and dried over Na2SO4, and concentrated under vacuum. Purification by column chromatography on silica gel eluting with methanol in dichloromethane (0-10%) afforded 0.85 g (77%) of title compound.
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[OH-].[K+].Cl.[N:13]1[CH:18]=[CH:17][C:16]([CH2:19]Cl)=[CH:15][CH:14]=1.C>CS(C)=O.C(OCC)(=O)C.O>[N:13]1[CH:18]=[CH:17][C:16]([CH2:19][O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[CH:1]=[O:9])=[CH:15][CH:14]=1
Reactant: ClCc1ccncc1
Reactant: O=Cc1ccccc1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=Cc1ccccc1OCc1ccncc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.1 %

Procedure:
A solution of salicylaldehyde (5 g, 40.9 mmol) in DMSO (75 mL) was treated with crushed potassium hydroxide (5.4 g, 81.8 mmol) and allowed to stir at room temperature for 1 hour. This was then treated with 4-picolyl chloride hydrochloride (6.8 g, 40.9 mmol) and the dark mixture allowed to stir overnight. The mixture was poured into water and extracted twice with ethyl acetate. The combined ethyl acetate extracts were washed with 5% NaOH, three times with water then with brine. Drying over MgSO4 and removal of the solvent under reduced pressure gave the crude product. This was taken up in ethyl acetate, treated with charcoal, filtered, and the solvent removed under reduced pressure to give 5.42 g (62.1%) of the product as an oil; MS-CI 214 (M+1).
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:18]([CH3:21])([CH3:20])[CH3:19])[S:8]/[C:9]/1=[N:10]\[C:11]([CH:13]1[CH2:17][CH2:16][NH:15][CH2:14]1)=[O:12])[CH2:2][CH2:3][CH3:4].[CH2:22]([O:24][C:25](Cl)=[O:26])[CH3:23]>>[CH2:1]([C:5]1=[CH:6][N:7]([C:18]([CH3:20])([CH3:19])[CH3:21])[S:8]/[C:9]/1=[N:10]\[C:11]([CH:13]1[CH2:17][CH2:16][N:15]([C:25]([O:24][CH2:22][CH3:23])=[O:26])[CH2:14]1)=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)Cl
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)C1CCNC1
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)C1CCN(C(=O)OCC)C1

Procedure:
The product from Example 104B and ethylchloroformate (Aldrich) were processed using the method described in Example 102 to afford the title compound. 1H NMR (DMSO-d6) δ 0.91 (t, J=7.3 Hz, 3H), 1.18 (t, J=6.9 Hz, 3H), 1.24-1.37 (m, 3H), 1.51-1.64 (m, 3H), 1.58 (s, 9H), 2.05-2.14 (m, 2H), 2.61-2.66 (m, 2H), 3.21-3.28 (m, 1H), 3.49-3.64 (m, 2H), 4.02 (q, J=7.1 Hz, 2H), 8.57 (s, 1H). (ESI+) m/z 410 (M+H)+.
Reaction SMILES: [N:1]1([C:6]2[N:10]([C:11]([CH3:14])([CH3:13])[CH3:12])[N:9]=[CH:8][C:7]=2[CH2:15]O)[CH:5]=[CH:4][CH:3]=[CH:2]1.S(Cl)([Cl:19])=O>ClCCl>[Cl:19][CH2:15][C:7]1[CH:8]=[N:9][N:10]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[N:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1
Reactant: CC(C)(C)n1ncc(CO)c1-n1cccc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)n1ncc(CCl)c1-n1cccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2.20 g of [5-(1H-pyrrol-1-yl)-1-t-butyl-1H-pyrazol-4-yl]methanol was dissolved in 20 ml of dichloromethane, and 0.73 ml of thionyl chloride was added. The mixture was stirred at room temperature for 1.5 hours and then concentrated under reduced pressure. After aqueous saturated sodium hydrogen carbonate was added, the residue was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 2.35 g of 4-(chloromethyl)-5-(1H-pyrrol-1-yl)-1-t-butyl-1H-pyrazole.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:9][CH2:8][CH2:7][NH:6]1)[CH:2]([CH3:4])[CH3:3].CC(C)CCN.[N:16]1[CH:17]=[CH:18][N:19]2[CH:24]=[CH:23][C:22]([CH2:25][NH:26][C:27]([C:29]3[S:33][C:32]([C:34]([O-])=[O:35])=[CH:31][CH:30]=3)=[O:28])=[CH:21][C:20]=12.[Li+].[N+](C1C=CC(C(O)=O)=CC=1)([O-])=O>>[N:16]1[CH:17]=[CH:18][N:19]2[CH:24]=[CH:23][C:22]([CH2:25][NH:26][C:27]([C:29]3[S:33][C:32]([C:34]([N:6]4[CH2:7][CH2:8][CH2:9][CH:5]4[CH2:1][CH:2]([CH3:4])[CH3:3])=[O:35])=[CH:31][CH:30]=3)=[O:28])=[CH:21][C:20]=12
Reactant: CC(C)CC1CCCN1
Reactant: O=C([O-])c1ccc(C(=O)NCc2ccn3ccnc3c2)s1
Agent: CC(C)CCN
Agent: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: [Li+]
Product: CC(C)CC1CCCN1C(=O)c1ccc(C(=O)NCc2ccn3ccnc3c2)s1

Procedure:
The title compound was prepared as described in Example 1A, substituting), 2-isobutylpyrrolidine for 3-methylbutan-1-amine and lithium 5-(imidazo[1,2-a]pyridin-7-ylmethylcarbamoyl)thiophene-2-carboxylate for 4-nitrobenzoic acid. 1H NMR (300 MHz, DMSO-d6) ppm 9.23 (t, J=6.0 Hz, 1H), 8.49 (dd, J=6.9, 0.9 Hz, 1H), 7.90-7.88 (m, 1H), 7.79 (d, J=4.0 Hz, 1H), 7.60 (d, J=4.0 Hz, 1H), 7.52 (d, J=1.2 Hz, 1H), 7.42-7.39 (m, 1H), 6.85 (dd, J=7.0, 1.7 Hz, 1H), 4.49 (d, J=5.9 Hz, 2H), 4.35-4.23 (m, 1H), 3.78-3.65 (m, 2H), 3.26 (s, 3H), 2.02-1.81 (m, 4H); MS (ESI(+)) m/e 411 (M+H)+.
Reaction SMILES: S1C2C=CC=CC=2N=C1N(COCC[Si](C)(C)C)C(C1C=CC=C2C=1CN(C1SC([CH2:32][N:33]3[CH2:38][CH2:37][N:36]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH2:35][CH2:34]3)=C(C(OC)=O)N=1)CC2)=O.C(C1SC(N2CCC3C(=C(C(=O)/N=C4/SC5C=CC=CC=5N/4COCC[Si](C)(C)C)C=CC=3)C2)=NC=1C(OC)=O)=[O:54].C1C=CC(N2CCNCC2)=CC=1.N1(C2C=C(O)C=CC=2)CCNCC1>>[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:44]=[C:43]([OH:54])[CH:42]=[CH:41][CH:40]=2)[CH2:35][CH2:34]1
Reactant: COC(=O)c1nc(N2CCc3cccc(C(=O)/N=c4/sc5ccccc5n4COCC[Si](C)(C)C)c3C2)sc1C=O
Reactant: COC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1CN1CCN(c2ccccc2)CC1
Agent: Oc1cccc(N2CCNCC2)c1
Agent: c1ccc(N2CCNCC2)cc1
Product: CN1CCN(c2cccc(O)c2)CC1

Procedure:
Compound 87A was prepared in a similar manner to the synthesis of compound 62A by substituting compound 45C and phenylpiperazine with paraformahyde and 3-(piperazin-1-yl)phenol, respectively: 1H NMR (DMSO-d6): δ 9.07 (s, 1H), 6.94-6.98 (m, 1H), 6.36 (d, J=8.13, 2.4 Hz, 2H), 8.28-8.29 (m, 1H), 6.18-6.21 (m, 1H), 3.04-3.07 (m, 4H), 2.41-2.43 (m, 4H), 2.21 (s, 3H). ESI (+)/MS: 193 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH2:14]1[O:17][CH:15]1C.[C:18]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[OH:17][C@H:15]([CH3:14])[CH2:13][O:12][C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([O:1][CH3:18])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: CC1CO1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(O)cc(OC)c1
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OC)cc(OC[C@@H](C)O)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
To a solution of compound methyl 3-hydroxy-5-methoxybenzoate (Example 1, step i, 90 mg, 0.5 mmol) and propylene oxide (120 mg, 2 mmol) in DMF (2 ml) was added K2CO3 (280 mg, 2 mmol). The reaction mixture was stirred at 100° C. overnight. After cooling to ambient temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified using normal phase chromatography, eluting with petroleum ether containing 50% ethyl acetate to give (R)-methyl 3-(2-hydroxypropoxy)-5-methoxybenzoate (100 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19](Br)=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].O.[C:32](OCC)(=[O:34])C>CO.N1C=CC=CC=1.[Cu](I)I>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([O:34][CH3:32])=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1
Reactant: CCOC(C)=O
Agent: I[Cu]I
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Solvent: CO
Product: COc1cncc2cccc(S(=O)(=O)N3CCC(NC(=O)OC(C)(C)C)C3)c12
Temperature: 25 °C

Procedure:
A solution of Intermediate 1 (337 mg) obtained in Example 1, Step A in methanol (2.7 ml) and pyridine (2.7 ml) is added with a solution of 28% sodium methylate (847 mg) in methanol, and then with copper iodide (70 mg), and the mixture is stirred at 65° C. for 30 hours. The reaction mixture is cooled to room temperature, and added with water (30 ml) and ethyl acetate (30 ml), and the insoluble matters are removed by filtration through Celite. The organic layer of the filtrate is separated, and the aqueous layer is extracted 3 times with ethyl acetate (20 ml for each time). The combined organic layer is washed 3 times with saturated brine (30 ml for each time), and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure, and the residue is purified by silica gel chromatography (chloroform:methanol=30:1) to obtain the title compound (98 mg (predictive yield)).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.FC(F)(F)S(O[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Si](C)(C)C)(=O)=O.[F-].[K+].C1OCCOCCOCCOCCOCCOC1>C1COCC1>[C:12]1([CH:11]2[O:18][CH:2]3[CH:3]=[CH:4][C:5]4[C:10]([N:1]3[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]2=3)=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1ccc2ncccc2c1
Reactant: O=Cc1ccccc1
Reactant: C[Si](C)(C)c1ccccc1OS(=O)(=O)C(F)(F)F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: C1=CC2OC(c3ccccc3)c3ccccc3N2c2ccccc21
Yield: 82 %

Procedure:
Following the general procedure, treatment of quinoline (0.064 g, 59 μL, 0.50 mmol) and benzaldehyde (0.080 g, 80 μL, 0.75 mmol) with 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (0.179 g, 146 μL, 0.60 mmol) in the presence of KF (0.070 g, 1.2 mmol) and 18-crown-6 (0.317 g, 1.2 mmol) in THF (2.0 mL) at −10° C. to room temperature for 12 hrs followed by flash column chromatography (Pet. ether/EtOAc=75/25) of the crude reaction mixture afforded 5-phenyl-5H,6aH-benzo[4,5][1,3]oxazino[3,2-a]quinoline as a yellow solid (0.128 g, 82% yield, dr determined by 1H NMR analysis of crude reaction mixture is >20:1).
Reaction SMILES: C([NH:8][C@@H:9]1[CH2:15][CH2:14][C@@H:13]2[N:16](CC3C=CC=CC=3)[C@@:10]1([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:11][C@H:12]2[CH2:24][OH:25])C1C=CC=CC=1.C1CC=CCC=1>C(O)C.[Pd]>[NH2:8][C@@H:9]1[CH2:15][CH2:14][C@@H:13]2[NH:16][C@@:10]1([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[CH2:11][C@H:12]2[CH2:24][OH:25]
Reactant: OC[C@@H]1C[C@@]2(c3ccccc3)[C@H](NCc3ccccc3)CC[C@@H]1N2Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCC=CC1
Product: N[C@@H]1CC[C@@H]2N[C@@]1(c1ccccc1)C[C@H]2CO
Yield: 75.5 %

Procedure:
(1R*,2R*,5S*,6R*)-2-Benzylamino-8-benzyl-6-hydroxymethyl-1-phenyl-8-azabicyclo[3.2.1]octane (Description 19; 220 mg, 0.53 mmol) was dissolved in ethanol (5 mL) and treated with 10% palladium on activated charcoal (100 mg), followed by 1,4-cyclohexadiene (1.5 mL). The suspension formed was heated at reflux for 24 hours, then cooled and filtered. The filtrate was concentrated in vacuo, and the oil remaining purified by silica chromatography to yield the title compound as a gum (92 mg, 0.4 mmol).
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3](Cl)=[O:4].[CH2:8]([O:10]/[CH:11]=[CH:12]/[CH3:13])[CH3:9].N1C=CC=CC=1>ClCCl>[Cl:1][C:2]([Cl:7])([Cl:6])[C:3](=[O:4])/[C:12](/[CH3:13])=[CH:11]/[O:10][CH2:8][CH3:9]
Reactant: C/C=C/OCC
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCO/C=C(\C)C(=O)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 119.7 %

Procedure:
To a solution of 2,2,2-trichloroacetyl chloride (10.6 g, 6.52 mL, 58.1 mmol) in dichloromethane (15 mL) cooled to −10° C. was added a mixture of (E)-1-ethoxyprop-1-ene (5 g, 6.43 mL, 58.1 mmol) and pyridine (4.59 g, 4.7 mL, 58.1 mmol) over a period of 15 min. After the addition was complete, the mixture was stirred at RT for 16 h. The resulting precipitate was filtered and washed with dichloromethane. The filtrate was concentrated in vacuo and dried at 40° C. in high vacuum to give the product as brown semisolid (16.1 g with 80% purity, 95.8%). The crude material was used directly in the next step without any further purification.
Reaction SMILES: [F:1][C:2]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:23]([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25]>CC(C)=O>[CH2:27]([O:26][C:24](=[O:25])[CH:23]([N:6]1[C:5]2[CH:11]=[C:12]([N+:13]([O-:15])=[O:14])[C:2]([F:1])=[CH:3][C:4]=2[O:9][CH2:8][C:7]1=[O:10])[CH3:29])[CH3:28]
Reactant: CCOC(=O)C(C)Br
Reactant: O=C1COc2cc(F)c([N+](=O)[O-])cc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(C)N1C(=O)COc2cc(F)c([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.9 %

Procedure:
A suspension of 7-fluoro-6-nitro-4H-benzo[1,4]oxazin-3-one (3.50 g, 16.50 mmol) and K2CO3 (3.42 g, 24.75 mmol) in acetone (100 mL) was stirred at rt for 15 min. A solution of ethyl 2-bromopropanoate (5.97 g, 33.0 mmol) in acetone (60 mL) was added dropwise and the reaction mixture was heated at reflux for 5 h. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was dissolved in DCM (50 mL) and washed with water (50 mL). The organic phase was separated and dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 0-30% EtOAc in petroleum ether) to give 2-(7-fluoro-6-nitro-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester as a white solid (3.29 g, 64%). 1H NMR (DMSO-d6, 400 MHz): δ 7.89 (d, J=7.2 Hz, 1H), 7.39 (d, J=11.6 Hz, 1H), 5.28 (q, J=7.2 Hz 1H), 4.86 (s, 2H), 4.02-4.16 (m, 2H), 1.48 (d, J=7.2 Hz, 3H), 1.12 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:9]=[N:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[C:6](=[O:20])[CH:5]=1)[NH2:3].[CH3:21]OC(OC)N(C)C>CN(C)C=O>[CH3:1][N:2]1[C:4]2[C:9](=[N:8][N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=3)[C:6](=[O:20])[CH:5]=2)[CH:21]=[N:3]1
Reactant: CN(N)c1cnn(-c2cccc(C(F)(F)F)c2)c(=O)c1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: Cn1ncc2nn(-c3cccc(C(F)(F)F)c3)c(=O)cc21

Procedure:
In 225 ml. of absolute dimethylformamide (dried over molecular sieves) under a nitrogen atmosphere are dissolved 8.5 grams of 5-(1-methylhydrazino)-2-(3'-trifluoromethylphenyl)-3(2H)-pyridazinone. To this solution are added 7.1 grams of N,N-dimethylformamide dimethyl acetal and the solution is refluxed for 72 hours. The reaction is followed by thin layer chromatography The reaction mixture is then evaporated to dryness in vacuo and column chromatographed on silica gel, eluting with a mixture of benzene-chloroform (50/50), to obtain the crude title product which is then refined by preparative chromatography on a silica gel plate, eluting with chloroform to give crystalline title product, which is then washed with diethyl ether, m.p. 160°-163° C.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[CH:6]1([C:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]([CH2:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:15](=[O:30])[N:14]([CH2:31][C:32]([NH:34][C:35]3[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=3)[C:38](O)=[O:39])=[O:33])[N:13]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH:6]1([C:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]([CH2:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:15](=[O:30])[N:14]([CH2:31][C:32]([NH:34][C:35]3[CH:43]=[CH:42][CH:41]=[C:37]([C:38]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:39])[CH:36]=3)=[O:33])[N:13]=2)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)Nc2cccc(C(=O)O)c2)N=C(C2CCCCC2)c2ccccc21
Reactant: CS(N)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)Nc2cccc(C(=O)NS(C)(=O)=O)c2)N=C(C2CCCCC2)c2ccccc21
Reaction time: 17 h
Yield: 82.3 %

Procedure:
Methanesulfonamide (96 mg, 1.00 mmol) was added to a solution of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid (Example 2)(409 mg, 0.80 mmol), EDC (207 mg, 1.08 mmol) and DMAP (122 mg, 1.00 mmol) in DCM (20 ml) at room temperature. After stirring for 17 h, the mixture was washed with 5% KHSO4 (50 ml), brine (50 ml) and dried (MgSO4). Filtration and evaporation of the solvent gave the crude product which was purified by flash column chromatography (MeOH-DCM (1:10) to afford the title compound as a white crystalline solid (392 mg, 83%). 1H NMR (DMSO-d6) 9.99 (1H, s), 8.02 (1H, s), 7.63-7.36 (5H, m), 7.23 (1H, t), 7.13 (1H, d), 4.73 (2H, dd), 4.29 and 4.25 (2H, d×2), 3.24 (3H, s), 2.87 (1H, m), 1.80-1.48 (6H, m), 1.30-1.09 (13H, m). The compound was further characterised as the N-methyl-D-glucamine salt. Found: C, 53.93; H, 7.07; N, 10.17%; C30H37N5O6S.C7H17NO5.2.0H2O requires: C, 53.74; H, 7.07; N, 10.16%.