Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl.[NH2:18][C:19]1[CH:28]=[C:27]([CH2:29][S:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:26]=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22]>C(Cl)Cl>[C:8]([NH:18][C:19]1[CH:28]=[C:27]([CH2:29][S:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:26]=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccc(CSc2ccccc2)cc1N
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CSc2ccccc2)cc1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.52 mL of triethylamine and 0.16 mL of benzoyl chloride were added to 3.8 mL of methylene chloride suspension containing 0.39 g of methyl 2-amino-4-((phenylthio)methyl)benzoate hydrochloride while ice-cooled and stirred at room temperature for 3 hours and 30 minutes. The solvent was evaporated under reduced pressure and ethyl acetate and 1.0 mol/L hydrochloric acid were added to the obtained residue. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent vas evaporated under reduced pressure, Hexane and diisopropyl ether were added to the obtained residue and a solid substance was separated by filtration to obtain 0.29 g of methyl 2-(benzamido)-4-((phenylthio)methyl)benzoate as white solid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:5][C:3]=1[NH2:4].[C:17]1(=O)[O:22][C:20](=[O:21])[C:19]2[CH2:23][CH2:24][CH2:25][CH2:26][C:18]1=2.C(O)(=O)C>O>[F:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:5][C:3]=1[N:4]1[C:20](=[O:21])[C:19]2[CH2:23][CH2:24][CH2:25][CH2:26][C:18]=2[C:17]1=[O:22]
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: Nc1cc(OC2CCCCC2)c(Cl)cc1F
Solvent: O
Solvent: CC(=O)O
Product: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCCC2)c(Cl)cc1F
Temperature: 25 °C
Yield: 69.7 %

Procedure:
2-Fluoro-4-chloro-5-cyclohexyloxyaniline (213 mg, 0.874 mmol), 3,4,5,6-tetrahydrophthalic anhydride (134 mg, 0.874 mmol) and acetic acid (10 ml) were charged into a 50 cc round-bottom flask, and heated for 15 hours while refluxing. After completion of the reaction, the reaction solution was cooled to room temperature, water (50 ml) was added thereto, and extracted with ethyl acetate (20 ml×3). The organic layers were combined, washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The drying agent was separated by filtration and the solvent was distilled off under reduced pressure to obtain a crude product (332 mg). The product was purified by silica gel column chromatography (development solvent: hexane/ethyl acetate=19/1) to obtain N-(2-fluoro-4-chloro-5-cyclohexyloxyphenyl)-3,4,5,6-tetrahydrophthalimide as a white solid (230 mg, 0.609 mmol, 70% yield). By recrystallization of the product from hexane/chloroform, it was isolated as white needle crystals.
Reaction SMILES: [Li]CCCC.[C:6]12([PH2:16])[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH2:9]3)[CH2:7]1)[CH2:13]2.[C:17](Cl)([CH3:20])([CH3:19])[CH3:18]>C1COCC1>[C:6]12([PH:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:13][CH:12]3[CH2:11][CH:10]([CH2:9][CH:8]([CH2:14]3)[CH2:7]1)[CH2:15]2
Reactant: PC12CC3CC(CC(C3)C1)C2
Reactant: CC(C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)PC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
nBuLi (20 cm3, 32 mmol 1.6M soln) was added over 1 hour to a cooled solution of 1-adamantyl phosphine (5.0 g, 30 mmol) in THF (100 cm3). The solution was allowed to warm to room temperature and stirred for a further 2 hours. The solution was recooled to 0° C. and tert-butylchloride (2.78 g, 30 mmol) was added and stirring continued for a further 16 hours at room temperature. The reaction mixture was quenched with water and the aqueous phase extracted with dichloromethane (2×50 ml). The organic phase was dried over sodium sulphate and evaporated in-vacuo to yield the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[C:11]([O:23][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)[C:10]=1[C:33]1[O:37][N:36]=[C:35]([C:38](O)=[O:39])[CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[F:64][CH2:65][CH2:66][NH2:67].CCN(C(C)C)C(C)C>C1COCC1.C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:12]=[C:11]([O:23][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)[C:10]=1[C:33]1[O:37][N:36]=[C:35]([C:38]([NH:67][CH2:66][CH2:65][F:64])=[O:39])[CH:34]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(-c2c(OCc3ccccc3)cc(OCc3ccccc3)cc2Oc2ccc([N+](=O)[O-])cc2)on1
Reactant: NCCF
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCCF)c1cc(-c2c(OCc3ccccc3)cc(OCc3ccccc3)cc2Oc2ccc([N+](=O)[O-])cc2)on1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.8 %

Procedure:
To a stirred solution of 5-[2,4-bis(benzyloxy)-6-(4-nitrophenoxy)phenyl]isoxazole-3-carboxylic acid (0.45 g, 0.84 mmol) in THF (30 mL) was added TBTU (0.300 g, 1.1 mmol). After stirring for 15 minutes at room temperature, 2-fluoroethylamine hydrochloride (0.1 g, 1 mmol) and DIPEA (0.58 mL) were subsequently added. After stirring overnight, the suspension was diluted with DCM and washed with brine, dried over Na2SO4 and evaporated to dryness. The residue was carefully chromatographed on silica gel eluting with hexane/ethyl acetate 3/1, to provide the title compound (0.46 g, 94% yield).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:5]=1[NH2:6].CS(C)=O.CC1C=CC(S(O[C:27]2[C:36]3[C:31](=[C:32]([O:39][CH:40]4[CH2:44][CH2:43][CH2:42][CH2:41]4)[C:33]([O:37][CH3:38])=[CH:34][CH:35]=3)[O:30][C:29](=[O:45])[CH:28]=2)(=O)=O)=CC=1>OP([O-])(O)=O.[K+]>[CH:40]1([O:39][C:32]2[C:33]([O:37][CH3:38])=[CH:34][CH:35]=[C:36]3[C:31]=2[O:30][C:29](=[O:45])[CH:28]=[C:27]3[NH:6][C:5]2[C:4]([Cl:3])=[CH:10][CH:9]=[CH:8][C:7]=2[Cl:11])[CH2:41][CH2:42][CH2:43][CH2:44]1
Reactant: COc1ccc2c(OS(=O)(=O)c3ccc(C)cc3)cc(=O)oc2c1OC1CCCC1
Reactant: Nc1c(Cl)cccc1Cl
Agent: O=P([O-])(O)O
Agent: [H-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc2c(Nc3c(Cl)cccc3Cl)cc(=O)oc2c1OC1CCCC1
Temperature: 50 °C
Reaction time: 0.67 h

Procedure:
Sodium hydride (10 mg, 60%, 0.25 mmol) was added to a solution of 2,6-dichloroaniline (40 mg, 0.25 mmol) and anhydrous DMSO (2 mL) at rt under N2. After 40 min, this mixture was added to a solution of 8-(cyclopentyloxy)-7-methoxy-2-oxo-2H-chromen-4-yl 4-methylbenzenesulfonate (70 mg, 0.16 mmol) and anhydrous DMSO (2 mL) at rt under N2. After 1.5 h at rt, the reaction was heated at 50° C. After an additional 1.5 h, a second aliquot of the sodium 2,6-dichloroanilide mixture was added. After an additional hour, the reaction was allowed to cool to rt, diluted with 1M KH2PO4 (40 mL), and extracted with ethyl acetate (40 mL×2). The combined extracts were dried, filtered, concentrated, and purified by silica gel chromatography (4:1→3:2; hexanes:ethyl acetate) to give 8-(cyclopentyloxy)-4-(2,6-dichlorophenylamino)-7-methoxy-2H-chromen-2-one: 1H NMR (400 MHz, DMSO-d6): δ 9.39 (s, 1H), 7.95 (d, 1H), 7.69 (d, 2H), 7.50 (t, 1H), 7.18 (d, 1H), 4.83 (m, 1H), 4.36 (s, 1H), 3.90 (s, 3H), 1.80-1.00 (m, 8H); MS (ESI): 419.9.
Reaction SMILES: C([Si]([O:8]/[C:9](/[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)=[CH:10]\[CH3:11])(C)C)(C)(C)C.CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:41]C)C=C4)N(CC2)C1.CS(N)(=O)=O.C(Cl)(Cl)Cl>C(O)(C)(C)C.O>[CH3:19][O:18][C:14]1[CH:13]=[C:12]([C:9](=[O:8])[C@H:10]([OH:41])[CH3:11])[CH:17]=[CH:16][CH:15]=1
Reactant: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Reactant: C/C=C(\O[Si](C)(C)C(C)(C)C)c1cccc(OC)c1
Agent: CS(N)(=O)=O
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC(C)(C)O
Product: COc1cccc(C(=O)[C@@H](C)O)c1

Procedure:
Compound 10f was synthesized by a procedure similar to that described for (R)-10a using (Z)-tert-butyl(1-(3-methoxyphenyl)prop-1-enyloxy)dimethylsilane, (9f, 8.1 g, 0.029 mol), AD-mix-β (40.7 g), and CH3SO2NH2 (2.8 g, 0.0294 mol) in tert-butyl alcohol-water (110 mL:110 mL) The reaction was quenched with sodium sulfite (29.1 g). After purification, 4.2 g (80%) of the desired 10f was isolated: [α]20D +71.1° (c 1.1, CHCl3); 1H NMR (CDCl3) δ 7.51-7.45 (m, 2H), 7.44-7.37 (m, 1H), 7.19-7.13 (m, 1H), 5.19-5.09 (m, 1H), 3.87 (s, 3H), 3.76 (d, 1H, J=6.5 Hz), 1.45 (d, 3H, J=7.1 Hz); 13C NMR (CDCl3) δ 202.3, 160.0, 134.7, 129.9, 121.1, 120.3, 113.1, 69.4, 55.5, 22.4. C10H12O3.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][CH2:11][OH:12])=[O:8])=[C:4]([Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:3]=1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26].O>C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][CH2:11][O:12][S:25]([CH3:24])(=[O:27])=[O:26])=[O:8])=[C:4]([Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:3]=1
Reactant: C[Si](C)(C)c1cc(Cl)sc1C(=O)NCCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)c1cc(Cl)sc1C(=O)NCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the compound of Example 263 (0.4 g) and 0.5 mL triethylamine in 10 mL CH2Cl2 at 0° C. was added methanesulfonyl chloride (0.2 mL) and the resulting reaction solution was stirred at RT for 2 h. Water was added and the two layers were separated. The organic solution was washed with brine, dried and concentrated. Purification by flash chromatography with 30% ethyl acetate-hexane gave 0.4 g of product as a white solid. m.p. 82-86° C.
Reaction SMILES: CC(C)([O-])C.[K+].[CH:7]1([CH2:13][OH:14])[CH2:12][CH2:11][CH:10]=[CH:9][CH2:8]1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[NH4+].[Cl-]>C1COCC1>[CH2:13]([O:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH:18]=[CH:17]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: BrCc1ccccc1
Reactant: OCC1CC=CCC1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: C1=CC(COCc2ccccc2)CCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.4 %

Procedure:
A solution of potassium t-butoxide (1.0M in THF, 8.27 mL, 8.27 mmol) was added dropwise to a solution of (±)-3 cyclohexene-1-methanol (853 mg, 7.60 mmol) in THF (35 mL) at 25° C. under N2. The resultant mixture was stirred at 25° C. for 30 minutes. Benzyl bromide (1.0 mL, 8.37 mmol) was added dropwise. The reaction mixture was allowed to stir at room temperature for 16 hours and then treated with saturated aqueous NH4Cl (5 mL) and concentrated. The residue was dissolved in ether (50 mL), washed with water (20 mL) and brine (20 mL), and dried over MgSO4. The solvent was evaporated under reduced pressure. The residue was subjected to radial chromatography on silica gel eluting with 5 percent EtOAc in hexane to give (±)-3-(benzyloxy)methyl-1-cyclohexene (1.42 g, 92 percent) as a colorless oil. NMR
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.CC(C)([O-])C.[Na+].[Br:14][C:15]1[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:18]2[CH:19]=[CH:20][C:15]([Br:14])=[CH:16][CH:17]=2)[CH:3]=1
Reactant: Brc1ccc(Br)cc1
Reactant: Nc1cccnc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Brc1ccc(Nc2cccnc2)cc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A solution of 3-aminopyridine (200 mg, 2.1 mmol) and 304 mg (3.2 mmol) of sodium tert-butoxide were added to 502 mg (2.1 mmol) of 1,4-dibromobenzene, 127 mg (0.21 mmol) of 4,5-bis(diphenylphosphino)-9,9-dimethylsantene, and 97 mg (0.11 mmol) of tris(dibenzylideneacetone)dipalladium in toluene (15 ml), and the mixture was stirred at 100° C. for 3 hr. The reaction solution was diluted with 20 ml of ethyl acetate, and the insolubles were filtered through a chromato-disk. The filtrate was concentrated under the reduced pressure, and the residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=2:1) to give 312 mg (yield 50%) of a mixture of the title compound with a debromination product thereof (about 3.5:1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3([C:24]([OH:26])=[O:25])[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)(O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.O1CCCC1.C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C.C(N(CC)C(C)C)(C)C>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3([C:24]([OH:26])=[O:25])[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(C3(C(=O)O)CC3)cc2)CC1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(C3(C(=O)O)CC3)cc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 1-{4-[1-(tert-butoxycarbonyl)-4-hydroxypiperidin-4-yl]phenyl}cyclopropanecarboxylic acid (300 mg, prepared as described in example 210, steps 1 & 2) and trifluoroacetic acid 2 mL was stirred at rt for 5 h. The reaction mixture was then concentrated. The crude product was dissolved in tetrahydrofuran (4 mL, 0.05 mol) and to this was added di-tert-butyldicarbonate (333 mg, 0.00152 mol) and N,N-diisopropylethylamine (6.0×10−2 μL, 0.0035 mol). The mixture was stirred at rt for 5 h and then diluted with AcOEt, washed with saturated NaHCO3 aqueous solution and 1M HCl successively, dried with MgSO4, and concentrated in-vacuo to afford the desired product.
Reaction SMILES: C(O)[C@H]1O[C@H](O[C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O.[NH2:24][C@H:25]([C:27]([OH:29])=[O:28])[CH3:26].N[C@H](C(O)=O)[CH2:32][C:33](=[O:35])[NH2:34].N[C@H](C(O)=O)CC(O)=O.N1CCC[C@H]1C(O)=O.N[C@H](C(O)=O)CO>[Cl-].OCC[N+](C)(C)C>[NH2:24][C@H:25]([C:27]([OH:29])=[O:28])[CH2:26][CH2:32][C:33](=[O:35])[NH2:34]
Reactant: C[C@H](N)C(=O)O
Reactant: NC(=O)C[C@H](N)C(=O)O
Agent: C[N+](C)(C)CCO
Agent: N[C@@H](CC(=O)O)C(=O)O
Agent: N[C@@H](CO)C(=O)O
Product: NC(=O)CC[C@H](N)C(=O)O

Procedure:
The defined oral diets contained 427 calories/100 g and included 0.2% (w/w) choline chloride, 10% corn oil, 46.9% dextrin-white, 23.4% sucrose., 5% salt mixture, 0.5% vitamin mixture. Both diets consisted of 14% amino acids, including 7.17% total essential amino acids and 6.83% total non-essential amino acids. The diet lacking GLN (-GLN) contained 0.937% each of alanine, asparagine, aspartic acid, proline and serine. The GLN-enriched diet (+GLN) contained 0.237% of these amino acids and 3.5% GLN. Thus, GLN represented 25% of total amino acids and 51% of non-essential amino acids in the +GLN diet.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[CH2:10][C@H:9]1[C:24]([O:26]C)=[O:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[CH2:10][C@H:9]1[C:24]([OH:26])=[O:25])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H]1C[C@H](Oc2ccc3ccccc3c2)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](Oc2ccc3ccccc3c2)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl (2S,4S)-1-tert-butoxycarbonyl-4-(2-naphthyloxy)-2-pyrrolidinylcarboxylate (5.37 g) in THF (116 ml) was added 0.25N NaOH (116 ml, 29.0 mmol). The resulting mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was acidified with 1N HCl, followed by extraction with chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue thus obtained was recrystallized from hexane-chloroform, whereby the title compound (4.44 g, 85% (2 steps)) was obtained as white crystalline powder.
Reaction SMILES: [CH2:1]1[C@@H:3]([NH3+:4])[C@H:2]1[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([F:12])[CH:6]=1.C1C=CC(C(O)C([O-])=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:31]1[C:32]2[N:43]=[N:42][N:41]([C@H:44]3[C@@H:48]4[O:49][C:50]([CH3:53])([CH3:52])[O:51][C@@H:47]4[C@@H:46]([O:54][CH2:55][CH2:56][OH:57])[CH2:45]3)[C:33]=2[N:34]=[C:35]([S:37][CH2:38][CH2:39][CH3:40])[N:36]=1>O>[F:12][C:7]1[CH:6]=[C:5]([C@@H:2]2[CH2:1][C@H:3]2[NH:4][C:31]2[C:32]3[N:43]=[N:42][N:41]([C@H:44]4[C@@H:48]5[O:49][C:50]([CH3:52])([CH3:53])[O:51][C@@H:47]5[C@@H:46]([O:54][CH2:55][CH2:56][OH:57])[CH2:45]4)[C:33]=3[N:34]=[C:35]([S:37][CH2:38][CH2:39][CH3:40])[N:36]=2)[CH:10]=[CH:9][C:8]=1[F:11]
Reactant: CCCSc1nc(Cl)c2nnn([C@@H]3C[C@H](OCCO)[C@H]4OC(C)(C)O[C@H]43)c2n1
Reactant: [NH3+][C@@H]1C[C@@H]1c1ccc(F)c(F)c1
Agent: O=C([O-])C(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCCSc1nc(N[C@@H]2C[C@H]2c2ccc(F)c(F)c2)c2nnn([C@@H]3C[C@H](OCCO)[C@H]4OC(C)(C)O[C@H]43)c2n1

Procedure:
trans-(1R,2S)-2-(3,4-Difluorophenyl)cyclopropanaminium (2R)-2-hydroxy-2-phenylethanoate (258 kg) and potassium carbonate (280 kg) were dissolved in water (1024 kg) and charged to the solution of 2-({(3aR,4S,6R,6aS)-6-[7-chloro-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}oxy)ethanol solution from example 5 above with a rate that kept the temperature of the reaction ≦30° C. After full conversion was reached (≧99.9%) the water layer was separated off. The organic layer was washed with a mixture of acetic acid (96 kg) and sodium chloride (96 kg) in water (768 kg) and then washed again with a mixture of acetic acid (32 kg) and sodium chloride (22 kg) in water (952 kg). A third wash of the organic layer was done with sodium chloride (96 kg) in water (864 kg), whereafter the organic layer was used in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[CH2:12][C:11]([NH2:15])=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].N1C=CC=CC=1.[N+](C1C=CC=CC=1)([O-])=O.[C:31](Cl)(=[O:35])[C:32]([CH3:34])=[CH2:33].[OH-].[Na+]>C(O)(=O)C.O.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[CH2:12][C:11]([NH:15][C:31](=[O:35])[C:32]([CH3:34])=[CH2:33])=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC1=NN(c2ccc(Cl)c(Cl)c2)C(=O)C1
Reactant: C=C(C)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: C=C(C)C(=O)NC1=NN(c2ccc(Cl)c(Cl)c2)C(=O)C1

Procedure:
Twenty grams (0.08 mole) of 1-(3,4-dichlorophenyl)-3-amino-2-pyrazoline-5-one, 15.2 ml (0.19 mole) of pyridine and 2.0 ml of nitrobenzene were added to 300 ml of tetrahydrofuran. To this mixture, cooled by ice, were added dropwise 19.6 g (0.19 mole) of methacryloyl chloride. The liquid, after 30-minute stirring, was poured into 2 liters of water, extracted with use of ethyl acetate, and dried with use of anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure at a temperature of from 25° to 35° C. To the remaining oily substance were added 60 ml of ethanol and 60 ml of water, and further a solution of 11.2 g (0.28 mole) of sodium hydroxide dissolved into water. This mixture was stirred for 30 minutes at room temperature, and neutralized with acetic acid. The thus deposited crystals were filtrated, and recrystallized from ethanol, whereby 14.4 g (57%) of Coupler Monomer (3) were obtained. M.P. 212°-213° C.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:25](OC(=O)C)(=[O:27])[CH3:26]>O1CCCC1>[O:11]=[C:10]1[NH:9][C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[NH:6][C:5]2[CH:16]=[CH:17][C:2]([NH:1][C:25](=[O:27])[CH3:26])=[CH:3][C:4]1=2
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2c(c1)C(=O)Nc1ccccc1N2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc2c(c1)C(=O)Nc1ccccc1N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
A solution of 2-amino-5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-one (Example 6, 200 mg, 0.89 mmol) and triethylamine in tetrahydrofuran (10 mL) was cooled to 0° C. (ice-water bath). To this was added acetic anhydride (90.6 mg, 0.89 mmol) dropwise over a period of 10 minutes. The mixture was allowed to warm to room temperature and stirred overnight. The mixture was concentrated at reduced pressure and the residue was chromatographed on silica gel (80% ethyl acetate/20% hexanes then 100% ethyl acetate and finally 2% methanol/ethyl acetate) to give a yellow solid (120 mg, 50.4%). H1 NMR (DMSO d6) δ: 9.82 (s, 1H), 9.80 (s, 1H), 7.82-7.81 (d, 1H, J=4.0), 7.68 (s, 1H), 7.58-7.55 (m, 11H), 6.95-6.86 (m, 5H), 1.97 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([OH:31])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9](I)[N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[C:32]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)#[N:33].C(=O)(O)[O-].[Mg].[Cl-].[NH4+]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([OH:31])[CH2:28][CH2:29][CH2:30]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9]([C:38]3[CH:39]=[C:34]([CH:35]=[CH:36][CH:37]=3)[C:32]#[N:33])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: Cc1ccc(S(=O)(=O)n2c(I)cc3c(-c4cnc(C5(O)CCC5)s4)c(Cl)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CN(C)C=O
Product: N#Cc1cccc(-c2cc3c(-c4cnc(C5(O)CCC5)s4)c(Cl)cnc3[nH]2)c1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
To a stirred ambient solution of 1-(5-(5-chloro-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl)cyclobutanol (Example 8A) (50 mg, 0.085 mmol) and 3-cyanophenylboronic acid (18.8 mg, 0.128 mmol) in N,N-dimethylformamide (2.0 mL) was added saturated aqueous bicarbonate solution (683 μl) followed by bis(triphenylphosphine)palladium dichloride (4.2 mg, 6.0 μmol). The mixture was heated to 70° C. for 4 hours and was then quenched by the addition of water and ethyl acetate. The layers were separated, and the aqueous layer was extracted with additional ethyl acetate. The combined organics were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in methanol (2 mL). Magnesium turnings (20.7 mg, 0.853 mmol) and solid ammonium chloride (18.26 mg, 0.341 mmol) were added, and the mixture stirred vigorously for 16 hours. The reaction was partitioned between ethyl acetate and saturated aqueous bicarbonate solution. The layers were separated, and the aqueous layer was extracted with additional ethyl acetate. The combined organics were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase high performance liquid chromatography (RP HPLC, 19×150 mm Atlantis Prep T3 OBD m column, eluting with a gradient of 5% B in A to 75% B in A over 25 minutes, wherein A is water containing 0.1% v/v trifluoroacetic acid and B is acetonitrile containing 0.1% v/v trifluoroacetic acid). The fractions containing the product were diluted with ethyl acetate and washed with saturated aqueous bicarbonate solution. The ethyl acetate solution was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound. 1H NMR (500 MHz, DMSO-d6) δ 12.71 (s, 1H), 8.57 (bs, 1H), 8.39 (s, 1H), 8.35 (d, J=8.4 Hz, 1H), 8.30 (s, 1H), 7.83 (d, J=7.7 Hz, 1H), 7.70-7.67 (m, 1H), 7.35 (bs, 1H), 6.70 (s, 2H), 2.68-2.59 (m, 2H), 2.46-2.38 (m, 2H), 2.06-1.89 (m, 2H); MS ESI(+) m/z 406.9 [M+H]+.