Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]([S:32]([C:35]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=1)(=[O:34])=[O:33])[C@H:6]([C:29]([OH:31])=[O:30])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](OCC1C2C=CC=CC=2C2C1=CC=CC=2)=[O:13])[CH:2]([CH3:4])[CH3:3].[C:42]([NH:50][C@H:51](C(O)=O)[CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)(=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>>[CH3:41][C:38]1[CH:39]=[CH:40][C:35]([S:32]([N:5]([C@H:6]([C:29]([OH:31])=[O:30])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([C@@H:51]([NH:50][C:42]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:49])[CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[O:13])[CH2:1][CH:2]([CH3:4])[CH3:3])(=[O:33])=[O:34])=[CH:36][CH:37]=1
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1ccccc1
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)[C@H](Cc2ccccc2)NC(=O)c2ccccc2)C(=O)O)cc1

Procedure:
The title compound was prepared from solid phase bound Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-Nε-(9-fluorenylmethoxycarbonyl)-L-lysine as described in general procedure Bb using Nα-benzoyl-L-phenylalanine (321 mg, 1.2 mmol). The final product was purified by preparative HPLC to yield 44 mg (58%) of the desired material.
Reaction SMILES: [N+](C1C=CC(C([O:10][CH2:11][C@@H:12]2[C@@H:17]([CH2:18][O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:16]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C@@H:15]([O:34][C@@H:35]([C:37]3[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[C:39]([C:47]([F:50])([F:49])[F:48])[CH:38]=3)[CH3:36])[O:14][CH2:13]2)=O)=CC=1)([O-])=O.[OH-].[Na+]>CO.C(O)C.CCOC(C)=O>[CH2:20]([O:19][CH2:18][C@H:17]1[C@H:16]([C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)[C@@H:15]([O:34][C@@H:35]([C:37]2[CH:42]=[C:41]([C:43]([F:46])([F:44])[F:45])[CH:40]=[C:39]([C:47]([F:50])([F:48])[F:49])[CH:38]=2)[CH3:36])[O:14][CH2:13][C@@H:12]1[CH2:11][OH:10])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: C[C@@H](O[C@H]1OC[C@H](COC(=O)c2ccc([N+](=O)[O-])cc2)[C@@H](COCc2ccccc2)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCO
Product: C[C@@H](O[C@H]1OC[C@H](CO)[C@@H](COCc2ccccc2)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 45 °C

Procedure:
The intermediate from example 1 step H (4.57 g, 6.22 mmol) was dissolved in a 1:1 mixture of methanol/ethanol (60 mL) followed by the addition of 5 N NaOH (12.0 mL). The vessel was heated to 45° C. for 1 hr. The reaction mixture was cooled to ambient temperature and diluted with 400 mL EtOAc. The EtOAc solution was washed twice with 2 N NaOH, dried over Na2SO4, filtered through a fritted funnel and concentrated in vacuo. The crude residue was purified on silica gel and eluted a combination of EtOAc/hexanes (1-30% EtOAc/hexanes linear gradient). This provided the title compound. 1H-NMR (CDCl3): δ 1.38 (d, 3H, J=6.5 Hz), 1,90-2.22 (m, 2H), 2.34-2.42 (m, 1H), 2.72 (dd, 1H, J=8.5, 10.5 Hz), 3.12-3.18 (m, 1H), 3.24-3.31 (m, 1H), 3.46-3.56 (m, 2H), 3.55-3.62 (m, 1H), 3.65-3.74 (m, 1H), 4.09 (dd, 1H, J=4.0, 11.5 Hz), 4.21 (d, 1H, J=8.5 Hz), 4.31 (s, 21H), 4.96 (q, 1H, J=6.5 Hz), 6.90-7.02 (m, 4H), 7.14-7.22 (m, 4H), 7.25-7.34 (m, 3H), 7.69 (s, 1H) ppm.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([CH2:19][CH2:20][C:21]([F:24])([F:23])[F:22])([C:17]#[N:18])[C:15]#[N:16])C1C=CC=CC=1.[I-].[Na+].O>C(#N)C>[OH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([CH2:19][CH2:20][C:21]([F:22])([F:23])[F:24])([C:17]#[N:18])[C:15]#[N:16]
Reactant: N#CC(C#N)(CCCCCOCc1ccccc1)CCC(F)(F)F
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: N#CC(C#N)(CCCCCO)CCC(F)(F)F
Temperature: 0 °C
Reaction time: 6 h
Yield: 30.3 %

Procedure:
1.8 g of 2-(5-benzyloxypentyl)-2-(3,3,3-trifluoropropyl)malononitrile was added to 20 ml of acetonitrile was cooled to 0° C. To the mixture, 1.6 g of sodium iodide added and 1.3 g of trifluoroborane-diethyl ether complex dissolved in 5 ml of acetonitrile was further added dropwise. The mixture was stirred at 0° C. for 1 hour and at room temperature for 6 hours. Thereafter, water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed successively with water and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.40 g of 2-(5-hydroxypentyl)-2-(3,3,3-trifluoropropyl)malononitrile.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCCCCC.[H-].[Na+].F[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1>CS(C)=O>[CH:4]1[CH:5]=[CH:6][C:1]([O:7][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)=[CH:2][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(Oc2ccccc2)cc1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
Phenol (1.89 g, 20 mmol) was added to a slurry of hexane-washed NaH (60% oil suspension, 820 mg, 20.5 mmol) in DMSO (20 mL), stirred under nitrogen at 20° C., producing strong gas evolution. After 30 minutes, 1-fluoro-4-nitrobenzene (2.82 g, 20 mmol) was added dropwise to the light grey slurry. After about 10 minutes, the reaction mixture became orange and quite strongly exothermic, and a lot of gas was evolved. After 2 hours, the reaction mixture was poured onto ice-water (200 mL), and the solid was collected by Buchner filtration, rinsed with water (2×50 mL), and air dried to give 4-nitrodiphenyl ether (3.945 g, 91.6%) as dull yellow crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[Cl:11].[CH2:12]([O:14][C:15]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)=[O:16])[CH3:13].C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC>[CH2:12]([O:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=2[Cl:11])=[CH:19][CH:18]=1)=[O:16])[CH3:13]
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: CCOC(=O)c1ccc(-c2cc([N+](=O)[O-])ccc2Cl)cc1
Yield: 93.2 %

Procedure:
A mixture of 2-bromo-1-chloro-4-nitro-benzene (2.5 g), 4-ethoxycarbonyl-phenyl boronic acid (2.05 g), cesium carbonate (3.44 g) and tetrakis(triphenylphosphine)palladium0 (catalytic quantity), in 1:2 aqueous DME (45 ml) was heated to reflux for 18 h. The mixture was then cooled and partitioned between water and ethyl acetate. The dried extracts were evaporated to give the product as a white solid (3.01 g). This material was used in the next stage without further purification.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=O)[C:3]=1[C:16]([O:18]CC)=[O:17].C1COCC1.[Li+].[OH-]>CO.C(O)(=O)C>[OH:1][C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([OH:18])=[O:17]
Reactant: CCOC(=O)c1c(O)c2cccc([N+](=O)[O-])c2[nH]c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: O=C(O)c1cnc2c([N+](=O)[O-])cccc2c1O
Temperature: 40 °C
Yield: 63.3 %

Procedure:
A mixture of 2-nitroaniline (6.907 g) and diethyl ethoxymethylenemalonate (10.812 g) is heated to 130° C. for 2 h with removal of ethanol by a Dean-Stark trap. The mixture is cooled to 80° C. Diphenyl ether (60 mL) is added and the mixture is heated to 250° C. for 2 h. The solution is cooled to room temperature. The resulting solid is collected, washed with hexanes and dried to yield 3.447 g of ethyl 4-hydroxy-8-nitroquinolone-3-carboxylate as a gold solid. To a mixture of this ester (1.2 g) in 66 mL of 1:1 MeOH:THF is added 18 mL of 1M LiOH. The reaction is maintained at 40° C. overnight. The reaction mixture is cooled to room temperature, then diluted with 35 mL glacial acetic acid. The resulting precipitate is collected, washed with H2 0 and hot isopropanol, and dried to yield 0.639 g of 4-hydroxy-8-nitroquinoline-3-carboxylic acid as a yellow solid. A mixture of this acid (0.20 g) and p-chlorobenzylamine (0.10 mL) are dissolved in 25 mL xylenes and heated to reflux. PCl3 (0.037 mL) is added dropwise and the mixture is refluxed for 4 hours. The reaction mixture is cooled to room temperature and H2O is added to quench excess PCl3. An orange solid precipitates, which is collected, washed with ether, and dried. The crude product is recrystallized with hot MeOH to yield 0.0367 g of the desired product as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH:10]=2)=[CH:6][N:5]=[C:4]([N+:21]([O-])=O)[CH:3]=1>CCOC(C)=O.[Pd]>[CH3:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH:10]=2)=[CH:6][N:5]=[C:4]([NH2:21])[CH:3]=1
Reactant: Cc1cc([N+](=O)[O-])ncc1Oc1ccnc(-c2cnn(C)c2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1cc(N)ncc1Oc1ccnc(-c2cnn(C)c2)c1
Yield: 99.9 %

Procedure:
A solution of 4-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)-2-nitropyridine (0.83 g, 2.67 mmol) in EtOAc (20 mL) was treated with palladium on carbon (50% wet, 0.284 g, 0.267 mmol) and hydrogenated (1 atm) overnight. The solids were removed via filtration through diatomaceous earth, rinsed well with EtOAc and the filtrate was concentrated to dryness to afford crude 4-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-amine (750 mg, 100%) as a white amorphous solid which was carried on to the next step without further purification. 1H NMR (400 MHz, DMSO-d6): δ 8.30 (d, J=5.7 Hz, 1H), 8.23 (s, 1H), 7.93 (d, J=0.7 Hz, 1H), 7.69 (s, 1H), 7.12 (d, J=2.4 Hz, 1H), 6.51 (dd, J=5.7, 2.4 Hz, 1H), 6.39 (s, 1H), 5.91 (s, 2H), 3.84 (s, 3H), 1.95 (s, 3H); MS (ESI) m/z: 282.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]3[N:9]2[CH:12]=[C:13]([C:15]([O:17]CC)=[O:16])[N:14]=3)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C.O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]3[N:9]2[CH:12]=[C:13]([C:15]([OH:17])=[O:16])[N:14]=3)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cn2c(ccc3ccc(Cl)cc32)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cn2c(ccc3ccc(Cl)cc32)n1

Procedure:
200 mg of ethyl 8-chloroimidazo-[1,2-a]-quinoline-2-carboxylate in 8 ml of ethanol and 2 ml of water were hydrolyzed with 1 ml of N sodium hydroxide solution. The mixture was acidified with 1.1 ml of N HCl as in Example 36 to obtain colorless needles of 8-chloroimidazo-[1,2-a]-quinoline-2-carboxylic acid melting at 288°-289° C.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].N=C1CC(C)CCN1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][N:15]=1>>[C:1]([OH:4])(=[O:3])[CH3:2].[NH:13]=[C:14]1[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][NH:15]1
Reactant: CCCCc1ccc(N)nc1
Agent: CC1CCNC(=N)C1
Solvent: CC(=O)O
Product: CCCCC1CCC(=N)NC1

Procedure:
The method of preparation of 2-imino-4-methylpiperidine acetate was used to convert 2-amino-5-(n-butyl)pyridine to the title compound except platinum oxide was used as the catalyst. Product was triturated with ether to give a white solid. The analysis of the product was found to be consistent with the proposed structure. MH+=155; 1H NMR (D2O): δ3.35-3.25 (m, 1H); 2.85-2.75 (m, 1H); 2.60-2.35 (m, 2H); 1.85-1.55 (m, 2H); 1.75 (s, 3H); 1.35-1.05 (m, 7H); 0.75-0.65 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:22])[C:11]=1[N:12]1[CH2:16][CH2:15][CH:14]([N:17]3[CH:21]=[CH:20][N:19]=[N:18]3)[CH2:13]1)[N:8]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[CH:7]=[C:6]([C:30]([O:32]CC)=[O:31])[C:5]2=[O:35]>[OH-].[Na+].C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:22])[C:11]=1[N:12]1[CH2:16][CH2:15][CH:14]([N:17]3[CH:21]=[CH:20][N:19]=[N:18]3)[CH2:13]1)[N:8]([C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)[CH:7]=[C:6]([C:30]([OH:32])=[O:31])[C:5]2=[O:35]
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2)c2c(F)c(N3CCC(n4ccnn4)C3)c(F)cc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(N3CCC(n4ccnn4)C3)c(F)cc2c1=O
Temperature: 90 °C

Procedure:
A suspension of ethyl 6,8-difluoro-1-(4-fluorophenyl)-7-[3-(1,2,3-triazol-1-yl)-pyrrolidin-1-yl]-1,4-dihydro-4-oxo-quinoline-3-carboxylate (180 mg, 0.37 mmol) in 20 ml NaOH solution (containing 15 mg NaOH) and THF (20 ml) was heated at 90° C. for 3.5 h. The THF was evaporated and the separated solid was redissolved in water layer by heating and acidified to pH 6.0. The precipitate was filtered, washed with water and dried in vac-oven at 40° C., gave the title compound as a light yellow solid. Yield: 89 mg, 52.7%; m.p. 303° C. 1H NMR (TFA) δ: 2.82 (m, 2H), 4.14-4.64 (m, 4H), 5.74 (m, 1H), 7.37 (m, 2H), 7.60 (m, 2H), 8.20 (dd, 1H), 8.54 (d, 1H), 8.65 (d, 1H), 9.03 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[O:12]C.B(Br)(Br)Br.O>ClCCl>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[OH:12]
Reactant: COc1cccc2c(F)cccc12
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Oc1cccc2c(F)cccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
A stirred solution of 2.08 g of 5-fluoro-1-methoxynaphthalene in 42 ml of dry dichloromethane was cooled to −60 to −65° C. after which was added 13 ml of 1M BBr3 in dichloromethane. The mixture was allowed to warm to room temperature, and stirred at RT for 1 h. The reaction mixture was again cooled to −60 to −65° C. after which was added an additional 13 ml of 1M BBr3 in dichloromethane. The mixture was allowed to warm to RT and stirred at RT for 1.5 h. The mixture was poured into cold water, extracted twice with dichloromethane, dried (sodium sulphate), filtered and concentrated to a purple/white solid. The material was dissolved in a minimum volume of dichloromethane and flash chromatographed on silica gel, eluting with ethyl acetate/dichloromethane/heptane to provide 1.58 g (83%) of 5-fluoro-1-hydroxynaphthalene as a white solid.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][C:6]1([CH3:17])[C:10]2[CH:11]=[C:12]([CH:15]=[O:16])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7]1.[Br:18]Br.Cl>ClCCl>[Br:18][C:14]1[C:9]2[O:8][CH2:7][C:6]([CH3:17])([CH3:5])[C:10]=2[CH:11]=[C:12]([CH:15]=[O:16])[CH:13]=1
Reactant: CC1(C)COc2ccc(C=O)cc21
Reactant: BrBr
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1(C)COc2c(Br)cc(C=O)cc21
Reaction time: 3 h
Yield: 91.4 %

Procedure:
To a solution of AlCl3 (1.22 g, 9.18 mmol) in dry dichloromethane (15 mL) was added dropwise at room temperature 3,3-dimethyl-2,3-dihydro-benzofuran-5-carbaldehyde (647 mg, 3.67 mmol) in dichloromethane (15 mL) followed by bromine (0.23 mL, 4.41 mmol) and the reaction stirred for 3 hours. 1N HCl was added slowly and the layers separated. The aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel (20% ethyl acetate in hexane) to give 856 mg of 7-bromo-3,3-dimethyl-2,3-dihydro-benzofuran-5-carbaldehyde (91%). 1H NMR (300 MHz; CDCl3): 1.40(s, 6H), 4.46 (s, 2H), 7.61 (s, 1H), 7.83 (s, 1H), 9.80 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([Cl:14])[C:5]2[CH:10]([CH3:11])[S:9](=[O:13])(=[O:12])[CH2:8][C:6]=2[N:7]=1.CCN(CC)CC.[CH3:22][C@H:23]1[CH2:28][O:27][CH2:26][CH2:25][NH:24]1>CN(C=O)C>[Cl:14][C:4]1[C:5]2[CH:10]([CH3:11])[S:9](=[O:13])(=[O:12])[CH2:8][C:6]=2[N:7]=[C:2]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][C@@H:23]2[CH3:22])[N:3]=1
Reactant: C[C@H]1COCCN1
Reactant: CC1c2c(Cl)nc(Cl)nc2CS1(=O)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1c2c(Cl)nc(N3CCOC[C@@H]3C)nc2CS1(=O)=O
Reaction time: 8 h
Yield: 26.6 %

Procedure:
To a solution of 2,4-dichloro-5-methyl-5,7-dihydrothieno[3,4-d]pyrimidine 6,6-dioxide (150.0 mg, 0.5926 mmol) and Et3N (119.9 mg, 1.2 mmol) in DMF (2.0 mL) was added (S)-3-methylmorpholine (59.9 mg, 0.6 mmol) dropwise. The reaction mixture stirred overnight, then quenched by addition of H2O and the resulting mixture extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=20:1-2/1) to provide 4-chloro-5-methyl-2-[(3S)-3-methylmorpholin-4-yl]-5,7-dihydrothieno[3,4-d]pyrimidine 6,6-dioxide (B) as a light yellow solid (50 mg, 13.5%). Further elution then provides 2-chloro-5-methyl-4-[(3S)-3-methylmorpholin-4-yl]-5,7-dihydrothieno[3,4-d]pyrimidine 6,6-dioxide (A) as an off-white soild (100 mg, 27%),
Reaction SMILES: [CH3:1][C:2]([CH3:17])([O:4][C:5]([NH:7][C@H:8]1[CH2:14][CH2:13][CH2:12][C@H:11]([CH3:15])[NH:10][C:9]1=[O:16])=[O:6])[CH3:3].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>O1CCCC1>[CH3:3][C:2]([CH3:1])([O:4][C:5]([NH:7][C@H:8]1[CH2:14][CH2:13][CH2:12][C@H:11]([CH3:15])[N:10]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:9]1=[O:16])=[O:6])[CH3:17]
Reactant: CCOC(=O)CBr
Reactant: C[C@H]1CCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CCC[C@@H]1C
Reaction time: 0.25 h

Procedure:
A solution of (3S-trans)-hexahydro-3-[[(1,1-dimethylethoxy)carbonyl]amino]-7-methyl-2H-azepin-2-one (313 mg., 1.3 mmol.) in tetrahydrofuran (8 ml.) at room temperature under argon was treated with the dropwise addition of 1.0M lithium bis(trimethylsilyl)amide in tetrahydrofuran (1.7 ml., 1.7 mmol.) immediately followed by the dropwise addition of ethyl bromoacetate (0.30 ml., 2.65 mmol.). The resulting mixture was stirred for 15 minutes, quenched with aqueous ammonium chloride, diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried (sodium sulfate), filtered and concentrated to a yellow oil. Following flash chromatography (E Merck silica gel) eluting with 2:1 hexane/ethyl acetate, 360 mg. of title compound was obtained as a light yellow oil; TLC (1:1 ethyl acetate:hexane) Rf =0.56.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:23](=[CH:24][CH:25]=1)[C:7]1=[CH:8][C:9]3[C:10](=O)[C:11]4[CH:12]=[C:13]([Br:21])[CH:14]=[CH:15][C:16]=4[C:17](=O)[C:18]=3[CH:19]=[C:6]1[C:5]2([CH3:27])[CH3:26].I.O.II>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:23](=[CH:24][CH:25]=1)[C:7]1=[CH:8][C:9]3[CH:10]=[C:11]4[C:16](=[CH:17][C:18]=3[CH:19]=[C:6]1[C:5]2([CH3:27])[CH3:26])[CH:15]=[CH:14][C:13]([Br:21])=[CH:12]4
Reactant: CC1(C)c2cc(Br)ccc2-c2cc3c(cc21)C(=O)c1ccc(Br)cc1C3=O
Agent: I
Agent: II
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)c2cc(Br)ccc2-c2cc3cc4cc(Br)ccc4cc3cc21
Reaction time: 48 h
Yield: 60.3 %

Procedure:
2,8-dibromo-13,13-dimethyl-13H-indeno[1,2-b]anthracene-6,11-dione (20 g, 0.04 mol) was dissolved in acetic acid (200 ml), and added with 57% HI (50 ml), followed by reflux-stirring for 48 hours. After the reaction was completed, the resultant solution was added with distilled water (500 ml). The produced solid was filtered and dissolved in toluene (200 ml) and iodine (4.05 g, 0.016 mol) was added thereto, followed by reflux-stirring for 3 hours. After the reaction was completed, through extraction and column chromatography, 2,8-dibromo-13,13-dimethyl-13H-indeno[1,2-b]anthracene (10.9 g, yield 59%) was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([C:16]([O:18]C)=[O:17])[CH:13]=[C:12]([O:20][CH:21]2[CH:25]([OH:26])[CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]2)[CH:11]=1)#[N:2].[OH-].[Li+].Cl>C1COCC1>[C:30]([O:29][C:27]([N:23]1[CH2:24][CH:25]([OH:26])[CH:21]([O:20][C:12]2[CH:13]=[C:14]([C:16]([OH:18])=[O:17])[CH:15]=[C:10]([C:4]3[CH:5]=[CH:6][C:7]([CH3:9])=[CH:8][C:3]=3[C:1]#[N:2])[CH:11]=2)[CH2:22]1)=[O:28])([CH3:33])([CH3:31])[CH3:32]
Reactant: COC(=O)c1cc(OC2CN(C(=O)OC(C)(C)C)CC2O)cc(-c2ccc(C)cc2C#N)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(OC3CN(C(=O)OC(C)(C)C)CC3O)cc(C(=O)O)c2)c(C#N)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a stirred solution of tert-butyl 3-(2′-cyano-5-(methoxycarbonyl)-4′-methylbiphenyl-3-yloxy)-4-hydroxypyrrolidine-1-carboxylate (310 mg, 0.68 mmol) in THF (3 mL) was added 2.5 M of aq. lithium hydroxide solution (1.5 mL, 3.8 mmol). The reaction mixture was stirred at 60° C. overnight. The aqueous solution was acidified with 15% HCl (aq.) to pH=5, and extracted with EtOAc. The combined organic layers were concentrated in vacuo to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]([CH3:20])[C:11](=[O:19])[CH:12]=[CH:13][C:14]=2[C:15]([O:17]C)=O)=[C:4]([F:21])[CH:3]=1.[Si:22]([O:29][C@@H:30]([CH3:34])[CH2:31][O:32][NH2:33])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]([CH3:20])[C:11](=[O:19])[CH:12]=[CH:13][C:14]=2[C:15]([NH:33][O:32][CH2:31][C@@H:30]([O:29][Si:22]([C:25]([CH3:26])([CH3:28])[CH3:27])([CH3:24])[CH3:23])[CH3:34])=[O:17])=[C:4]([F:21])[CH:3]=1
Reactant: C[C@@H](CON)O[Si](C)(C)C(C)(C)C
Reactant: COC(=O)c1ccc(=O)n(C)c1Nc1ccc(Br)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H](CONC(=O)c1ccc(=O)n(C)c1Nc1ccc(Br)cc1F)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 2-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (0.050 g, 0.14 mmol) and (S)-O-(2-(tert-butyldimethylsilyloxy)propyl) hydroxylamine (0.072 g, 0.35 mmol) in THF (1.50 mL) at 0° C. was slowly added lithium bis(trimethylsilyl)amide (0.70 ml, 0.70 mmol). After addition, the reaction mixture was stirred for 1 hour at room temperature and then quenched by with saturated NaHCO3. The reaction mixture was partitioned between EtOAc and sat NaCl. The layers were separated and the aqueous layer was back-extracted with EtOAc (1×). The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure to yield a crude brown solid that was used without further purification in the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1>>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][CH:11]=[C:2]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[CH:3]=1
Reactant: COC(=O)c1cccc(Br)c1
Reactant: COc1ccc(N)cc1
Product: COC(=O)c1cccc(Nc2ccc(OC)cc2)c1

Procedure:
Reaction of methyl 3-bromobenzoate with p-anisidine according to general procedure A provided methyl ester of Compound 11 as a yellow oil (93% yield). 1H NMR (CDCl3, 500 MHz): δ=7.57 (s, 1H), 7.50 (d, J=7.6 Hz, 1H), 7.28 (m, 1H), 7.07-7.12 (m, 3H), 6.90 (d, J=8.8 Hz, 2H), 5.62 (s, 1H), 3.90 (s, 3H), 3.83 (s, 3H). 13C NMR (CDCl3, 125 MHz): δ=167.5, 156.0, 145.8, 135.2, 131.5, 129.5, 123.1, 120.7, 119.7, 116.4, 115.0, 55.8, 52.2.