Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([CH3:25])[CH:3]=1.[O:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31]>>[CH2:23]([C:19]1[CH:20]=[C:21]([CH3:22])[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:28]4[CH2:29][CH2:30][O:26][C:27]4=[O:31])=[CH:3][C:4]=3[CH3:25])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=1)[CH3:24]
Reactant: O=C1NCCO1
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C)CC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3C)CC2)c(C)c1
Yield: 79.6 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-methylphenyl)[4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (350 mg) described in Preparation Example 129 and oxazolidin-2-one (114 mg), the title compound (283 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][O:6][CH:7]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][C:14]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:15]#[N:16])[CH2:8]1.[OH-:32].[K+]>C(O)(C)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][O:6][CH:7]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][C:14]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:15]([NH2:16])=[O:32])[CH2:8]1
Reactant: N#CC(CCN1CCC(OCc2cccc(Cl)c2)C1)(c1ccccc1)c1ccccc1
Reactant: [OH-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: NC(=O)C(CCN1CCC(OCc2cccc(Cl)c2)C1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 83.7 %

Procedure:
To 1.80 g of 4-[3-(3-chlorobenzyloxy)pyrrolidine-1-yl]2,2-diphenylbutyronitrile was added 1.41 g of potassium hydroxide and 15 ml of tert-butanol, and the mixture was refluxed for 48 hours. The reaction mixture was poured into ice water, then extracted with methylene chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride:methanol=10:1) to obtain 1.57 g of the aimed compound as a yellow oil.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][C:12]([O:21][CH3:22])=[CH:13][C:14]=3[O:19][CH3:20])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:29]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)[CH:30]([CH3:32])[CH3:31].CN(C)C(=O)C>CN(C)C=O.C(OCC)(=O)C>[CH2:29]([N:33]1[CH2:38][CH2:37][N:36]([C:2]2[N:7]=[C:6]([C:8]3[NH:17][C:16](=[O:18])[C:15]4[C:10](=[CH:11][C:12]([O:21][CH3:22])=[CH:13][C:14]=4[O:19][CH3:20])[N:9]=3)[CH:5]=[CH:4][CH:3]=2)[CH2:35][CH2:34]1)[CH:30]([CH3:32])[CH3:31]
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cccc(F)n3)nc2c1
Reactant: CC(C)CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cccc(N4CCN(CC(C)C)CC4)n3)nc2c1
Temperature: 110 °C
Reaction time: 20 h
Yield: 34.1 %

Procedure:
To a suspension of 2-(6-fluoropyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.108 g, 0.36 mmol) in N,N-dimethylformamide (1.5 mL) was added K2CO3 (0.15 g, 1.07 mmol) and 1-isobutyl-piperazine (88.94, 0.54 mmol). The resulting mixture was heated at 110° C. for 6 h. After that time N,N-dimethylacetamide (1.5 mL) was added and heating was continued for 20 h. After that time the reaction mixture was cooled to rt, diluted with ethyl acetate and filtered. The filtrate was concentrated under reduced pressure and the residue was washed with water, and dried under high vacuum. The product was purified by flash column chromatography (silica gel, 99:1 dichloromethane/methanol) to give 2-(6-(4-isobutylpiperazin-1-yl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.052 g, 34%) as a yellow solid: mp 188-189° C.; 1H NMR (400 MHz, CDCl3) δ 10.33 (br s, 1H), 7.83 (d, J=7.42 Hz, 1H), 7.65 (dd, J=8.59, 7.42, 1H), 6.76-6.88 (m, 2H), 6.48 (d, J=2.34 Hz, 1H), 3.99 (s, 3H), 3.94 (s, 3H), 3.64 (t, J=4.88 Hz, 4H), 2.55 (t, J=4.88 Hz, 4H), 2.17 (d, J=7.42 Hz, 2H), 1.75-1.95 (m, 1H), 0.95 (d, J=6.64 Hz, 6H); ESI MS m/z 424 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:17]2[C@@H:16]3[C:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C:11](=[O:20])[CH2:10][CH2:9]4)=[CH:6][CH2:5][C:4]=2[CH:3]=1.C1(C)C=CC(S(O)(=O)=[O:28])=CC=1.N1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCCC1.O1C=CCCC1.C(OCC)(=O)C>[O:28]1[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]1[O:1][C:2]1[CH:19]=[CH:18][C:17]2[C@@H:16]3[C:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C:11](=[O:20])[CH2:10][CH2:9]4)=[CH:6][CH2:5][C:4]=2[CH:3]=1
Reactant: c1ccncc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C[C@]12CC[C@H]3C(=CCc4cc(O)ccc43)[C@@H]1CCC2=O
Agent: C1=COCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@]12CC[C@H]3C(=CCc4cc(OC5CCCCO5)ccc43)[C@@H]1CCC2=O

Procedure:
A suspension of 2.0 g of 3-hydroxy-estra-1,3,5(10),7-tetraen-17-one in 20 ml of tetrahydrofuran and 2.0 ml of dihydropyran is stirred with 9.6 mg of para-toluenesulfonic acid for 24 hours at room temperature. Then, 0.3 ml of pyridine is added, diluted with ethyl acetate, washed with sodium bicarbonate solution as well as with saturated sodium chloride solution, dried on sodium sulfate, concentrated by evaporation in a vacuum, and chromatographed on silica gel with hexane/acetone. 1.9 g of 3-tetrahydropyranyloxy-estra-1,3,5(10),7-tetraen-17-one is obtained as colorless crystals with a melting point of 147-149° C., [α]D22 =+209.7° (c=0.5% in pyridine).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](O)=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.S1(CCCC1)(=O)=O.S(N)([NH2:29])(=O)=O.[OH-].[Na+]>ClCCl.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]#[N:29])=[CH:4][CH:3]=1
Reactant: O=C(O)C=Cc1ccc(F)cc1
Reactant: NS(N)(=O)=O
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=S1(=O)CCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#C/C=C/c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
A suspension of 3-(4-fluorophenyl)acrylic acid (2.5 g, 15 mmol) in dry dichloromethane (50 ml) was treated with DMF (2 drops), oxalyl chloride (2.6 ml, 30 mmol) and the reaction was stirred at room temperature under argon for 3 h. The reaction mixture was evaporated to dryness and azeotroped with dichloromethane (25 ml×2) and evaporated to dryness giving a yellow oil. The acid chloride was mixed with sulfolane (15 ml) and treated with sulfamide (1.73 g, 0.018 moles) (A. Hulkenberg and J. J. Troost, Tetrahedron Letters Vol.23, No. 14, 1505-1508, 1982) and the reaction mixture was heated to 120° C. for 3 h. The reaction mixture was cooled, poured into 1N NaOH (100 ml) and extracted with 1:1 diethyl ether:hexane (3×75 ml). The organic extracts were combined, washed with water (3×50 ml), dried (MgSO4) and evaporated to dryness. Purification by flash column chromatography eluted with 2:1 hexane:ethyl acetate gave E-3-(4-fluorophenyl)acrylonitrile as a cream solid (2.12 g, 96%); 1H-NMR (CDCl3) 5.77, 5.83 (1H, d), 7.16 (2H, m), 7.26, 7.40 (1H, d), 7.45 (2H, m). MS (APCI+) M+1=148, C9H6FN requires 147.
Reaction SMILES: [N:1]([C:4]1[CH:15]=[CH:14][C:7]([O:8][CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])=[CH:6][CH:5]=1)=[C:2]=[S:3].[N:16]#[C:17][NH2:18].CC(C)([O-])C.[K+].Br[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=1)=[O:28]>C(#N)C.C(O)(C)(C)C.CCOCC.Cl.CCOCC>[NH2:16][C:17]1[N:18]=[C:2]([NH:1][C:4]2[CH:15]=[CH:14][C:7]([O:8][CH2:9][CH2:10][N:11]([CH3:12])[CH3:13])=[CH:6][CH:5]=2)[S:3][C:26]=1[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=1)=[O:28]
Reactant: N#CN
Reactant: CN(C)CCOc1ccc(N=C=S)cc1
Reactant: COc1cccc(C(=O)CBr)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CC#N
Solvent: CCOCC
Product: COc1cccc(C(=O)c2sc(Nc3ccc(OCCN(C)C)cc3)nc2N)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
To a stirred mixture of [2-(4-isothiocyanato-phenoxy)-ethyl]-dimethylamine (0.6 g, 2.7 mmol) (from Step A) and cyanamide (0.123 g, 2.95 mmol) in acetonitrile (10 mL) and tert-butanol (10 mL), a solution of potassium tert-butoxide (2.7 mL, 1.0 M in tert-BuOH) was added. After 30 minutes at room temperature, 2-bromo-3′-methoxyacetophenone was added. The reaction mixture was stirred at room temperature for 1 hour and then refluxed for 1 hour. The chilled reaction mixture was diluted with ether and excess anhydrous hydrochloric acid/ether solution was added. The solids were filtered, washed with ether and then dissolved in dichloromethane/aqueous sodium bicarbonate. The dried (Na2SO4) organic solution was diluted with toluene (25 mL), concentrated, and refluxed to remove dichloromethane, The cooled mixture was diluted with hexane and filtered to give 0.47 g (42%) of [4-amino-2-[4-(2-dimethylaminoethoxy)-phenylamino]-thiazol-5-yl]-(3-methoxy-phenyl)-methanone as a yellow solid, mp 130° C. (dec). Mass spectrum (ES) MH+=413.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[C:5]([OH:10])([CH3:9])[C:6]([OH:8])=O)[CH3:2].O1CCCC1.Cl.[F:18][C:19]([F:24])([F:23])[CH2:20][CH2:21][NH2:22].Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>>[CH2:1]([O:3][C:4](=[O:11])[C:5]([OH:10])([CH3:9])[C:6]([NH:22][CH2:21][CH2:20][C:19]([F:24])([F:23])[F:18])=[O:8])[CH3:2]
Reactant: CCOC(=O)C(C)(O)C(=O)O
Reactant: NCCC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C)(O)C(=O)NCCC(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 94 %

Procedure:
To a solution of 2.00 g (8.51 mmol) 2-hydroxy-2-methyl-malonic acid monoethyl ester in 60 ml of tetrahydrofuran 1.27 g (8.51 mmol) of 3,3,3-trifluoropropylamine hydrochloride, 1.67 g (8.51 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, 1.17 g (8.51 mmol) of 1-hydroxybenzotrizole hydrate and 4.46 ml (25.5 mmol) of N,N-diisopropyl-ethylamine were added. The mixture was stirred at room temperature for 18 h. Silicagel was added and the solvent was removed by distillation. The residue was purified by chromatography on silicagel dichloromethane/methanol 7:3 to yield 2.33 g (94%) of the title compound, MS m/e (%): 258.1 (M+H+, 100).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH3:16])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:17]#[N:18].[Br:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[F:27])[NH2:23]>COC(O)C.C(OCC)(=O)C>[Br:19][C:20]1[CH:21]=[C:22]([NH:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:15][CH3:16])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:17]#[N:18])[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: Nc1ccc(F)c(Br)c1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1[N+](=O)[O-]
Agent: COC(C)O
Solvent: CCOC(C)=O
Product: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Br)c3)c2cc1[N+](=O)[O-]
Yield: 74.1 %

Procedure:
A mixture of 3.52 g (9.7 mmol) of 4-chloro-7-methoxy -6-nitro-3-quinolinecarbonitrile and 2.0 g (10.7 mmol) of 3-bromo-4-fluoro aniline in 150 ml of methoxyethanol was refluxed under nitrogen for 5.5 hours. The reaction mixture was diluted with ethyl acetate and wash with sodium bicarbonate solution and sodium chloride solution. The organic layer was dried with sodium sulfate and then solvent was removed under vacuum. The residue was chromatographed on silica gel eluting with mixture of ethyl acetate and methanol to give 3 g of yellow solid: mass spectrum (electrospray, m/e): 416.8 and 418.8.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[N:11]([S:19]([C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[CH3:30][C:31]1[O:35][C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[N:33][C:32]=1[CH2:42][CH2:43]OS(C)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[N:11]([S:19]([C:22]1[CH:23]=[CH:24][C:25]([O:28][CH2:43][CH2:42][C:32]2[N:33]=[C:34]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[O:35][C:31]=2[CH3:30])=[CH:26][CH:27]=1)(=[O:21])=[O:20])[C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13]
Reactant: Cc1oc(-c2ccccc2)nc1CCOS(C)(=O)=O
Reactant: COC(=O)c1ccc(Cl)cc1N(C(=O)OC(C)(C)C)S(=O)(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Cl)cc1N(C(=O)OC(C)(C)C)S(=O)(=O)c1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1

Procedure:
A mixture of the title E compound, 2-[(4-hydroxybenzenesulfonyl)-(t-butoxycarbonyl)-amino]-4-chloro-benzoic acid methyl ester (300 mg, 0.73 mmol), the title F compound, methanesulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl ester (246 mg, 0.87 mmol) and cesium carbonate (475 mg, 1.46 mmol) is stirred in DMF at 60° C. overnight. The mixture is cooled and the product is taken up in EtOAc. The solution is washed with brine, dried over anhydrous magnesium sulfate, and concentrated to give the crude product which is purified by flash chromatography on silica gel using an EtOAc (15%)-hexane (85%) mixture as the eluent to afford 4-chloro-2-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzenesulfonyl-(t-butoxycarbonyl)amino}benzoic acid methyl ester as a white foam.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9](=[O:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Se](=O)(O)[OH:13].O1CCOCC1>O>[CH:8]([C:9]([CH:10]=[O:13])=[O:11])=[CH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)C=Cc1ccccc1
Reactant: O=[Se](O)O
Solvent: C1COCCO1
Solvent: O
Product: O=CC(=O)C=Cc1ccccc1

Procedure:
A solution containing 100 parts of 4-phenyl-3-buten-2-one, 106 parts of selenous acid, 160 parts of dioxane and 20 parts of water is heated to the reflux temperature. After the initial vigorous reaction has subsided, the mixture is heated at that temperature for an additional 30 minutes. The supernatant is then decanted from the metallic selenium and is concentrated under reduced pressure. Distillation of the residue under reduced pressure affords, as a yellow oil, styrylglyoxal, boiling at about 120° at 2.5 mm. pressure.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.CN(C)/[CH:20]=[CH:21]\[N+:22]([O-:24])=[O:23]>ClCCl>[N+:22]([CH:21]=[CH:20][C:6]1[C:5]2[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)[NH:8][CH:7]=1)([O-:24])=[O:23]
Reactant: CN(C)/C=C\[N+](=O)[O-]
Reactant: Fc1ccc2cc[nH]c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])C=Cc1c[nH]c2cc(F)ccc12
Temperature: 2.5 °C
Reaction time: 0.75 h

Procedure:
Combine 6-fluoroindole (108 g, 0.8 mol) and dichloromethane (324 ml). Cool in an ice bath. Add trifluoroacetic acid (308 ml) over a few minutes (exothermic). Add a solution of Z-1-dimethylamino-2-nitroethylene (94.7 g, 0.816 mol) in dichloromethane (600 ml) during 40 minutes while maintaining the temperature at about 0-5° C. After 45 minutes, warm to about 20° C. After 2 hours, pour over 1.2 L ice water and stirring overnight with seeding to give a solid. Collect the solid by filtration, wash first with 100 ml of a mixture dichloromethane-cyclohexane 1/1, then with 750 ml of water and dry at 4° C. to give 3-(2-nitrovinyl)-6-fluoroindole.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][C:18]1[CH:22]=[C:21]([C:23](Cl)=[O:24])[O:20][N:19]=1>CC(C)=O>[C:6]([C:5]1[CH:9]=[CH:10][C:2]([NH:1][C:23]([C:21]2[O:20][N:19]=[C:18]([CH3:17])[CH:22]=2)=[O:24])=[CH:3][CH:4]=1)([OH:8])=[O:7]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: Cc1cc(C(=O)Cl)on1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(C(=O)Nc2ccc(C(=O)O)cc2)on1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
To a stirred suspension of 6.9g of p-aminobenzoic acid and 3.5 g of potassium carbonate in 60 ml of acetone was added 7.3 g of 3-methylisoxazole-5-carbonyl chloride. The mixture was stirred at room temperature for 1 hr. and then refluxed for 1 hr. The precipitate was filtered off and dissolved in water. The solution was acidified with concentrated hydrochloride acid. The precipitate was filtered off and washed with ethanol. There was obtained 9.1 g of N-(p-carboxyphenyl)-3-methylisoxazole-5-carboxamide. Melting point: above 300° C. Yield: 73.4%.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([CH:9]([CH3:15])[C:10]([O:12]CC)=[O:11])[N:5]=[CH:4][C:3]=1[NH:16][C@@H:17]1[CH2:22][C@@H:21]2[CH2:23][C@@H:19]([C:20]2([CH3:25])[CH3:24])[C@H:18]1[CH3:26].[OH-].[Na+].C(OCC)(=O)C>O1CCOCC1>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH:9]([CH3:15])[C:10]([OH:12])=[O:11])[N:5]=[CH:4][C:3]=1[NH:16][C@@H:17]1[CH2:22][C@@H:21]2[CH2:23][C@@H:19]([C:20]2([CH3:24])[CH3:25])[C@H:18]1[CH3:26]
Reactant: CCOC(=O)C(C)n1ncc(N[C@@H]2C[C@@H]3C[C@H]([C@H]2C)C3(C)C)c(Br)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C(=O)O)n1ncc(N[C@@H]2C[C@@H]3C[C@H]([C@H]2C)C3(C)C)c(Br)c1=O
Yield: 158.3 %

Procedure:
Ethyl 2-{5-bromo-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}propanoate (149 mg, 0.349 mmol) in 1,4-dioxane (1 mL) was stirred with 1 M aqueous sodium hydroxide (0.698 mL, 0.698 mmol) at room temperature for 5.5 hours. After completion of the reaction, ethyl acetate was added, and the organic layer was washed with 1 M hydrochloric acid and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give the desired product (220 mg, quant.).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].N(CCO)CCO>C1COCC1.C(OCC)C>[C:4]1([C@@H:1]([OH:3])[CH3:2])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Solvent: OCCNCCO
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@H](O)c1ccccc1
Reaction time: 7 h
Yield: 75.3 %

Procedure:
Under a nitrogen atmosphere, with stirring, acetophenone (3.05 mL, 25 mmol) was added to a solution of diisopinocampheylchloroborane (9.0 g, 28 mmol) in THF (20 mL0 at -25° C. A yellow color developed immediately. The reaction was complete after 7 h at -25° C. (followed by 11B NMR after methanolysis of an aliquot). The volatiles were pumped off at aspirator pressure and the α-pinene was removed under reduced pressure (0.1 mm Hg, 8 h). The residue was dissolved in ethyl ether (100 mL0 and diethanolamine (2.2 equiv) was added. The separated solid was filtered off after 2 h and washed twice with pentane (~30 mL). The combined ether and pentane filtrates were concentrated. The residue, upon distillation (bp 118° C., 22 mm Hg) provided [S]-1-phenylethanol (2.3 g, 72% yield) [α]20D -42.6° (neat) after purification by preparative gas liquid chromotagraphy on Carbowax 20 M; 98% ee based on -43.5° for maximum reported rotation. Gas chromotagraphy analysis of its α-methoxy-α-(trifuloromethyl)phenylacetate (made from (+)-MTPA chloride, Aldrich) on Supelcowax glass capillary column (15 m) showed a composition of 98.7% S+1.3% R (i.e., 97.4% ee), in good agreement with the optical rotation measurement.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[CH2:11][N:12]([CH3:15])[CH2:13][CH2:14][C:3]=12.[Li]C(C)(C)C.[CH:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)=[O:22]>CCOCC>[OH:22][CH:21]([C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[CH2:11][N:12]([CH3:15])[CH2:13][CH2:14][C:3]=12)[C:23]1[CH:24]=[CH:25][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:31][CH:32]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CN1CCc2c(Br)c3ccccc3n2C1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: COC(=O)c1ccc(C(O)c2c3n(c4ccccc24)CN(C)CC3)cc1
Reaction time: 0.25 h
Yield: 59.6 %

Procedure:
To a solution of 5-bromo-2-methyl-1,2,3,4-tetrahydropyrimido[1,6-a]indole (0.254 g) in 8 mL of ether cooled at −78° C. was added t-BuLi (1.4 mL, 1.7 M in pentane) dropwise. After attiring at −78° C. for 15 min, a solution of methyl 4-formylbenzoate (0.200 g in 2 mL of ether) was added quickly by a syringe. The reaction mixture was wormed to r.t. over 10 min, and quenched with 10 mL of saturated aqueous solution of NH4Cl, and 20 mL of EtOAc was added. The solid was collected by filtration to give 0.2 g of the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@H:9]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][Si](C)(C)[N-][Si](C)(C)C.[Li+].CI>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[CH:11]([CH3:21])[CH2:10][C@H:9]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)OC(=O)[C@@H]1CCC(=O)N1C(=O)OC(C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1C[C@@H](C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C1=O
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a solution of tert-butyl N-tert-butoxycarbonyl-pyroglutamate (11.5 g, 40 mmol) in THF (200 mL) stirring at −78° C., was added a 1 M solution of lithium hexamethyldisilazide in THF (42 mL, 42 mmol) dropwise over 5 minutes. After 30 minutes, methyliodide (3.11 mL, 50 mmol) was added. After an additional 2 hours at −78° C., the cooling bath was removed and 50% saturated aqueous ammonium chloride (200 mL) was added. The solution was stirred for 20 minutes, then extracted with ether (3×200 mL). The combined organic layers were washed with brine (200 mL), dried (Na2SO4), filtered and concentrated. The residue was chromatographed with 1:1 ethylacetate/hexanes to give Boc-PyroGlu(4-methyl)-OtBu (10.6 grams, 35.4 mmol, 88%) as a mixture of isomers (2:1 cis to trans).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([O:10][C@@H:11]([C:16]([O:29][CH3:30])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([O:14]C)=[O:13])[N:4]=1.[OH-].[Na+]>CO.O>[OH:1][CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([O:10][C@@H:11]([C:16]([O:29][CH3:30])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:12]([OH:14])=[O:13])[N:4]=1
Reactant: COC(=O)[C@@H](Oc1nc(C)cc(CO)n1)C(OC)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(c1ccccc1)(c1ccccc1)[C@H](Oc1nc(C)cc(CO)n1)C(=O)O
Temperature: 25 °C
Yield: 77.6 %

Procedure:
To a solution of the compound of Example 11 (0.8 g, 1.96 mmol) in methanol (10 mL) is added a solution of sodium hydroxide (0.392 g, 9.8 mmol) in water (5 mL) and the resultant mixture refluxed for 2 hr. The reaction is cooled to room temperature and the methanol is removed under reduced pressure on a rotary evaporator. The residual aqueous phase is washed with ether (2×10 mL), and then the pH of the aqueous phase is adjusted to 2-3 with 2N sulfuric acid and extracted with ethyl acetate (2×20 mL) to yield the title compound (0.6 g, 80%). MS m/z 395.1 (M+.+1); [α]D20=+141.09° (c=1, CH3OH).
Reaction SMILES: C(OC(=O)NC[C:9]1[C:10]([O:28][CH3:29])=[N:11][CH:12]=[C:13]([N:15]2[C:20](=[O:21])[NH:19][C:18]3[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=3[S:16]2(=[O:27])=[O:26])[CH:14]=1)(C)(C)C.[F:31][C:32]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[C:36]([F:42])[C:33]=1[CH2:34]Br.C([O-])([O-])=O.[K+].[K+].C(O)(C(F)(F)F)=O.FC1C=C(OC)C=C(F)C=1[CH2:59][N:60]1C2C=CC=CC=2S(=O)(=O)N(C2C=CC(OC)=C(NC)N=2)C1=O>CN(C=O)C.C(Cl)Cl>[F:31][C:32]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[C:36]([F:42])[C:33]=1[CH2:34][N:19]1[C:18]2[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=2[S:16](=[O:27])(=[O:26])[N:15]([C:13]2[CH:12]=[N:11][C:10]([O:28][CH3:29])=[C:9]([NH:60][CH3:59])[CH:14]=2)[C:20]1=[O:21]
Reactant: COc1cc(F)c(CBr)c(F)c1
Reactant: COc1ncc(N2C(=O)Nc3ccccc3S2(=O)=O)cc1CNC(=O)OC(C)(C)C
Reactant: CNc1nc(N2C(=O)N(Cc3c(F)cc(OC)cc3F)c3ccccc3S2(=O)=O)ccc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNc1cc(N2C(=O)N(Cc3c(F)cc(OC)cc3F)c3ccccc3S2(=O)=O)cnc1OC

Procedure:
The title compound (120 mg, 0.24 mmol) was prepared in two steps from tert-butyl[5-(1,1-dioxido-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazin-2-yl)-2-methoxypyridin-3-yl]methylcarbamate (IntA35) (130 mg, 0.3 mmol), 2,6-difluoro-4-methoxybenzyl bromide (85 mg, 0.36 mmol) and K2CO3 (124 mg, 0.9 mmol) in DMF (1.5 mL); followed by TFA (2 mL) in DCM (3 mL) at rt using the methods of (179).