Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17](=[O:37])[C:18]([N:21]2[C:26](=[O:27])[CH:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:24](=[N:34][OH:35])[O:23][C:22]2=[CH2:36])([CH3:20])[CH3:19])[CH:12]=[C:13]([Cl:15])[CH:14]=1>N1C=CC=CC=1>[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17](=[O:37])[C:18]([N:21]2[C:26](=[O:27])[CH:25]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:24](=[N:34][O:35][C:1](=[O:3])[CH3:2])[O:23][C:22]2=[CH2:36])([CH3:20])[CH3:19])[CH:12]=[C:13]([Cl:15])[CH:14]=1
Reactant: C=C1OC(=NO)C(c2ccccc2)C(=O)N1C(C)(C)C(=O)Nc1cc(Cl)cc(Cl)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: C=C1OC(=NOC(C)=O)C(c2ccccc2)C(=O)N1C(C)(C)C(=O)Nc1cc(Cl)cc(Cl)c1
Temperature: 0 °C

Procedure:
Acetic anhydride (3 ml) was added to a stirred solution of N-(3,5-dichlorophenyl)-2-(2,3-dihydro-6-hydroxyiminomethylene-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanamide (0.4 g) in pyridine (3 ml) at -5° C. After 1.5 hours the mixture was poured into ice/water and extracted (ethyl acetate). The extract was washed with hydrochloric acid (2M) and with brine, dried (magnesium sulphate) and evaporated. The residue was purified by dry column chromatography on silica gel, eluting with hexane/ethyl acetate to give N-(3,5-dichlorophenyl)-2-(6-acetoxyiminomethylene-2,3-dihydro-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanamide (compound 118, 0.32 g) as an off-white solid, m.p. 125-127° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][CH:7]=1.C([Li])CCC.[C:19](=[O:21])=[O:20].CO>O1CCCC1>[F:1][C:2]1[C:3]([C:19]([OH:21])=[O:20])=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: Fc1ccc(-c2ccccc2)nc1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc(-c2ccccc2)ncc1F
Temperature: -45 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
To a solution of 5-fluoro-2-phenylpyridine (760.0 mg, 4.39 mmol) in tetrahydrofuran (15.0 ml) was added n-butyllithium (2.11 ml, 2.50 M in THF, 5.27 mmol) at −45° C. The mixture was stirred for 1 h at −45° C., then poured into THF containing dry ice. Stirred for 1 h, then MeOH (2 ml) was added. The solution was concentrated, and purified on Flashmaster II to get 560 mg (58%) of 5-fluoro-2-phenylisonicotinic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[CH:19]([N:22]([CH:37]([CH3:39])[CH3:38])[CH2:23][CH2:24][NH:25][C:26]([C:28]1[C:32]([CH3:33])=[C:31]([CH:34]=O)[NH:30][C:29]=1[CH3:36])=[O:27])([CH3:21])[CH3:20]>C(O)C.N1CCCCC1>[CH:37]([N:22]([CH:19]([CH3:21])[CH3:20])[CH2:23][CH2:24][NH:25][C:26]([C:28]1[C:32]([CH3:33])=[C:31]([CH:34]=[C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[CH:17][C:9]=3[C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[NH:13][C:12]2=[O:18])[NH:30][C:29]=1[CH3:36])=[O:27])([CH3:38])[CH3:39]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN(C(C)C)C(C)C
Reactant: COc1cccc(-c2cccc3c2CC(=O)N3)c1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1cccc(-c2cccc3c2C(=Cc2[nH]c(C)c(C(=O)NCCN(C(C)C)C(C)C)c2C)C(=O)N3)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 73.8 %

Procedure:
To a solution of 4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diisopropylamino-ethyl)-amide (73 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. The reaction solution was evaporated, and purified on a silica gel column eluting with MeOH—CH2Cl2 5:95 to provide pure product 5-[4-(3-methoxy-phenyl) 2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diisopropylamino-ethyl)-amide as a yellow solid (95 mg, 79%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:14]([O:16]C)=O)[C:10]([O:12]C)=O.[CH3:18][C:19]1[O:23][C:22]([C:24]2[CH:28]=[N:27][NH:26][C:25]=2[NH2:29])=[N:21][N:20]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([OH:12])=[N:29][C:25]2[N:26]([N:27]=[CH:28][C:24]=2[C:22]2[O:23][C:19]([CH3:18])=[N:20][N:21]=2)[C:14]=1[OH:16]
Reactant: Cc1nnc(-c2cn[nH]c2N)o1
Reactant: COC(=O)C(C(=O)OC)c1ccc(F)cc1Cl
Product: Cc1nnc(-c2cnn3c(O)c(-c4ccc(F)cc4Cl)c(O)nc23)o1
Temperature: 185 °C
Reaction time: 3 h

Procedure:
0.789 g of dimethyl 2-chloro-4-fluorophenylmalonate and 0.79 ml of tributyalmine were added to 0.5 g of the 4-(5-methyl-[1,3,4]oxadiazol-2-yl)-2H-pyrazol-3-ylamine obtained under Ac), and the mixture was stirred at 185° C. for 3 h. Concentration gave a glass-like substance.
Reaction SMILES: [F:1][CH:2]([F:15])[O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:6][C:5]=1[CH3:14].C1C(=O)N([Br:23])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[F:15][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:6][C:5]=1[CH2:14][Br:23]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(S(C)(=O)=O)ccc1OC(F)F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CS(=O)(=O)c1ccc(OC(F)F)c(CBr)c1
Temperature: 25 °C

Procedure:
To a solution of sulfone 15 from above (0.92 g) dissolved in CCl4 (20 mL) was added NBS (0.83 g) and a catalytic amount of benzoyl peroxide and the resulting mixture was irradiated with a sum lamp under reflux for 4 hours. After cooling to room temperature, the solid was filtered off and the filtrate was concentrated. The crude product was purified by silica gel chromatography. Eluting with ethyl acetate/hexanes (1:5) furnished 2-difluoromethoxy-5-methanesulfonylbenzyl bromide.
Reaction SMILES: C(OCC[N:7]1[C:13]2[CH:14]=[CH:15][C:16](Cl)=[CH:17][C:12]=2[C:11]2(C3C=CC=CC=3F)OCC[N:10]2[CH2:9][C:8]1=O)(=O)C.[OH-:30].[Na+].O>CO>[N:7]1[C:13]2=[CH:14][CH2:15][CH2:16][C:17](=[O:30])[C:12]2=[CH:11][N:10]=[CH:9][CH:8]=1
Reactant: [OH-]
Reactant: CC(=O)OCCN1C(=O)CN2CCOC2(c2ccccc2F)c2cc(Cl)ccc21
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C1CCC=C2N=CC=NC=C12
Reaction time: 3 h

Procedure:
A solution of 0.5g (0.0012 M) of 7-(2-acetoxyethyl)-10-chloro-11b-(2-fluorophenyl)-2,3,5,11b-tetrahydrooxazolo[3,2-d] [1,4]benzodiazepin-6(7H)-one in 5 ml of methanol was treated with 2 ml of 3N sodium hydroxide. After 3 hours, 50 ml of water was added and the solution was extracted with 40 ml of dichloromethane, which was then dried over anhydrous sodium sulfate and evaporated to dryness. The residue was crystallized from a mixture of methanol and water to give 10-chloro-11b-(2-fluorophenyl)-7-(2-hydroxyethyl)-2,3,5,11b-tetrahydrooxazolo)3,2-d) [1,4]benzodiazepin-6(7H)-one as white prisms, m.p. and m.m.p. 141°-146°.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](O)=[C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)[CH:7]=1.C(C1C=CC([NH:46][C:47](=[O:49])[CH3:48])=CC=1)(=O)C.[OH-].[K+]>C(O)C>[C:47]([NH:46][C:3]1[CH:4]=[CH:5][C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)=[CH:7][CH:2]=1)(=[O:49])[CH3:48]
Reactant: CC(=O)Nc1ccc(C(C)=O)cc1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)Nc1ccc(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)cc1
Yield: 15 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with N-(4-acetyl-phenyl)-acetamide (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (19 mg, 15% yield). MS: 505.26 (M+H+); HPLC Procedure A, retention time=9.94 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:14](=[O:18])[NH:13][CH:12]=[N:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C1CCN2C(=NCCC2)CC1.[CH3:63][C:64]1[NH:65][C:66]2[C:71]([CH:72]=1)=[CH:70][C:69](O)=[CH:68][CH:67]=2>>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([O:18][C:69]3[CH:70]=[C:71]4[C:66](=[CH:67][CH:68]=3)[NH:65][C:64]([CH3:63])=[CH:72]4)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2c(nc[nH]c2=O)C1
Reactant: Cc1cc2cc(O)ccc2[nH]1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cc2cc(Oc3ncnc4c3CCN(C(=O)OC(C)(C)C)C4)ccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirring solution of 4-oxo-4,5,6,8-tetrahydro-3H-pyrido[3,4-d]pyrimidine-7-carboxylic acid tert-butyl ester, Example 31-A, (300 mg, 1.2 mmol) in I (5 mL) is added PyBOP (800 mg, 1.55 mmol) and DBU (0.2 mL, 1.43 mmol). After 20 min 2-methyl-1H-indol-5-ol (211 mg, 1.43 mmol) is added. The mixture is then stirred at room temperature for 16 h. At that point the reaction is concentrated under reduced pressure and the residue is dissolved in EtOAc and washed by water and brine. The organic layer is dried over sodium sulfate, concentrated under reduced pressure. The residue is purified by FCC (EtOAc/heptane from 0% to 40%) to give the title compound. MS (ESI) m/z 381.0 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[C:18]([F:35])=[C:19](/[CH:23]=[C:24](/[C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[Cl:34])\[C:25]#[N:26])[CH:20]=[CH:21][CH:22]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([Cl:16])[C:18]=2[F:35])[C:24]([C:25]#[N:26])([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[Cl:34])[CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH:8]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#C/C(=C\c1cccc(Cl)c1F)c1ccc(Cl)cc1Cl
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1Cl
Yield: 66.3 %

Procedure:
In a manner similar to the method described in Example 1c, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 1a (2.1 g, 10 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(2,4-dichloro-phenyl)-acrylonitrile (2.2 g, 6.7 mmol) prepared in Example 56a, AgF (2 g, 16 mmol), and triethylamine (5 g, 50 mmol) in dichloromethane (200 mL) at room temperature for 20 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-4-(2,4-dichloro-phenyl)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (2.4 g, 66%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][N:8]1[C@@H:11]([CH3:12])[C@@H:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]1=[O:24].[OH-:25].[Na+]>O1CCOCC1>[C:18]1([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C@H:10]([C@@H:11]([NH:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH3:12])[C:9]([OH:24])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: [OH-]
Reactant: C[C@H]1[C@@H](CCCCCc2ccccc2)C(=O)N1OC1CCCCO1
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@H](NOC1CCCCO1)[C@@H](CCCCCc1ccccc1)C(=O)O
Temperature: 23 °C
Reaction time: 24 h
Yield: 71 %

Procedure:
To a solution of (3R,4S)-1-(2-tetrahydropyranyloxy)-3-(5-phenyl-1-pentyl)-4-methylazetidin-2-one (140 mg, 0.428 mmol) in dioxane (1.2 mL) is added 1 M aqueous sodium hydroxide (0.64 mL). The solution is stirred at 23° C. for 24 h, then extracted with hexanes (10 mL). The aqueous layer is acidified to pH=3 with saturated aqueous sodium bisulfate solution, and is extracted with two 20 mL portions of ethyl acetate. The combined organics are washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to provide (2R,3S)-2-(5-phenyl-1-pentyl)-3-(2-tetrahydropyranyloxyamino)butanoic acid as an oil (105 mg, 71% yield).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.II.[CH:11]([C:13]1[CH:14]=[C:15]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[CH:18]=1)=[O:12]>O1CCCC1>[OH:12][CH:11]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[C:13]1[CH:14]=[C:15]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:16]=[C:17]([C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)[CH:18]=1
Reactant: Brc1ccccn1
Reactant: CCOC(=O)c1cc(C=O)cc(-c2ccc(C)cc2)c1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(-c2ccc(C)cc2)cc(C(O)c2ccccn2)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The Grignard reagent was generated by treatment of magnesium (100 mg, 4.3 mmol) with a solution of 2-bromopyridine (600 mg, 3.8 mmol) and iodine (30 mg) in tetrahydrofuran (5 mL) under nitrogen at 60° C. for 1 hour. The mixture was cooled at 0° C. and ethyl 5-formyl-4′-methylbiphenyl-3-carboxylate (332 mg, 1.24 mmol) was added. The reaction mixture was stirred at 0° C. for 2 h and then quenched by addition of 3 mL of 2 N aq. H2SO4. The mixture was extracted with EtOAc (20 mL×2). The combined organic layers were washed with 1 N aq. NaOH, brine, dried over anhydrous MgSO4, filtered, and concentrated. The residue was chromatographed to yield a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[CH2:5][N:6]1[C:11](=[O:12])[C:10]2[C:13]([O:22][CH3:23])=[C:14]3[C:19](=[O:20])[N:18]([CH3:21])[CH2:17][CH2:16][N:15]3[C:9]=2[C:8]([CH2:24]Cl)=[N:7]1.[C-:30]#[N:31].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[CH2:5][N:6]1[C:11](=[O:12])[C:10]2[C:13]([O:22][CH3:23])=[C:14]3[C:19](=[O:20])[N:18]([CH3:21])[CH2:17][CH2:16][N:15]3[C:9]=2[C:8]([CH2:24][C:30]#[N:31])=[N:7]1
Reactant: [C-]#N
Reactant: COc1c2n(c3c(CCl)nn(Cc4ccc(F)c(Cl)c4)c(=O)c13)CCN(C)C2=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c2n(c3c(CC#N)nn(Cc4ccc(F)c(Cl)c4)c(=O)c13)CCN(C)C2=O
Temperature: 25 °C

Procedure:
A mixture of 2-(3-chloro-4-fluorobenzyl)-4-(chloromethyl)-10-methoxy-8-methyl-7,8-dihydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-dione (0.16 g, 0.37 mmol; Example 100) and sodium cyanide (30 mg, 0.61 mmol) in anhydrous DMF (2 mL) was heated in a sealed tube at room temperature overnight. The product mixture was concentrated under vacuum. The residue was partitioned between dichloromethane and brine. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a 0 to 10% methanol in chloroform gradient. Collection and concentration of appropriate fractions afforded the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH:3]([CH3:14])[CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[N:11][CH:12]=1.O.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23]([OH:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1.[CH2:28](OCC)C>C(OCC)(=O)C>[C:17]1([CH3:27])[CH:18]=[CH:19][C:20]([S:23]([OH:26])(=[O:24])=[O:25])=[CH:21][CH:22]=1.[CH3:15][N:2]([CH3:1])[CH:3]([CH3:14])[CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH3:28])[C:10]([Cl:13])=[N:11][CH:12]=1
Reactant: CC(CCOc1ccc(Cl)nc1)N(C)C
Reactant: CCOCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(OCCC(C)N(C)C)cnc1Cl
Reaction time: 0.08 h

Procedure:
A solution of the product 45A (63 mg, 0.26 mmol) in ethyl acetate (1 mL) was treated with p-toluenesulfonic acid monohydrate (49 mg, 0.27 mmol) and stirred for 5 minutes. Then ethyl ether (30 ml) was added and stirred for an additional 5 minutes. The ether was decanted and the procedure was repeated. The residue was then dried under vacuum to provide 48 as a white solid. MS (CI/NH3) m/e 243(M+H)+. 1H NMR (D2O, 300 MHz) δ: 1.39 (d, J=7 Hz, 3H), 2.09 (m, 1H), 2.33 (m, 1H), 2.37 (s, 3H), 2.38 (s, 3H), 2.87 (s, 6H), 3.70 (m, 1H), 4.15-4.27 (m, 2H), 7.35 (d, J=8 Hz, 2H), 7.37 (d, J=4 Hz, 1H) 7.68 (d, J=8 Hz, 2H), 7.87 (d, J=3 Hz, 1H). Analysis calculated for C12H19N2ClO.1.3C7H8O3S.H2O: C, 52.30; H, 6.53; N, 5.78; Found: C, 52.00; H, 6.33; N, 6.10
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[CH:10]([CH2:19][CH2:20][CH:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[OH:22])[C:9]2=[O:30])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I:37][CH:38](I)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:11]([C:12]3[CH:13]=[CH:14][C:15]([O:18][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][I:37])=[CH:16][CH:17]=3)[CH:10]([CH2:19][CH2:20][CH:21]([C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[OH:22])[C:9]2=[O:30])=[CH:6][CH:7]=1
Reactant: CCCCCCCCCC(I)I
Reactant: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(O)cc2)N1c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(OCCCCCCCCCCI)cc2)N1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
150 mg of 1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4 hydroxyphenyl)azetidin-2-one are dissolved in 10 ml of absolute dimethylformamide. 120 mg of powdered potassium carbonate and 865 mg of diiododecane are then added. The reaction solution is stirred at room temperature overnight. After concentration using a rotary evaporator and oil pump vacuum at 40° C., the residue is purified using an SiO2 cartridge (n-heptane; n-heptane/ethyl acetate-4:1). The product is obtained as an oil. C34H40F2INO3 (675) MS (ESI): M+-18
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]1([CH3:30])[CH:24]=[CH:23][CH:22]=[C:21](/[CH:25]=[CH:26]/[C:27](O)=[O:28])[CH:20]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:27](=[O:28])/[CH:26]=[CH:25]/[C:21]3[CH:20]=[C:19]([CH3:30])[CH:24]=[CH:23][CH:22]=3)=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: Cc1cccc(/C=C/C(=O)O)c1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)/C=C/c3cccc(C)c3)n2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-m-tolyl-acrylic acid.
Reaction SMILES: O1[C@@H:6]2[C@H:2]1[C@H:3]([OH:19])[C:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:5]2>CO>[C:7]1([C:4]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:3]([OH:19])[CH:2]=[CH:6][CH2:5]2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O[C@H]1[C@H]2O[C@H]2CC1(c1ccccc1)c1ccccc1
Solvent: CO
Product: OC1C=CCC1(c1ccccc1)c1ccccc1

Procedure:
(+)-rel-(1R,2R,3S)-2,3-epoxy-5,5-diphenylcyclopentan-1-ol [(+) isomer rich mixture; [α]D22 =+45.34° (C=0.743, CH3OH)] (-)-5,5-diphenyl-2-cyclopenten-1-ol were obtained according to a similar manner to that of Preparation 20.
Reaction SMILES: C([O:3][C:4](=[O:19])[C:5]([CH3:18])([CH3:17])[C:6]([NH:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:7])C.[OH-].[K+].C(O)C>O>[CH3:17][C:5]([CH3:18])([C:6]([NH:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:7])[C:4]([OH:19])=[O:3]
Reactant: CCOC(=O)C(C)(C)C(=O)NCCN1CCOCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C(=O)O)C(=O)NCCN1CCOCC1

Procedure:
34.1 g 2,2-Dimethyl-N-(2-morpholin-4-yl-ethyl)-malonamic acid ethyl ester, 8.4 g potassium hydroxide, 200 ml ethanol and 4.5 ml H2O were stirred at 80° C. for 6 hours. Then most of the solvent was removed and the pH was adjusted to pH 3-4 with about 100 ml 2N HCl. The solvent was evaporated and toluol was added and then removed. To the final residue methanol was added and the suspension was filtered to remove salts. The solvent was removed and the residue was dissolved in H2O and lyophilized. The product was characterized by 1H-NMR.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[O:4][C:3]=1[CH:13]([OH:15])[CH3:14].CN1CC(=O)OB([C:26]2[S:30][CH:29]=[N:28][CH:27]=2)OC(=O)C1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:15][CH:13]([C:3]1[O:4][C:5](=[O:12])[C:6]2[C:11]([C:2]=1[C:26]1[S:30][CH:29]=[N:28][CH:27]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH3:14]
Reactant: CC(O)c1oc(=O)c2ccccc2c1Br
Reactant: CN1CC(=O)OB(c2cncs2)OC(=O)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(O)c1oc(=O)c2ccccc2c1-c1cncs1
Yield: 100.3 %

Procedure:
4-Bromo-3-(1-hydroxyethyl)-1H-isochromen-1-one (Intermediate A2, 0.1 g, 0.372 mmol), 6-methyl-2-(thiazol-5-yl)-1,3,6,2-dioxazaborocane-4,8-dione (0.134 g, 0.56 mmol), Pd(PPh3)4 (0.021 g, 0.019 mmol) and Cs2CO3 (0.182 g, 0.56 mmol) in DMF (1 mL) were heated under microwave irradiation at 120° C. for 1 hrs and 15 min. Then, further 6-methyl-2-(thiazol-5-yl)-1,3,6,2-dioxazaborocane-4,8-dione (0.134 g, 0.56 mmol), Pd(PPh3)4 (0.021 g, 0.019 mmol) and Cs2CO3 (0.182 g, 0.56 mmol) were added and then resulting mixture was reacted for 5 hrs at 100° C. The crude product was purified via reverse phase chromatography with a Biotage C18 30 g SNAP column (Phase A, water 95%, ACN 4.9%, formic acid 0.1%; Phase B ACN 99.9%, formic acid 0.1%) to give the title compound (102 mg).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH2:8][CH2:7]2.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>C1C=CC=CC=1>[CH3:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2
Reactant: Cc1c([N+](=O)[O-])ccc2c1NCC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: ClCCl
Product: Cc1c([N+](=O)[O-])ccc2cc[nH]c12
Yield: 99.5 %

Procedure:
A solution of 2,3-dihydro-7-methyl-6-nitroindole (3.1 g, 17.4 mmol) in 75 mL of benzene is treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ, 4.34 g, 19.1 mmol). The solution turns black and over the next 15 minutes, turns to green with a green precipitate. This mixture is distributed between 400 mL of aqueous potassium carbonate solution and 500 mL of methylene chloride. The organic solution is removed, dried over magnesium sulfate, filtered and evaporated to dryness on a rotary evaporator to afford 3.05 g of 7-methyl-6-nitroindole as a yellow solid (99% yield).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27][C:28](=O)[O:29]C1C=CC([N+]([O-])=O)=CC=1>CC#N>[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27][C:28]([N:10]1[CH2:11][CH2:12][C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@H:9]1[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:8][CH:7]=1)=[O:29]
Reactant: O=C(Nc1ccccn1)Oc1ccc([N+](=O)[O-])cc1
Reactant: FC(F)(F)c1ccc([C@H]2NCCc3ccccc32)cc1
Solvent: CC#N
Product: O=C(Nc1ccccn1)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1
Temperature: 70 °C

Procedure:
To a solution of (R)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (100 mg, 0.361 mmol) in MeCN (2 mL) was added 4-nitrophenyl pyridin-2-ylcarbamate (467 mg, 1.80 mmol). The resulting mixture was then heated at 70° C. for 16 h, cooled to RT and filtered. The white solid obtained was washed with DCM (2×2 mL). The combined filtrates were then concentrated and the residue purified by silica gel flash column chromatography (0%-100% EtOAc/hexane) to give the title compound as a colorless solid. MS (ESI, positive ion) m/z: 398 (M+H).