Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]([CH3:64])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:60]([CH3:63])[CH2:61][CH3:62])[C@H:24]([O:58][CH3:59])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:56][CH3:57])[C@@H:34]([CH3:55])[C:35]([NH:37][C@@:38]1([C:47]([N:49]2[CH2:54][CH2:53][CH2:52][CH2:51][O:50]2)=[O:48])[CH2:40][C@@H:39]1[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])([OH:3])=O.FC(F)(F)C(O)=O.[NH2:72][CH2:73][CH2:74][N:75]([CH3:88])[C:76](=[O:87])[CH2:77][CH2:78][CH2:79][N:80]1[C:84](=[O:85])[CH:83]=[CH:82][C:81]1=[O:86].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[O:86]=[C:81]1[CH:82]=[CH:83][C:84](=[O:85])[N:80]1[CH2:79][CH2:78][CH2:77][C:76]([N:75]([CH3:88])[CH2:74][CH2:73][NH:72][C:1](=[O:3])[CH2:4][CH2:5][CH2:6][N:7]([CH3:64])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:60]([CH3:63])[CH2:61][CH3:62])[C@H:24]([O:58][CH3:59])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:56][CH3:57])[C@@H:34]([CH3:55])[C:35]([NH:37][C@@:38]1([C:47]([N:49]2[CH2:54][CH2:53][CH2:52][CH2:51][O:50]2)=[O:48])[CH2:40][C@@H:39]1[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:17])[CH3:18])=[O:13])[CH:9]([CH3:10])[CH3:11])=[O:87]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@]1(C(=O)N2CCCCO2)C[C@@H]1c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Reactant: CN(CCN)C(=O)CCCN1C(=O)C=CC1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@]1(C(=O)N2CCCCO2)C[C@@H]1c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)NCCN(C)C(=O)CCCN1C(=O)C=CC1=O)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6 mg (7 μmol) of N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-{[(1S,2R)-1-(1,2-oxazinan-2-ylcarbonyl)-2-phenylcyclopropyl]amino}-3-oxopropyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (Intermediate 61) were combined with 2.8 mg (8 μmol) of N-(2-aminoethyl)-4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-methylbutanamide trifluoroacetate, 10.1 mg (27 μmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate and 5 μl of N,N-diisopropylethylamine in 2 ml of DMF and stirred at RT overnight. Then another 5 mg (23.5 μmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate and 3 μl of N,N-diisopropylethylamine were added. After stirring at RT for a further 5 h, the solvent was removed under reduced pressure and the remaining residue was purified by means of preparative HPLC. The corresponding fractions were concentrated and, by lyophilization from dioxane, 1.3 mg (15% of theory) of the title compound were obtained.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([OH:15])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:3])[CH3:2].Br[CH2:17][CH2:18][O:19][CH3:20].[H-].[Na+]>CN(C=O)C.CC(=O)OCC>[C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([O:15][CH2:17][CH2:18][O:19][CH3:20])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(O)cc(C(C)(C)C)c1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCOc1cc(C(=O)OC)cc(C(C)(C)C)c1

Procedure:
Methyl 3-tert-butyl-5-hydroxybenzoate (O6.043; 2.18 g) and 1-bromo-2-methoxyethane (1.18 ml) were dissolved in DMF (30 ml) and sodium hydride (301 mg) was added while stirring. After stirring at RT for 2 h, the solvent was drawn off. The residue was taken up in EA, and the mixture was washed with water, dried and concentrated. The residue was purified using silica gel (80 g cartridge, n-heptane/MtB ether gradient of 0-30% in 60 min). 2.0 g of the title compound were obtained.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[N:13][C:12]([CH2:16][OH:17])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]>CC(C)=O.[O-2].[Mn+4].[O-2]>[CH2:1]([N:3]1[C:15]2[CH:14]=[N:13][C:12]([CH:16]=[O:17])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: CCn1c2ccccc2c2cc(CO)ncc21
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(C)=O
Product: CCn1c2ccccc2c2cc(C=O)ncc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of (9-ethyl-9H-β-carbolin-3-yl)-methanol (560 mg, 2.47 mmol, 1 eq) in acetone (20 mL) was added manganese (IV) oxide (2.942 g, 33.84 mmol, 14 eq). The solution was stirred at rt. After 3 d, as only 50% conversion is observed, more manganese (IV) oxide was added (229 mg, 2.63 mmol, 1.1 eq) and the mixture was heated to 50° C. for 2.5 d. After this time, the reaction was cooled down to rt, filtered through CELITE®, and the solid was washed with dichloromethane. The filtrates were combined and concentrated under reduced pressure. The residue was purified by column chromatography eluting with ethyl acetate to give the title compound as a yellow oil. Mass Spec m/z=225 [M+H+].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[C:21](=[O:22])[C:20]3[CH:23]=[CH:24][C:25]([NH2:27])=[CH:26][C:19]=3[S:18]2(=[O:29])=[O:28])[CH2:9][CH2:8]1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>>[N:3]1[CH:4]=[CH:5][CH:6]=[N:1][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[C:21](=[O:22])[C:20]3[CH:23]=[CH:24][C:25]([NH:27][C:30](=[O:32])[CH3:31])=[CH:26][C:19]=3[S:18]2(=[O:28])=[O:29])[CH2:9][CH2:8]1
Reactant: Nc1ccc2c(c1)S(=O)(=O)N(CCCCN1CCN(c3ncccn3)CC1)C2=O
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc2c(c1)S(=O)(=O)N(CCCCN1CCN(c3ncccn3)CC1)C2=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
200 ml of acetic anhydride are added to 0.06 mol of 2-(4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl)-6-amino1,2-benzoisothiazol-3(2H)one 1,1-dioxide, and the mixture is stirred at room temperature for 12 hours. It is then evaporated to dryness, isopropyl ether is added and the mixture is stirred for 1 hour. It is then filtered and the colourless crystals are dried in vacuo.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:16][C:17](=[O:26])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=2I)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:15])[CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+]>CCO.O1CCOCC1.[Pd]>[CH2:1]([O:3][C:4]([C:6]1([NH:16][C:17](=[O:26])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=2[CH:4]=[C:6]([CH3:14])[CH3:7])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:15])[CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2I)Cc2ccc(F)cc2C1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2C=C(C)C)Cc2ccc(F)cc2C1
Yield: 145.8 %

Procedure:
To a solution of 5-fluoro-2-(2-iodo-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (400 mg, 0.85 mmol) and 2,2-dimethyethylenelboronic acid (342 mg, 3.42 mmol) in EtOH (10 mL) and dioxane (5 mL) is added palladium anchored homogeneous catalyst, FibreCatPd(0) (4.84% Pd, 186 mg, 8.5% mmol) and 2M aqueous solution of K2SO4 (1.71 mL, 3.42 mmol). The resulting reaction mixture is covered with argon and run in a microwave reaction: 120° C., 7 h. After concentration in vacuo, the residue is purified by HPLC to give a pure product (148) as a colorless oil (245 mg, 73%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([N:19]([CH3:21])[CH3:20])=[CH:16][CH:17]=3)[C:11](=[O:12])[O:10]2)=[CH:5][CH:4]=1.[CH3:22][N:23]([CH3:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>[Cl-].[Zn+2].[Cl-]>[CH3:22][N:23]([CH3:30])[C:24]1[CH:29]=[CH:28][C:27]([CH:9]([C:18]2[CH:17]=[CH:16][C:15]([N:19]([CH3:21])[CH3:20])=[CH:14][C:13]=2[C:11]([OH:10])=[O:12])[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:26][CH:25]=1
Reactant: CN(C)c1ccccc1
Reactant: COc1ccc(C2OC(=O)c3cc(N(C)C)ccc32)cc1
Agent: [Cl-]
Agent: [Zn+2]
Product: COc1ccc(C(c2ccc(N(C)C)cc2)c2ccc(N(C)C)cc2C(=O)O)cc1

Procedure:
Following the procedure described in Example 26, part A, 9.9 g of 3-(4-methoxyphenyl)-6-dimethylaminophthalide, prepared as described in Example 12, part A above, and 89.0 ml of N,N-dimethylaniline were interacted in the presence of 9.5 g of anhydrous zinc chloride at room temperature to obtain 13.7 g of 2-(4-dimethylamino-4'-methoxybenzhydryl)-5-dimethylaminobenzoic acid as an off-white colored solid melting at 185°-190° C.
Reaction SMILES: [C:1]1([O:7][C:8](=[O:33])[N:9]([C@:11]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)([CH2:22][CH:23]=[CH2:24])[CH2:12][N:13]([CH3:21])[C:14](=[O:20])[CH2:15][C:16]([F:19])([F:18])[F:17])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH2:34].[OH-].[Na+].OO>O1CCCC1>[C:1]1([O:7][C:8](=[O:33])[N:9]([C@:11]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)([CH2:22][CH2:23][CH2:24][OH:34])[CH2:12][N:13]([CH3:21])[C:14](=[O:20])[CH2:15][C:16]([F:19])([F:18])[F:17])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CC[C@@](CN(C)C(=O)CC(F)(F)F)(c1ccc(Cl)c(Cl)c1)N(C)C(=O)Oc1ccccc1
Reactant: O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(C[C@](CCCO)(c1ccc(Cl)c(Cl)c1)N(C)C(=O)Oc1ccccc1)C(=O)CC(F)(F)F
Reaction time: 1 h
Yield: 70 %

Procedure:
Under argon, phenyl[1-(3,3,3-trifluoro-N-methylpropanamido)-2-(S)-(3,4-dichlorophenyl)-4-penten-2-yl]methylcarbamate (410 mg) was dissolved in anhydrous tetrahydrofuran (4 mL). Under cooling with ice, a 1.06M solution (0.80 mL) of borane tetrahydrofuran complex in tetrahydrofuran was added thereto, and the mixture was stirred for 1 hour. Water (0.3 mL), 3N aqueous sodium hydroxide (0.9 mL), and 30% aqueous hydrogen peroxide (0.9 mL) were added to the reaction mixture, and the resultant mixture was stirred for 1 hour at room temperature. The reaction mixture was extracted with ethyl acetate, sequentially washed with water and saturated brine, and dried over sodium sulfate anhydrate. The solvent was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (n-hexane:ethyl acetate=1:2), to thereby give the title compound (311 mg, 70.0%).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][N:12]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:13](=[O:20])[C@H:14]([CH2:16][C:17](O)=[O:18])[CH2:15][C:4]=2[CH:3]=1.[NH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]2([CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[NH:28][C:27]1=[O:41].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][N:12]([CH2:21][C:22]([F:24])([F:23])[F:25])[C:13](=[O:20])[C@H:14]([CH2:16][C:17](=[O:18])[N:38]3[CH2:37][CH2:36][C:29]4([C:30]5[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=5)[NH:26][C:27](=[O:41])[NH:28]4)[CH2:40][CH2:39]3)[CH2:15][C:4]=2[CH:3]=1
Reactant: O=C1Nc2ccccc2C2(CCNCC2)N1
Reactant: O=C(O)C[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(CC(F)(F)F)C1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1Nc2ccccc2C2(CCN(C(=O)C[C@@H]3Cc4cc(Cl)c5[nH]ncc5c4CN(CC(F)(F)F)C3=O)CC2)N1
Reaction time: 12 h
Yield: 79.8 %

Procedure:
To a solution of (S)-2-(4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetic acid (50 mg, 0.133 mmol) in dichloromethane (25 mL) was added 1′H-spiro[piperidine-4,4′-quinazolin]-2′(3′H)-one (31 mg, 0.14 mmol) followed by 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (47 mg, 0.15 mmol) and triethylamine (1.0 mL). After 12 h, the reaction mixture was washed with aqueous NaHCO3 followed by 1.0 M HCl and dried (Na2SO4). The solvent was removed and the crude product was purified by flash chromatography using 7% MeOH in dichloromethane to give (S)-4-chloro-7-(2-oxo-2-(2′-oxo-2′,3′-dihydro-1′H-spiro[piperidine-4,4′-quinazoline]-1-yl)ethyl)-9-(2,2,2-trifluoroethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one (61 mg, 79%) as awhite powder. MS (ESI) 575 (M+H); Rf=2.133.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH:9]([C:10]([O:12][CH3:13])=[O:11])[CH2:8][C:7](=[O:14])[CH2:6]1)=[O:4].[CH2:15](O)[CH2:16][OH:17].B(F)(F)F.CCOCC.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:15]1[CH2:16][O:17][CH:6]2[CH:5]([C:3]([O:2][CH3:1])=[O:4])[CH:9]([C:10]([O:12][CH3:13])=[O:11])[CH2:8][CH:7]2[O:14]1
Reactant: COC(=O)C1CC(=O)CC1C(=O)OC
Reactant: OCCO
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)C1CC2OCCOC2C1C(=O)OC
Reaction time: 1.5 h
Yield: 89.7 %

Procedure:
In 250 ml of dichloromethane were dissolved 124 g of 3,4-dimethoxycarbonylcyclopentanone and 155 g of ethylene glycol and to the solution was added dropwise 94 g of boron trifluoride ethyl etherate at 0° - 5°C. After completion of the addition, the reaction mixture was stirred for 2 hours at 10° - 16°C and next for 1.5 hours at 16° - 23°C. After completion of the reaction, the reaction mixture was added dropwise to 1.5l of a saturated aqueous sodium bicarbonate containing pieces of ice in order to decompose the excess of the boron trifluoride etherate. The mixture was extracted three times with 1 l of ether. The extract was washed with a saturated aqueous sodium chloride and a saturated aqueous sodium bicarbonate and dried over anhydrous sodium sulfate. The solvent was distilled off from the extract to give 135.7 g of the desired product as colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]#[C:15][CH3:16])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:18][NH:19][O:20][CH3:21].C1C=C2N=NN(O)C2=CC=1.O.C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]#[C:15][CH3:16])[C:10]([N:19]([O:20][CH3:21])[CH3:18])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CNOC
Reactant: CC#CCC(NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC#CCC(NC(=O)OC(C)(C)C)C(=O)N(C)OC
Reaction time: 3 h
Yield: 88.1 %

Procedure:
The product from Step I (10.58 g, 46.6 mmol), N,O-dimethylhydroxylamine hydrochloride (9.09 g, 93.2 mmol), HOBT hydrate (9.44 g, 69.9 mmol) and triethylamine (13.0 mL, 93.2 mmol) were stirred in dry DMF (150 mL) at 0° C. under nitrogen. EDC hydrochloride (11.5 g, 60.6 mmol) was added, and the reaction was stirred for 3 hours. The solution was partitioned between 2:1 ethyl acetate:hexane and water, washed with water, 10% aq. HCl, sat. NaHCO3 soln and brine, then dried with sodium sulfate. The solvent was removed in vacuo to give the title compound (11.10 g, 88 % yield) as an orange oil
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.I[C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cu]>[O:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: Oc1ccccn1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-n2ccccc2=O)cc1
Temperature: 175 °C
Reaction time: 4 h
Yield: 35.5 %

Procedure:
A mixture of 2-hydroxypryidine (2.40 g), ethyl 4-iodobenzoate (6.97 g), potassium carbonate (3.83 g) and copper (253 mg) in N,N-dimethylformamide (12 ml) was stirred for 4 hours at 175° C. under nitrogen atmosphere. Insoluble material was filtered off, and the filtrate was concentrated in vacuo. To the residue was added ethyl acetate and 1N hydrochloric acid, the organic layer was washed with water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated in vacuo to give ethyl 4-(2-oxo-1,2-dihydropyridin-1yl)benzoate (2.18 g) as brown powder.
Reaction SMILES: [CH3:1][N:2]1[C@H:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:5][CH2:4][C@@H:3]1[C:12]([O:14]CC)=O.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C(C)=CC=CC=1>[CH2:17]([NH:24][C:12]([C@H:3]1[N:2]([CH3:1])[C@@H:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:5][CH2:4]1)=[O:14])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)[C@H]1CC[C@@H](C(=O)OCC)N1C
Solvent: Cc1ccccc1C
Product: CCOC(=O)[C@H]1CC[C@@H](C(=O)NCc2ccccc2)N1C

Procedure:
A solution of diethyl cis-1-methylpyrrolidine-2,5-dicarboxylate (10.95 g, 0.0478 mole) and benzylamine (5.2 ml, 0.048 mole) in 30 ml xylene was refluxed 72 hours at 140° C. After evaporation of the xylene in vacuo, the oily residue was fractionated on a Vigreux column. After an initial fraction of the starting compound (0.49 g), the product was collected: 7.11 g (boiling point 160° C, 0.25 mm).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:19][C:20]([O:22]C)=[O:21])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Br:18])=[O:10].[OH-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:19][C:20]([OH:22])=[O:21])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Br:18])=[O:10]
Reactant: COC(=O)Cc1ccc(NC(=O)Nc2ccccc2Br)c(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(NC(=O)Nc2ccccc2Br)c(Br)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 94.2 %

Procedure:
To a stirred solution of methyl 3-bromo-4-[N′-(2-bromophenyl)ureido]phenylacetate (770 mg, 1.74 mmol) in THF (10 ml) was added 0.25 N NaOH (10 ml). After stirring at room temperature for 14 h, the solvent was concentrated in vacuo. The residue was triturated by the addition of 1 N HCl and dried at 60° C. for 2 days under a reduced pressure to give 3-bromo-4-[N′-(2-bromophenyl) ureido]phenylacetic acid (702 mg, 94%) as colorless powder. 1H-NMR (DMSO-d6) δ3.56 (s, 2H), 6.99 (dt, J=7.8, 1.5 Hz, 1H), 7.21 (dd, J=8.3, 1.7 Hz, 1H), 7.33 (dt, J=7.1, 1.5 Hz, 1H), 7.53 (d, J=1.7 Hz, 1H), 7.62 (dd, J=8.1, 1.5 Hz, 1H), 7.82 (d, J=8.3 Hz, 1H), 7.93 (dd, J=8.1, 1.5 Hz, 1H), 8.82 (s, 1H), 8.86 (s, 1H), 12.39 (s, 1H); MS (ESI) m/z 428 (M++1), 430 (M++3).
Reaction SMILES: [Br:1][C:2]1[C:3]2[C:4]3[C:15]([CH3:16])=[N:14][N:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:12](=[O:23])[C:5]=3[N:6]([CH3:11])[C:7]=2[CH:8]=[CH:9][CH:10]=1.[Br:24]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>>[Br:1][C:2]1[C:3]2[C:4]3[C:15]([CH2:16][Br:24])=[N:14][N:13]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:12](=[O:23])[C:5]=3[N:6]([CH3:11])[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nn(-c2ccccc2)c(=O)c2c1c1c(Br)cccc1n2C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: Cn1c2cccc(Br)c2c2c(CBr)nn(-c3ccccc3)c(=O)c21
Reaction time: 15 h
Yield: 48 %

Procedure:
A solution of 10.1 g (27.1 mmol) of 9-bromo-1,5-dimethyl-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indol-4-one, of 6 g (34 mmol) of N-bromosuccinimide and of 0.46 g (2.8 mmol) of 2,2′-azobis(2-methylpropionitrile) is heated at reflux for 5 h. 3 g (17 mmol) of N-bromosuccinimide and 0.23 g (1.4 mmol) of 2,2′-azobis(2-methylpropionitrile) are again added. The mixture is heated at reflux for 2 h, left at room temperature for 15 h and again heated at reflux for 5 h. The mixture is concentrated under reduced pressure and the residue is taken up in water and extracted with ethyl acetate. The organic phase is dried, the solvent is evaporated under reduced pressure and the residue is purified by chromatography on a column of silica gel. 5.9 g (13 mmol) of product are isolated.
Reaction SMILES: Cl[C:2]1(C(O)=O)[C:4]2([CH2:9][CH2:8][C:7]([C:25]#[N:26])([C:10]3[C:18]4[C:17]5[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=5[O:15][C:14]=4[C:13]([O:23][CH3:24])=[CH:12][CH:11]=3)[CH2:6][CH2:5]2)[O:3]1.[OH2:30]>CS(C)=O>[C:25]([C:7]1([C:10]2[C:18]3[C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[O:15][C:14]=3[C:13]([O:23][CH3:24])=[CH:12][CH:11]=2)[CH2:8][CH2:9][CH:4]([C:2]([OH:3])=[O:30])[CH2:5][CH2:6]1)#[N:26]
Reactant: O
Reactant: COc1ccc(C2(C#N)CCC3(CC2)OC3(Cl)C(=O)O)c2c1oc1ccccc12
Solvent: CS(C)=O
Product: COc1ccc(C2(C#N)CCC(C(=O)O)CC2)c2c1oc1ccccc12
Temperature: 100 °C

Procedure:
At room temperature, to a solution of the epoxy acid (0.380 g, 0.0009 mol) (as formed in step 2) in DMSO (8 ml)/Water (0.8 ml) sodium chloride (0.055 g, 0.000.9 mol) was charged and the reaction mass was heated to 100° C. for 7 hrs. Once the product has formed, the reaction mass was quenched with water and extracted with ethyl acetate. The organic layer was dried with sodium sulfate and concentrated under vacuum. 4-cyano-4-(4-methoxy-dibenzofuran-1-yl)-cyclohexane carboxylic acid was isolated by column chromatography. Yield 0.035 g, (10.8%)
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[C:5]=1[F:14])[CH:2]=C.[O:15]=[O+][O-].CSC>CO>[F:14][C:5]1[C:6]2[CH2:10][O:9][C:8](=[O:11])[C:7]=2[CH:12]=[CH:13][C:4]=1[CH2:1][CH:2]=[O:15]
Reactant: C=CCc1ccc2c(c1F)COC2=O
Reactant: O=[O+][O-]
Solvent: CO
Solvent: CSC
Product: O=CCc1ccc2c(c1F)COC2=O
Temperature: 25 °C

Procedure:
To a solution of 5-allyl-4-fluoro-2-benzofuran-1(3H)-one (30 mg, 0.16 mmol) in MeOH at −78° C. was bubbled ozone through until it turned light blue. After excess ozone was removed by bubbling nitrogen through the solution, dimethyl sulfide (0.1 mL, 1.1 mmol) was added into the reaction. The solution was allowed to warm to RT. The crude material was purified by MPLC to deliver (4-fluoro-1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde. LC-MS (IE, m/z): 195 [M+1]+.
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[C:10]([CH:12]=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1.O>CN(C)C=O>[C:1]1([C:7]2[N:8]([C:17]3[N:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:9]=[C:10]([CH:12]=[O:13])[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1c[nH]c(-c2ccccc2)n1
Reactant: Clc1ncccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cn(-c2ncccn2)c(-c2ccccc2)n1
Reaction time: 0.5 h
Yield: 15.7 %

Procedure:
To a solution of 2-phenyl-1H-imidazole-4-carbaldehyde (700 mg) in dimethylformamide (30 mL) was added sodium hydride (60% in oil, 180 mg) at room temperature and the mixture was stirred for 30 min. 2-Chloropyrimidine (489 mg) was further added and the mixture was stirred for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→2:3) to give the title compound as a yellow oil (yield 160 mg, yield 16%).