Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2([C:12]3[N:16]([CH:17]4[CH2:33][N:21]5[C:22]6[C:27]([C:28]([CH2:29][C:30]([OH:32])=[O:31])=[C:20]5[CH2:19][CH2:18]4)=[CH:26][CH:25]=[CH:24][CH:23]=6)[N:15]=[N:14][CH:13]=3)CCCC2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:34]C1C=CC(CC#C)=CC=1.FC1C=CC(CCl)=CC=1.C([Si](C)(C)C)#C.[N-]=[N+]=[N-]>>[F:34][C:4]1[CH:5]=[CH:6][C:1]([CH2:7][C:12]2[N:16]([C@H:17]3[CH2:33][N:21]4[C:22]5[C:27]([C:28]([CH2:29][C:30]([OH:32])=[O:31])=[C:20]4[CH2:19][CH2:18]3)=[CH:26][CH:25]=[CH:24][CH:23]=5)[N:15]=[N:14][CH:13]=2)=[CH:2][CH:3]=1
Reactant: C#CCc1ccc(F)cc1
Reactant: O=C(O)Cc1c2n(c3ccccc13)CC(n1nncc1C1(c3ccccc3)CCCC1)CC2
Agent: C#C[Si](C)(C)C
Agent: Fc1ccc(CCl)cc1
Agent: [N-]=[N+]=[N-]
Product: O=C(O)Cc1c2n(c3ccccc13)C[C@H](n1nncc1Cc1ccc(F)cc1)CC2

Procedure:
The title compound was prepared using enantiomerically pure propyl (7-azido-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)acetate from EXAMPLE 6 and 1-fluoro-4-prop-2-yn-1-ylbenzene prepared from 4-fluorobenzyl chloride and ethynyltrimethylsilane described in EXAMPLE 8. EXAMPLE 28.1 and 28.2 were prepared from the chiral azide with the retention time of 10.3 and 11.5 min respectively from EXAMPLE 6. MS (+ESI) m/z: 405.1.
Reaction SMILES: [OH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH2:19][CH2:20][Cl:21]>CN(C)C=O.C(OCC)(=O)C>[Cl:21][CH2:20][CH2:19][CH2:18][N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[S:3][C:2]1=[O:1]
Reactant: Oc1nc2ccccc2s1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1sc2ccccc2n1CCCCl
Temperature: 55 °C
Reaction time: 18 h
Yield: 95.2 %

Procedure:
To a solution of 2-hydroxybenzothiazole (2.0 g, 13.2 mmol) and potassium carbonate (2.74 g, 19.8 mmol) in N,N-dimethylformamide (20 mL), was added 1-bromo-3-chloropropane (3.92 mL, 39.7 mmol, d=1.6). After stirring at 55° C. for 18 hours, the reaction mixture was diluted with ethyl acetate (100 mL), washed with dilute citric acid, water and brine. The organic phase was dried over MgSO4 and concentrated to obtain 3-(3-chloropropyl)benzo[d]thiazol-2(3H)-one (2.86 g, 95%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:15])=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]#[CH:13])[C:6]=2[CH:14]=1.[C:16]1(=O)[O:21][C:19](=[O:20])[C:18]2[CH2:22][CH2:23][CH2:24][CH2:25][C:17]1=2.O>C(O)(=O)C>[F:15][C:3]1[C:2]([N:1]2[C:19](=[O:20])[C:18]3[CH2:22][CH2:23][CH2:24][CH2:25][C:17]=3[C:16]2=[O:21])=[CH:14][C:6]2[N:7]([CH2:11][C:12]#[CH:13])[C:8](=[O:10])[S:9][C:5]=2[CH:4]=1
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: C#CCn1c(=O)sc2cc(F)c(N)cc21
Solvent: O
Solvent: CC(=O)O
Product: C#CCn1c(=O)sc2cc(F)c(N3C(=O)C4=C(CCCC4)C3=O)cc21
Yield: 18.9 %

Procedure:
5-Amino-6-fluoro-3-(2-propynyl)-2(3H)-benzothiazolone (0.43 g) and 3,4,5,6-tetrahydrophthalic anhydride (0.32 g) were suspended in acetic acid (5 ml), and the resultant suspension was heated under reflux for 5 hours. After being allowed to cool, water was added thereto, and the resultant mixture was extracted with ethyl acetate. The extract was washed with water and an aqueous sodium bicarbonate solution, dried and concentrated. The residue was purified by silica gel thin layer chromatography with a mixture of ethyl acetate and hexane (1:4) to give 2-[6-fluoro-3-(2-propynyl)-2(3H)-benzothiazolon-5-yl]-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (0.13 g). m.p., 193°-195° C. Recrystallization from 2-propanol gave the purified product. m.p., 198°-199° C.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:19])([F:18])[C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Br)=[CH:12][CH:11]=1.[NH2:20][C:21]1[C:26]2[O:27][CH2:28][CH2:29][O:30][C:25]=2[C:24]([C:31]2[O:35][C:34](=[O:36])[N:33]([CH:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)[N:32]=2)=[CH:23][C:22]=1[Cl:43]>C(#N)C>[NH2:20][C:21]1[C:26]2[O:27][CH2:28][CH2:29][O:30][C:25]=2[C:24]([C:31]2[O:35][C:34](=[O:36])[N:33]([CH:37]3[CH2:38][CH2:39][N:40]([CH2:14][C:13]4[CH:16]=[CH:17][C:10]([C:9]([F:19])([F:18])[F:8])=[CH:11][CH:12]=4)[CH2:41][CH2:42]3)[N:32]=2)=[CH:23][C:22]=1[Cl:43]
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: Nc1c(Cl)cc(-c2nn(C3CCNCC3)c(=O)o2)c2c1OCCO2
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Nc1c(Cl)cc(-c2nn(C3CCN(Cc4ccc(C(F)(F)F)cc4)CC3)c(=O)o2)c2c1OCCO2
Reaction time: 2 h

Procedure:
1.58 ml (11.38 mmol) of triethylamine and 0.88 g (5.68 mmol) of 4-(trifluoromethyl)benzyl bromide, in solution in 5 ml of acetonitrile, are successively added at room temperature, with magnetic stirring and under an argon atmosphere, to a solution of 1 g (2.84 mmol) of 5-(8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-3-(piperidin-4-yl)-1,3,4-oxadiazol-2(3H)-one in 60 ml of acetonitrile and the mixture is stirred for 2 h. The solvent is evaporated under reduced pressure, the residue is taken up in chloroform, the solution is washed a number of times with water and dried and the solvent is evaporated under reduced pressure. The residue is crystallized from acetone and 1.14 g of white solid are obtained. Melting point: 198° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C:5](=[O:7])[NH:4][C:3]1=[N:8][C:9](=[O:11])O.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=1.O>CN(C=O)C>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:9]([N:8]=[C:3]2[NH:4][C:5](=[O:7])[CH2:6][N:2]2[CH3:1])=[O:11])=[N:14][CH:15]=1
Reactant: Cc1ccc(N)nc1
Reactant: CN1CC(=O)NC1=NC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)N=C2NC(=O)CN2C)nc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 76.9 %

Procedure:
A mixture of 2.33 g (10.0 mM) of the phenyl carbamate 8 and 1.08 g (10.0 mM) of 2-amino-5-methylpyridine in 9 ml of anhydrous DMF was stirred at 70° C. for 2 hrs., cooled and poured into water with stirriang. The resulting precipitate was collected, washed with water and then acetone to give 1.9 g of the above urea as a pale yellow solid, m.p. 227° C. (dec.).
Reaction SMILES: [CH2:1](I)[CH3:2].[O:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9](=[CH2:13])[C:10]([OH:12])=[O:11].C(N(C(C)C)CC)(C)C>C(#N)C>[O:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9](=[CH2:13])[C:10]([O:12][CH2:1][CH3:2])=[O:11]
Reactant: CCI
Reactant: C=C(C(=O)O)c1ccco1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C=C(C(=O)OCC)c1ccco1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
Ethyl iodide (64 mL, 0.796 mol) was added to furylacrylic acid (100 g, 0.724 mol), diisopropylethyl amine (140 mL, 0.796 mmol), in acetonitrile (1100 mL), and the mixture was heated to 60° C. After 18 h, the dark solution was cooled to room temperature and concentrated in vacuo. The resulting brown sludge was diluted with Et2O (500 mL), washed with 1 N aqueous HCl (2×250 mL), washed with 0.2 N aqueous NaOH (2×250 mL), washed with saturated aqueous NaH.CO3 (1×250 ML), dried (MgSO4), filtered, and concentrated to a black oil (114 g, 95%). 1H NMR (DMSO-d6, 300 MHz) δ 7.84 (d, J=1.7 Hz, 1H), 7.46 (d, J=15.6 Hz, 1H), 6.97 (d, J=3.4 Hz, 1H), 6.33 (dd, J=3.4 Hz, J=1.7 Hz, 1H), 6.22 (d, J=15.9 Hz, 1H), 4.17 (q, J=7.1 Hz, 2H), 1.24 (t, J=7.1 Hz, 3H); MS (APCI) m/z 167 (M+H)+.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]([C:11]([F:14])([F:13])[F:12])=[CH:5][C:6]([O:8]CC)=O.[Cl:15][C:16]1[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][C:17]=1[CH2:24][N:25]=[C:26]=[O:27].O>CN(C)C=O>[Cl:15][C:16]1[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][C:17]=1[CH2:24][N:25]1[C:6](=[O:8])[CH:5]=[C:4]([C:11]([F:12])([F:13])[F:14])[NH:3][C:26]1=[O:27]
Reactant: O=C=NCc1cc(Cl)cc(Cl)c1Cl
Reactant: CCOC(=O)C=C(N)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1cc(C(F)(F)F)[nH]c(=O)n1Cc1cc(Cl)cc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 53.4 %

Procedure:
Under a nitrogen atmosphere, a stirred suspension of 0.62 gram (0.01 5 mole) of 60% sodium hydride (in mineral oil) in 30 mL of N,N-dimethylformamide was cooled to below 7° C., and a solution of 2.8 grams (0.015 mole) of ethyl 3-amino-4,4,4-trifluoro-2-butenoate in 15 mL of N,N-dimethylformamide was added dropwise at a rate to maintain the reaction mixture below 7° C. Upon completion of addition, the reaction mixture was stirred for about 45 minutes, during which time the reaction mixture temperature was about 2°-4° C. After this time a solution of 3.2 grams of 2,3,5-trichlorophenylmethyl isocyanate in 10 mL of N,N-dimethylformamide was added dropwise at a rate to maintain the reaction mixture temperature at about 2°-4° C. Upon completion of addition, the reaction mixture was stirred for about 10 minutes at 2°-4° C. and then warmed to 70°-85° C., where it was stirred for 3 hours. After this time the reaction mixture was allowed to cool to ambient temperature, where it stirred for about 16 hours. The reaction mixture was then poured into water, and the mixture was extracted with ethyl acetate. The extract was then washed with one portion of water. The water layer and the wash were combined and acidified with concentrated hydrochloric acid. The resultant solid was collected by filtration, yielding, when dried, 0.5 gram of solid. To collect additional product, the ethyl acetate extract was again washed, this time with five 150 mL portions of water. The combined washes were acidified with concentrated hydrochloric acid. The resultant solid was collected by filtration. The solid was dissolved in ethyl acetate and washed with water. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding a solid residue. The solid was combined with the 0.5 gram of material collected above, yielding 2.7 grams of 3-(2,3,5-trichlorophenylmethyl)-6-trifluoromethyluracil, mp 199°-202° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O.[Br-].[CH2:24]([O:26][C:27]1[CH:52]=[CH:51][CH:50]=[C:49]([O:53][CH2:54][CH3:55])[C:28]=1[CH2:29][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:25].CC(C)([O-])C.[K+]>C1COCC1>[CH2:54]([O:53][C:49]1[CH:50]=[CH:51][CH:52]=[C:27]([O:26][CH2:24][CH3:25])[C:28]=1/[CH:29]=[CH:18]/[C:17]1[CH:16]=[C:15]([CH2:14][CH2:13][CH2:12][N:3]2[C:4](=[O:11])[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]2=[O:1])[CH:22]=[CH:21][CH:20]=1)[CH3:55]
Reactant: O=Cc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Reactant: CCOc1cccc(OCC)c1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOc1cccc(OCC)c1/C=C/c1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice-cold mixture of phthalimide 29 (0.440 g, 1.5 mmol) in THF (25 mL) was added (2,6-diethoxybenzyl)triphenylphosphonium bromide (0.860 g, 1.65 mmol) and potassium tert-butoxide (0.336 g, 3.0 mmol) portionwise. The reaction was allowed to warm to room temperature and stirred for 2 h. The mixture was then quenched with water and extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (7% EtOAc-hexanes) gave (E)-2-(3-(3-(2,6-diethoxystyryl)phenyl)propyl)isoindoline-1,3-dione as a brown oil. Yield (0.055 g, 8%): 1H NMR (400 MHz, CDCl3) δ 7.80-7.83 (m, 2H), 7.67-7.70 (m, 2H), 7.62 (d, J=16.8 Hz, 1H), 7.45 (d, J=16.8 Hz, 1H), 7.29-7.31 (m, 1H), 7.22 (t, J=7.6 Hz, 1H), 7.17 (d, J=6.4 Hz, 1H), 7.11 (t, J=8.4 Hz, 1H), 7.06 (d, J=7.2 Hz, 1H), 6.60 (d, J=8.4 Hz, 2H), 4.11 (dt, J=7.2, 6.8 Hz, 4H), 3.78 (t, J=7.2 Hz, 2H), 2.71 (t, J=7.6 Hz, 2H), 2.03-2.11 (m, 2H), 1.50 (t, J=7.2 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[CH:6][C:5]([Br:12])=[CH:4][N:3]=1.[NH2:13][NH2:14]>C1COCC1>[NH2:1][C:2]1[C:7]([S:8]([NH:13][NH2:14])(=[O:10])=[O:9])=[CH:6][C:5]([Br:12])=[CH:4][N:3]=1
Reactant: NN
Reactant: Nc1ncc(Br)cc1S(=O)(=O)Cl
Solvent: C1CCOC1
Product: NNS(=O)(=O)c1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-Amino-5-bromopyridine-3-sulfonyl chloride (94 mg, 0.35 mmol) was taken into THF (2 mL) followed by addition of anhydrous hydrazine (40 uL, 1.4 mmol) and the mixture was stirred for 10 minutes at room temperature. The mixture was concentrated and dried to give 2-amino-5-bromopyridine-3-sulfonohydrazide as a white solid, which was then taken into ethanol (2 mL) followed by addition of sodium acetate (320 mg, 3.9 mmol) and ethyl iodide (140 uL, 1.75 mmol). The mixture was refluxed for 12 h then cooled to room temperature and concentrated. The residue was partitioned with ethyl acetate and water and the organic phase washed with brine then dried over sodium sulfate, filtered and concentrated to give 5-bromo-3-(ethylsulfonyl)pyridin-2-amine (67 mg, 72%) as a yellow oil. MS (EI) for C7H9N2SO2Br: 265, 267 (MH+).
Reaction SMILES: C(OC(=O)C)(=O)C.[N:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:15].[CH:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=1)=O.[OH-].[Na+]>O>[CH3:14][C:13]1[N:8]=[C:9](/[CH:15]=[CH:16]/[C:18]2[CH:19]=[CH:20][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:23]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: Cc1cccc(C)n1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COC(=O)c1ccc(/C=C/c2cccc(C)n2)cc1
Yield: 65.1 %

Procedure:
An acetic anhydride solution (100 mL) of 2,6-lutidine (65 g) and methyl 4-formylbenzenecarboxylate (20 g) was stirred overnight at 180° C. The reaction solution was poured into water with ice, and aqueous 5 N sodium hydroxide solution was added thereto until it became alkaline. The resulting mixture was extracted with ethyl acetate, and the organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated off, and the resulting residue was purified through silica gel column chromatography (hexane/ethyl acetate=9/1 to 4/1) to obtain the entitled compound (20.1 g).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]1[CH2:13][CH2:12][C@@:11]([NH:33]C(=O)OC(C)(C)C)([CH2:14][C:15]#[C:16][C:17]2[N:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[CH:20]=[CH:19][N:18]=2)[C:10]1=[O:41]>ClCCl>[NH2:33][C@@:11]1([CH2:14][C:15]#[C:16][C:17]2[N:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[CH:20]=[CH:19][N:18]=2)[CH2:12][CH2:13][N:9]([CH3:8])[C:10]1=[O:41]
Reactant: CN1CC[C@](CC#Cc2nccc(-c3ccc(C(F)(F)F)cc3)n2)(NC(=O)OC(C)(C)C)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CC[C@@](N)(CC#Cc2nccc(-c3ccc(C(F)(F)F)cc3)n2)C1=O
Reaction time: 1 h
Yield: 77.6 %

Procedure:
Trifluoroacetic acid (2 mL, 26.9 mmol) was added to a solution of tert-butyl N-[(3S)-1-methyl-2-oxo-3-[3-[4-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]prop-2-ynyl]pyrrolidin-3-yl]carbamate (which may be prepared as described in Description 7) (555 mg, 1.17 mmol) in dichloromethane (10 mL) at 20° C. and the reaction was stirred for 1 hr. The reaction was quenched by the addition of sat. NaHCO3 and the phases were separated. The organic layer was dried (Na2SO4) and the solvent evaporated to afford the (3S)-3-amino-1-methyl-3-[3-[4-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]prop-2-ynyl]pyrrolidin-2-one (D8) (340 mg, 0.9082 mmol, 77.6% yield) as a yellow oil.
Reaction SMILES: [C:1]1([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Cl-].[Cl-].[Al+3].[CH3:18][O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.Cl>ClCCl>[CH3:18][O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([C:11]2[CH:10]=[CH:9][C:8]([O:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:13][CH:12]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc(Oc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 77.5 %

Procedure:
Diphenyl oxide (52.2 g), 100 ml of dichloromethane, and 42.8 g of aluminum trichloride are added to a flask equipped with a mechanical stirrer, an addition funnel and a reflux condenser with a drying tube. 4-Methoxybenzoyl chloride (anisoyl chloride, 50 g) is added over 30 minutes. The mixture is stirred at ambient temperature for 2 days and then poured into 200 ml of 4M HCl. The organic layer is washed with 1M NaCl, dried with MgSO4, and evaporated. After bulb-to-bulb distillation at 215° C. using 0.3 mm Hg pressure, product is recrystallized from dry ethanol to give 69.1 g (78 percent yield) of the title compound, with a melting point of 118° C.-119° C.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]3[C:7](=[CH:18][NH:19][CH:20]=3)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.CC(C)([O-])C.[K+].Cl[C:30]([O:32][CH3:33])=[O:31]>CN(C)C=O.O>[CH3:33][O:32][C:30]([N:19]1[CH:20]=[C:6]2[C:7]([CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]3[CH:3]=[C:2]([Cl:1])[CH:22]=[CH:21][C:5]=32)=[CH:18]1)=[O:31]
Reactant: COC(=O)Cl
Reactant: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCc1c[nH]cc1-2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)n1cc2c(c1)-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Reaction time: 0.25 h

Procedure:
In one portion 6.0 g (18.3 mmol) of 8-chloro-6-(2-chlorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine was added to a solution of 3.0 g (26.5 mmol) of potassium t-butoxide in 50 ml of dimethylformamide which was cooled to 0°. When solution was complete 1.8 ml (2.3 g; 24.5 mmol) of methyl chloroformate was added and the resulting mixture was stirred for 15 min. The mixture was diluted with 150 ml of water and the resulting precipitate was collected by filtration. The precipitate was dissolved in methylene chloride and washed with water. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure. The residue crystallized from ether to give an off-white solid. Recrystallization from a mixture of methylene chloride and ether gave off-white fine needles, mp 185°-186° (dec.).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:24]=[CH:23][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=3)[C:18]#[N:19])[O:12][C:13]=2[CH3:14])=[C:5]([O:25][CH3:26])[CH:4]=1.[OH:27][C:28]1[C:32]([CH:33]=[O:34])=[CH:31][N:30]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:29]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:33]([C:32]1[C:28]([O:27][CH2:2][C:3]2[CH:24]=[CH:23][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([C:15]4[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=4)[C:18]#[N:19])[O:12][C:13]=3[CH3:14])=[C:5]([O:25][CH3:26])[CH:4]=2)=[N:29][N:30]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:31]=1)=[O:34]
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2cccc(C#N)c2)oc1C
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2cccc(C#N)c2)oc1C
Temperature: 80 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
A mixture of 3-[4-{(4-chloromethyl-2-methoxyphenoxy)methyl}-5-methyl-1,3-oxazol-2-yl]benzonitrile (4.32 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (2.0 g), anhydrous potassium carbonate (1.47 g) and N,N-dimethylformamide (100 mL) was stirred at 80° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 3-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl)-2-methoxyphenoxy}methyl]-5-methyl-1,3-oxazol-2-yl}benzonitrile (5.30 g, yield 96%) as colorless crystals. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 161-162° C.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:27])=[C:8](C(O)=O)[NH:9][C:10]=1[CH:11]=[C:12]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[NH:14][C:13]1=[O:23])([OH:3])=[O:2].[OH-].[K+].O.Cl>C(O)CO>[CH3:22][O:21][C:17]1[CH:16]=[C:15]2[C:20]([C:12](=[CH:11][C:10]3[NH:9][CH:8]=[C:7]([CH3:27])[C:6]=3[CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:13](=[O:23])[NH:14]2)=[CH:19][CH:18]=1
Reactant: COc1ccc2c(c1)NC(=O)C2=Cc1[nH]c(C(=O)O)c(C)c1CCC(=O)O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: COc1ccc2c(c1)NC(=O)C2=Cc1[nH]cc(C)c1CCC(=O)O
Temperature: 200 °C
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
4-(2-carboxyethyl)-3-methyl-5-(6-methoxy-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic acid (501 mg) suspended in ethylene glycol (10 mL) was heated in a sealed tube in a pre-heated oil bath at 200° C. for 2 hours. The reaction mixture was cooled to 90° C. and potassium hydroxide (2 pellets) was added. The mixture was then stirred at 90° C. for 30 minutes, after which time it was cooled, poured into water, and acidified with 2 N hydrochloric acid to pH 2. The precipitate was filtered, washed with water, and dried in a vacuum oven overnight to give 221 mg (48%) of 3-[2-(6-methoxy-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-4-methyl-1H-pyrrol-3-yl]-propionic acid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:22]=C)=[C:4]([CH:9]=[C:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].CC(C)=[O:26].C(#N)C.I([O-])(=O)(=O)=O.[Na+]>[Os]=O.O>[Cl:1][C:2]1[C:3]([CH:22]=[O:26])=[C:4]([CH:9]=[C:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6]
Reactant: C=Cc1c(C(=O)OC)cc(Cc2ccc(OC)cc2)c(C)c1Cl
Reactant: CC(C)=O
Agent: O=[Os]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1cc(Cc2ccc(OC)cc2)c(C)c(Cl)c1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3-chloro-5-(4-methoxybenzyl)-4-methyl-2-vinylbenzoate (0.31 g) in a mixed solvent of acetone (3.60 mL)-acetonitrile (3.60 mL)-water (3.60 mL) were added osmium oxide (fixed catalyst I) (0.12 g) and sodium periodate (1.00 g), and the mixture was stirred overnight at room temperature. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.31 g) as a crude product. This compound was used in the next step without an additional purification.
Reaction SMILES: [CH:1]([C:3]1[CH:16]=[CH:15][C:6]([CH:7]=[C:8]2[S:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])=[CH:5][CH:4]=1)=O.[C:17]1([NH2:24])[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH2:23]>>[O:13]=[C:11]1[NH:10][C:9](=[O:14])[C:8](=[CH:7][C:6]2[CH:15]=[CH:16][C:3]([C:1]3[NH:23][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[N:24]=3)=[CH:4][CH:5]=2)[S:12]1
Reactant: Nc1ccccc1N
Reactant: O=Cc1ccc(C=C2SC(=O)NC2=O)cc1
Product: O=C1NC(=O)C(=Cc2ccc(-c3nc4ccccc4[nH]3)cc2)S1

Procedure:
2-[4-[(2,4-Dioxothiazolidin-5-ylidene)methyl]phenyl]benzimidazole was prepared from 5-(4-formylbenzylidene)-2,4-thiazolidinedione and 1,2-phenylenediamine by following General Procedure 2.