Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])SC)#[N:2].[CH2:18]([NH2:21])[C:19]#[CH:20]>C(#N)C>[C:1]([NH:3][C:4]([NH:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])=[N:21][CH2:18][C:19]#[CH:20])#[N:2]
Reactant: C#CCN
Reactant: CSC(=NCCSCc1[nH]cnc1C)NC#N
Solvent: CC#N
Product: C#CCN=C(NC#N)NCCSCc1[nH]cnc1C
Yield: 116.4 %

Procedure:
A mixture of N-cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-S-methyl isothiourea (3.00 g, 0.0111 mole) and propargyl amine (2.50 g, 0.045 mole) in acetonitrile (60 ml) was stirred at reflux for 65 hours, and then was heated in a stainless steel pressure vessel at 120°-130° for 38 hours. The reaction mixture was cooled, decanted from a tar, and then evaporated to leave a gum (3.57 g). This material was placed on silica gel (100-200 mesh) and eluted with a mixture of methylene chloride (97 parts) and methanol (3 parts). The product obtained from a middle fraction was crystallized by trituration under acetonitrile, and then was recrystallized from acetonitrile to yield the title compound (0.236 g; 7.7%); m.p. 146°-149.5°.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]([F:37])([F:36])[O:21][C:22]1[CH:23]=[C:24]([C:28]2[O:32][CH:31]=[N:30][C:29]=2[C:33](O)=[O:34])[CH:25]=[CH:26][CH:27]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:33]([C:29]3[N:30]=[CH:31][O:32][C:28]=3[C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([O:21][C:20]([F:36])([F:19])[F:37])[CH:23]=3)=[O:34])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: O=C(O)c1ncoc1-c1cccc(OC(F)(F)F)c1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3ncoc3-c3cccc(OC(F)(F)F)c3)cn2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-(3-trifluoromethoxy-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 01b: tR=1.00 min; [M+H]+=461.09.
Reaction SMILES: CCOCC.[CH:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([CH3:17])[CH3:16])[C:10]=1[N:18]=[CH:19][C:20]1[N:25]=[C:24]([C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=[CH:28][C:27]=2[CH2:36][NH:37][C:38]2[C:43]([CH3:44])=[CH:42][C:41]([CH3:45])=[CH:40][C:39]=2[CH3:46])[CH:23]=[CH:22][CH:21]=1)([CH3:8])[CH3:7].[CH:47]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1[Li])([CH3:49])[CH3:48]>O>[CH:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([CH3:17])[CH3:16])[C:10]=1[NH:18][CH:19]([C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][C:50]=1[CH:47]([CH3:49])[CH3:48])[C:20]1[N:25]=[C:24]([C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=[CH:28][C:27]=2[CH2:36][NH:37][C:38]2[C:39]([CH3:46])=[CH:40][C:41]([CH3:45])=[CH:42][C:43]=2[CH3:44])[CH:23]=[CH:22][CH:21]=1)([CH3:8])[CH3:7]
Reactant: [Li]c1ccccc1C(C)C
Reactant: Cc1cc(C)c(NCc2ccc3ccccc3c2-c2cccc(C=Nc3c(C(C)C)cccc3C(C)C)n2)c(C)c1
Solvent: CCOCC
Solvent: O
Product: Cc1cc(C)c(NCc2ccc3ccccc3c2-c2cccc(C(Nc3c(C(C)C)cccc3C(C)C)c3ccccc3C(C)C)n2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Et2O (40 mL) was added to compound 6b (1.48 g, 2.74 mmol) to form a yellow suspension. At −80° C. an Et2O (5 mL) solution of 2-isopropylphenyllithium (0.690 g, 5.47 mmol) was added dropwise over 5 minutes. Upon the start of the addition the mixture became dark purple. The mixture was allowed to slowly warm to ambient temperature while stirring overnight. Then water was added (30 mL) and the yellow organic layer was separated and dried with brine. Further drying over MgSO4 followed by filtration and evaporation afforded crude diamine 7p as a yellow oil that was found by 1H NMR spectroscopy to be contaminated with about 10% of the imine 6b. The product was purified on basic alumina eluted with 5:1 hexanes:dichloromethane, gradually increasing the amount of ethyl acetate to 8%. The product eluted just before the imine impurity. Yield: 1.5 g, 83%. The 1H NMR spectrum of 7p in CD2Cl2 solution is complex due to the presence of more than one diastereoisomer.
Reaction SMILES: Br[C:2]1[C:3](Br)=[C:4](Br)[C:5]([Br:13])=[C:6]2[C:11](=[O:12])[NH:10][C:8](=[O:9])[C:7]=12.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([SH:23])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][C:2]2[C:3]([S:23][C:20]3[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=3)=[C:4]([S:23][C:20]3[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=3)[C:5]([Br:13])=[C:6]3[C:11]([NH:10][C:8](=[O:9])[C:7]=23)=[O:12])=[CH:19][CH:18]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: O=C1NC(=O)c2c(Br)c(Br)c(Br)c(Br)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1NC(=O)c2c(Sc3ccc(Cl)cc3)c(Sc3ccc(Cl)cc3)c(Sc3ccc(Cl)cc3)c(Br)c21
Yield: 25.1 %

Procedure:
2 g (4.46 millimols) of tetrabromophthalimide, 1.61 g (11.15 millimols) of p-chlorothiophenol, 2.31 g (16.73 millimols) of potassium carbonate and 20 ml of tetrahydrofuran are stirred at 25° C. for 14 hours. After acidification with dilute HCl solution, the mixture is extracted with tetrahydrofuran/toluene and the extracts are dried and evaporated. After recrystallisation from toluene/cyclohexane, 0.61 g (25% of theory) of 3,4,5-tris-(p-chlorophenylthio)-6-bromophthalimide is obtained; melting point 164°-9° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[C:25](O)(=[O:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>ClCCl>[C:25]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:13][C:11]=3[N:12]=2)=[CH:6][CH:7]=1)(=[O:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCc1ccc2oc(-c3ccc(O)cc3)nc2c1
Reactant: CCCCCCC(=O)O
Solvent: ClCCl
Product: CCCCCCCCc1ccc2oc(-c3ccc(OC(=O)CCCCCC)cc3)nc2c1
Yield: 60.9 %

Procedure:
In a 30 ml round-bottom flask, 0.50 g (1.55 m mole) of 2-(4-hydroxyphenyl)-5-octylbenzooxazole, 0.22 g (1.69 m mole) of heptanoic acid and 10 ml of dichloromethane were placed, followed by adding 0.32 g (1.55 m mole) of N,N-dicyclohexylcarbodiimide and 0.04 g of 4-pyrrodinopyridine in order at room temperature under stirring, and stirring at room temperature for 85 minutes. The resultant N,N'-dicyclohexylurea was filtered off and the filtrate was dried under reduced pressure to precipitate a resultant. The resultant was purified by silica gel column chromatography (eluent: toluene) and recrystallized from acetone to obtain 0.41 g of 2-(4-heptanoyloxyphenyl)-5-octylbenzooxazole (Yield: 60.9%). ##STR81##
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[C:7]([NH2:9])[N:6]=[CH:5]1)([CH3:3])[CH3:2].[C:10](Cl)([O:12][CH2:13][C:14]([Cl:17])([Cl:16])[Cl:15])=[O:11].C([O-])(O)=O.[Na+]>CCOC(C)=O>[CH:1]([N:4]1[CH:8]=[C:7]([NH:9][C:10](=[O:11])[O:12][CH2:13][C:14]([Cl:17])([Cl:16])[Cl:15])[N:6]=[CH:5]1)([CH3:3])[CH3:2]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC(C)n1cnc(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)n1cnc(NC(=O)OCC(Cl)(Cl)Cl)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 30.7 %

Procedure:
To a stirring solution of 1-isopropyl-1H-imidazol-4-amine (0.532 g, 4.25 mmol) in EtOAc (70 ml) was added Troc-Cl (0.614 ml, 4.46 mmol) followed by satd. NaHCO3 (17.23 ml 12.75 mmol). The biphasic mixture was stirred briskly at RT. After 6 h, the layers were separated and the aqueous was extracted with EtOAc (1×). The combined organics were washed with satd. NaHCO3 (1×) and brine (1×), dried, evaporated and triturated (EtOAc/hexanes). The solids were collected by filtration, rinsed with hexanes and dried on the filter to afford 2,2,2-trichloroethyl 1-isopropyl-1H-imidazol-4-ylcarbamate (0.392 g, 31% yield) as a pink-orange solid. 1H NMR (400 MHz, DMSO-d6): δ 10.2 (s, 1H), 7.49 (s, 1H), 7.02 (s, 1H), 4.80 (s, 2H), 4.3-4.25 (m, 1H), 1.35 (d, 6H); MS (ESI) m/z: 300.0 (M+H+), 302.0 (M+2+H+).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[CH2:7])[C:5]2([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[O:4][C:3]1=[O:13].[F:14][C:15]([F:35])([F:34])[C:16]1[CH:29]=[CH:28][C:27]2[S:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH2:30][CH2:31][CH2:32]Cl)[C:18]=2[CH:17]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(C(C)=O)C(C)C>[CH3:1][N:2]1[C:6](=[CH2:7])[C:5]2([CH2:12][CH2:11][N:10]([CH2:32][CH2:31][CH2:30][N:19]3[C:18]4[CH:17]=[C:16]([C:15]([F:35])([F:14])[F:34])[CH:29]=[CH:28][C:27]=4[S:26][C:25]4[C:20]3=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:9][CH2:8]2)[O:4][C:3]1=[O:13]
Reactant: FC(F)(F)c1ccc2c(c1)N(CCCCl)c1ccccc1S2
Reactant: C=C1N(C)C(=O)OC12CCNCC2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: C=C1N(C)C(=O)OC12CCN(CCCN1c3ccccc3Sc3ccc(C(F)(F)F)cc31)CC2
Reaction time: 6 h
Yield: 75.3 %

Procedure:
A mixture containing 11.0 g of 3-methyl-4-methylene-2-oxo-1-oxa-3,8-diazaspiro[4,5]decane, 41.3 g of 3-(2-trifluoromethyl-10H-phenothiazin-10-yl)propyl chloride, 16.6 g of anhydrous potassium carbonate and 0.6 g of potassium iodide in 110 ml of methyl isobutyl ketone is refluxed under nitrogen while stirring for 6 hours. After evaporating the solvent under reduced pressure benzene and water are added to the evaporation residue, the organic phase is separated, washed with water to neutral, dried over anhydrous sodium sulfate, then the solution is evaporated under reduced pressure. The solid residue is boiled with hexane, after cooling down the precipitate is filtered off and recrystallized from ethanol to give the title compound in a yield of 75.3%; m.p.: 116°-117.5° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([CH2:13][C:14](=[O:16])[CH3:15])[CH2:12][CH2:11][CH2:10]1.[Br:19]Br.O>CO>[Br:19][CH2:15][C:14](=[O:16])[CH2:13][C:9]1([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:17])([F:18])[F:1])[CH2:10][CH2:11][CH2:12]1
Reactant: BrBr
Reactant: CC(=O)CC1(c2ccccc2C(F)(F)F)CCC1
Solvent: O
Solvent: CO
Product: O=C(CBr)CC1(c2ccccc2C(F)(F)F)CCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 58.8 %

Procedure:
To an ice-cooled solution of 1-[1-(2-trifluoromethyl-phenyl)-cyclobutyl]-propan-2-one (2.56 g, 10 mmol) in MeOH (15 ml) was added Br2 (0.5 ml, 10 mmol) slowly via a syringe. The reaction mixture was stirred for 15 min at 0° C., then 30 min at room temperature. To the reaction mixture was added H2O (15 ml) and the mixture stirred for 15 min at room temperature. The reaction was monitored by TLC, and TLC showed no starting material left 15 min after addition of H2O. The resulting solution was extracted twice with 25% n-hexane in EtOAc. The combined organic extracts were washed twice with saturated aqueous NaHCO3 solution, dried over sodium sulfate and concentrated by evaporation in a vacuum. The residue was purified by column chromatography on silica-gel with 2% ether-hexane to yield 1.97 g of product.
Reaction SMILES: [CH3:1][C@@:2]1([CH2:9][S:10](Cl)(=[O:12])=[O:11])[C:6](=[O:7])[NH:5][C:4](=[O:8])[NH:3]1.Cl.[F:15][C:16]([F:35])([CH:32]([F:34])[F:33])[CH2:17][O:18][C:19]1[CH:31]=[CH:30][C:22]([O:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:21][CH:20]=1>ClCCl.C(N(CC)CC)C>[CH3:1][C@:2]1([CH2:9][S:10]([N:27]2[CH2:28][CH2:29][CH:24]([O:23][C:22]3[CH:21]=[CH:20][C:19]([O:18][CH2:17][C:16]([F:15])([F:35])[CH:32]([F:34])[F:33])=[CH:31][CH:30]=3)[CH2:25][CH2:26]2)(=[O:12])=[O:11])[NH:3][C:4](=[O:8])[NH:5][C:6]1=[O:7]
Reactant: C[C@]1(CS(=O)(=O)Cl)NC(=O)NC1=O
Reactant: FC(F)C(F)(F)COc1ccc(OC2CCNCC2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@]1(CS(=O)(=O)N2CCC(Oc3ccc(OCC(F)(F)C(F)F)cc3)CC2)NC(=O)NC1=O
Reaction time: 16 h
Yield: 24.1 %

Procedure:
[(4S)-4-methyl-2,5-dioxoimidazolidin-4-yl]methanesulphonyl chloride (0.453 g) was added to a solution of 4-{4-(2,2,3,3-tetrafluoropropoxy)phenoxy]-piperidine hydrochloride (0.69 g) in dichloromethane (25 ml) and triethylamine (1.7 ml) at ambient temperature. Stirred for 16 hours and evaporated to dryness. The residue was purified by column chromatography (using λ230 nm as the detecting wavelength) eluting with a 0-10% methanol and dichloromethane. Yielded a solid product, which was dried under vacuum at 50° C. to yield the title compound (0.24 g). NMR Spectrum: (DMSOd6) δ 10.7 (s, 1H), 8.0 (s, 1H), 6.95 (m, 4H), 6.6 (tt, 1H), 4.5 (m, 2H), 4.4 (m, 1H), 3.5 (d, 1H), 3.3 (m, 3H), 3.1 (m, 2H), 1.9 (m, 2H), 1.7 (m, 2H), 1.35 (s, 3H). Mass Spectrum M−H− 495.89
Reaction SMILES: [CH2:1]([CH:8]1[O:13][CH2:12][CH2:11][NH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:14][C:15]([F:20])([F:19])[C@@H:16]1[CH2:18][O:17]1>>[CH2:1]([CH:8]1[O:13][CH2:12][CH2:11][N:10]([CH2:18][C@H:16]([OH:17])[C:15]([F:20])([F:19])[F:14])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CC2CNCCO2)cc1
Reactant: FC(F)(F)[C@@H]1CO1
Product: O[C@@H](CN1CCOC(Cc2ccccc2)C1)C(F)(F)F
Reaction time: 0.5 h

Procedure:
In a 25 mL round-bottom flask was placed 2-benzylmorpholine (354 mg, 2 mmol,), followed by (S)-2-(trifluoromethyl)oxirane (224 mg, 2.00 mmol). The mixture was stirred for 30 min. Another 100 uL of (S)-2-(trifluoromethyl)oxirane was added. Reaction mixture was continued at room temperature overnight, then concentrated in vacuo to afford (S)-3-(2-benzyl-morpholin-4-yl)-1,1,1-trifluoro-propan-2-ol a colorless oil (600 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]3[CH2:16][CH2:15]3)=[C:10]([CH:17]=[C:18]3[C:22]([CH3:24])([CH3:23])[O:21][C:20]([CH3:26])([CH3:25])[C:19]3=[O:27])[CH:9]=2)=[C:4]([F:28])[CH:3]=1.[OH-:29].[Li+]>CO.OO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]3[CH2:16][CH2:15]3)=[C:10]([CH:17]3[C:18]4([C:19](=[O:27])[C:20]([CH3:26])([CH3:25])[O:21][C:22]4([CH3:23])[CH3:24])[O:29]3)[CH:9]=2)=[C:4]([F:28])[CH:3]=1
Reactant: [OH-]
Reactant: CC1(C)OC(C)(C)C(=Cc2cc(-c3ccc(Cl)cc3F)ccc2C2CC2)C1=O
Agent: OO
Agent: [Li+]
Solvent: CO
Product: CC1(C)OC(C)(C)C2(OC2c2cc(-c3ccc(Cl)cc3F)ccc2C2CC2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 438.7 %

Procedure:
To a solution of 4-[1-(4′-chloro-4-cyclopropyl-2′-fluorobiphenyl-3-yl)methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one (19.80 g, 0.050 mol) in methanol (830 ml) at 35° C. is added 50% aqueous hydrogen peroxide (5.00 ml, 0.075 mmol), followed immediately by 2M lithium hydroxide (5.00 ml, 0.01 mol) solution. The mixture is stirred at this temperature for a further 2 hours, then allowed to cool to room temperature. Then reaction mixture is quenched with 10% sodium metabisulfite (negative KI-starch indicator test) then diluted with diethyl ether. Most of the methanol is removed under vacuum, and the crude mixture is partitioned between distilled water and diethyl ether. The aqueous phase is further extracted with diethyl ether (×2), then all organics are combined and washed with saturated sodium bicarbonate (×2) then brine. After anhydrousing over magnesium sulfate the suspension is filtered and the filtrate concentrated in vacuo to afford 2-(4′-chloro-4-cyclopropyl-2′-fluorobiphenyl-3-yl)-4,4,6,6-tetramethyl-1,5-dioxa-spiro[2.4]heptan-7-one (18.2 g) as an orange foam. This material is of sufficient purity to use directly in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:18])[CH:10]([NH:12][C:13](=[O:17])[O:14][CH2:15][CH3:16])[CH3:11])[CH:5]=[CH:6][C:7]=1[OH:8].[H-].[Na+].Cl[CH2:22][C:23]([NH:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=1)=[O:24]>CN(C)C=O>[CH3:37][O:36][C:30]1[CH:29]=[C:28]([CH2:27][CH2:26][NH:25][C:23](=[O:24])[CH2:22][O:8][C:7]2[CH:6]=[CH:5][C:4]([C:9](=[O:18])[CH:10]([NH:12][C:13]([O:14][CH2:15][CH3:16])=[O:17])[CH3:11])=[CH:3][C:2]=2[Cl:1])[CH:33]=[CH:32][C:31]=1[O:34][CH3:35]
Reactant: COc1ccc(CCNC(=O)CCl)cc1OC
Reactant: CCOC(=O)NC(C)C(=O)c1ccc(O)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)NC(C)C(=O)c1ccc(OCC(=O)NCCc2ccc(OC)c(OC)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.1 %

Procedure:
505 mg of ethyl N-[2-(3-chloro-4-hydroxyphenyl)-1-methyl-2-oxoethyl]carbamate [prepared as described in step (b) above] were added to a suspension of 81 mg of sodium hydride (as a 55% w/w suspension in mineral oil) in 6 ml of anhydrous dimethylformamide, whilst ice-cooling. The mixture was then stirred at room temperature for 1 hour. The suspension was then cooled, and 476 mg of α-chloro-N-[2-(3,4-dimethoxyphenyl)ethyl]acetamide (prepared as described in Preparation 1) were added thereto. The mixture was stirred at room temperature for 2 hours and then at 100° C. (bath temperature) for 3 hours. At the end of this time, the dimethylformamide used as the solvent was removed by evaporation under reduced pressure, and water was added to the residue. The aqueous mixture was extracted with ethyl acetate, and the extract was washed with a saturated aqueous solution of sodium chloride, dried and concentrated by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel. After elution of impurities with a 2:1 by volume mixture of ethyl acetate and hexane, 556 mg of the title compound were obtained from the fractions eluted with ethyl acetate as a pale yellow powder melting at 113°-114° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]2[N:14]3[CH2:18][C:19](C(OCC)=O)=[C:20]([O-:21])[C:13]3=[CH:12][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K+]>CC(O)=O.O>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]2[N:14]3[CH2:18][CH2:19][C:20](=[O:21])[C:13]3=[CH:12][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1=C([O-])c2cc3cc(OCc4ccccc4)ccc3n2C1
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCn2c1cc1cc(OCc3ccccc3)ccc12
Temperature: 25 °C
Yield: 81 %

Procedure:
To a 3-neck, 5L RB flask equipped w/a mechanical stirrer, temperature probe, and a reflux condenser was added potassium 7-(benzyloxy)-2-(ethoxycarbonyl)-3H-pyrrolo[1,2-a]indol-1-olate (206 g, 530 mmol) followed by AcOH:H2O (2:1, v/v, 2.65 L). The mixture was heated to reflux for 40 h and cooled to room temperature. Upon cooling a light brown precipitate formed. The mixtures from all four batches were combined and filtered. The solid was washed with H2O and hexanes. The filtrates were further diluted with water (1 L) and an additional solid precipitated. The 2nd crop was filtered and the solid washed with water and hexanes. Both crops were combined and dried in a vacuum oven (50° C., 2 Ton) to give 7-(benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-one (493 g from all 4 batches, 1.72 mol, 81% yield) as a brown solid. Exact mass calculated for C18H15NO2: 277.1, found: LCMS m/z=278.2, [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 3.20 (t, J=6.4 Hz, 2 H), 4.40 (t, J=6.4 Hz, 2 H), 5.11 (s, 2 H), 6.91 (s, 1 H), 7.13 (dd, J1=9.0, J2=2.3 Hz, 1 H), 7.20 (d, J=2.3 Hz, 1 H), 7.33 (m, 2 H), 7.39 (m, 2 H), 7.47 (m, 2 H).
Reaction SMILES: N[CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([Cl:19])[C:16]=3[F:18])[C:11]([S:20][C:21]3[C:22]([F:32])=[C:23]([CH:29]=[CH:30][CH:31]=3)[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:10]2[CH:33]2[CH2:35][CH2:34]2)[CH:6]=[N:5]1.C([O-])([O-])=O.[Cs+].[Cs+].BrCC[CH2:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47]>CN(C=O)C>[C:49]([O:48][C:46](=[O:47])[CH2:45][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([Cl:19])[C:16]=3[F:18])[C:11]([S:20][C:21]3[C:22]([F:32])=[C:23]([CH:29]=[CH:30][CH:31]=3)[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:10]2[CH:33]2[CH2:35][CH2:34]2)[CH:6]=[N:5]1)([CH3:52])([CH3:51])[CH3:50]
Reactant: CCOC(=O)c1cccc(Sc2c(C3CC3)n(-c3cnn(CCN)c3)c3c(F)c(Cl)ccc23)c1F
Reactant: CC(C)(C)OC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(Sc2c(C3CC3)n(-c3cnn(CCCC(=O)OC(C)(C)C)c3)c3c(F)c(Cl)ccc23)c1F
Temperature: 0 °C
Reaction time: 16 h
Yield: 69.6 %

Procedure:
To a stirred solution of indole 1 (Example 11, Step 3; 200 mg, 0.42 mmol) in DMF (5 mL) under inert atmosphere were added Cs2CO3 (206 mg, 0.63 mmol) and tert-butyl 4-bromobutanoate (141 mg, 0.63 mmol) at RT and stirred for 16 h. The mixture was diluted with ice cold water (20 mL) and extracted with EtOAc (3×30 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to obtain the crude. This was purified (silica gel chromatography; 20% EtOAc/hexanes) to afford compound 2 (180 mg, 70%) as a pale brown oil. 1H NMR (400 MHz, CDCl3): δ 7.67 (s, 1H), 7.64 (s, 1H), 7.63-7.60 (m, 1H), 7.18 (d, J=8.4 Hz, 1H), 7.10-7.06 (m, 1H), 6.93 (t, J=8.0 Hz, 1H), 6.77 (t, J=7.6 Hz, 1H), 4.41 (q, 2H), 4.28 (t, J=6.8 Hz, 2H), 2.28-2.19 (m, 4H), 1.74-1.66 (m, 1H), 1.46 (s, 9H), 1.41 (t, J=7.2 Hz, 3H), 1.06-1.02 (m, 2H), 0.89-0.84 (m, 2H); LC-MS (ESI): m/z 618.6 (M+H+).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[NH:6][CH:7]=1)=[O:2].[I:12]I>C(Cl)(Cl)Cl>[CH:1]([C:3]1[CH:4]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[NH:6][C:7]=1[I:12])=[O:2]
Reactant: COC(=O)c1cc(C=O)c[nH]1
Reactant: II
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(C=O)c(I)[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 3 (3.40 g, 22.2 mmol) in CHCl3 (20 mL) at 0° C. was added CF3COOAg (5.40 g, 24.4 mmol) followed by I2 (3.10 g, 24.4 mmol). The resulting mixture was stirred for 16 hours in the dark at room temperature. The reaction mixture was filtered through Celite and the filtrate was washed with saturated aqueous solution of Na2S2O3 (2×20 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. MPLC purification (CH2Cl2:diethyl ether/95:5) of the residue gave 4 as a white solid (0.72 g, 32% based on the recovered starting material). Along with 4, two minor compounds methyl-4-formyl-5-iodo-1H-pyrrole-2-carboxylate, methyl 4-formyl-3,5-diiodo-1H-pyrrole-2-carboxylate and the starting material 3 were also isolated. 1H NMR (DMSO-d6) δ 13.30 (bs, 1H), 9.52 (s, 1H), 7.04 (s, 1H), and 3.77 (s, 3H); 13C NMR (DMSO-d6) δ 187.13, 160.36, 128.78, 127.79, 115.58, 87.40, and 52.42.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([OH:37])([C:31]4[N:35]([CH3:36])[CH:34]=[N:33][CH:32]=4)[C:19]4[CH:30]=[CH:29][C:22]([C:23]([O:25]C(C)C)=[O:24])=[CH:21][CH:20]=4)[CH:16]=3)[N:11]([CH3:38])[C:10](=[O:39])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Li+].[OH-]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([OH:37])([C:31]4[N:35]([CH3:36])[CH:34]=[N:33][CH:32]=4)[C:19]4[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:29][CH:30]=4)[CH:16]=3)[N:11]([CH3:38])[C:10](=[O:39])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)OC(=O)c1ccc(C(O)(c2ccc3c(c2)c(-c2cccc(Cl)c2)cc(=O)n3C)c2cncn2C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1cncc1C(O)(c1ccc(C(=O)O)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Yield: 10.8 %

Procedure:
A mixture of (±)-1-methylethyl 4-[[4(3-chlorophenyl)-1,2-dihydro-1-methyl-2-oxo-6-quinolinyl]hydroxy(1-methyl-1H-imidazol-5-yl)methyl]benzoate (described in Example B12) (0.00369 mol) and LiOH. H2O (0.00369 mol) in THF (15 ml) and H2O (8 ml) was stirred at room temperature for 72 hours, poured out into H2O and washed with EtOAc. The aqueous layer was evaporated, taken up in 2-propanone/H2O and acidified with HCl/diethyl ether. The aqueous layer was evaporated. A part of the residue (0.3 g) was taken up in EtOH/diethyl ether. The precipitate was filtered off and dried, yielding 0.2 g (71%) of (±)-4-[[4-(3-chlorophenyl)-1,2-dihydro-1-methyl-2-oxo-6-quinolinyl]hydroxy(1-methyl-1H-imidazol-5-yl)methyl]benzoic acid, mp. >260° C.