Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([F:9])[CH:3]=1.C([Li])CCC.[CH2:15]([CH:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1)[CH2:16][CH2:17][CH2:18][CH3:19].Cl>O1CCCC1.CCCCCC.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:23]2[CH2:24][CH2:25][CH:20]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:21][CH:22]=2)=[C:4]([F:9])[CH:3]=1
Reactant: Fc1cc(Br)ccc1I
Reactant: CCCCCC1CCC(=O)CC1
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCC1CC=C(c2ccc(Br)cc2F)CC1
Reaction time: 0.5 h
Yield: 57.3 %

Procedure:
200 g (0.665 mol) of 1-bromo-3-fluoro-4-iodobenzene were dissolved in 800 ml of tetrahydrofuran, and 440 ml (0.698 mmol) of a 15 percent solution of n-butyllithium in hexane were added dropwise at −70° C. After 30 minutes, a solution of 117 g (0.698 mol) of 4-pentylcyclohexanone in 200 ml of tetrahydrofuran was added, and the batch was left to stirr for 60 minutes, hydrolysed using water and acidified using conc. hydrochloric acid. The organic phase was separated off, washed with water and dried over sodium sulfate, and the solvent was removed under reduced pressure. The crude product was subsequently dissolved in 1.4 l of toluene and, after addition of 6 g of toluenesulfonic acid, heated on a water separator until water of reaction was no longer separated off. The solution was washed with water and evaporated, and the residue was filtered through silica gel with n-heptane, giving 124 g (58%) of 4-bromo-2-fluoro-1-(4-pentylcyclohex-1-enyl)benzene as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[C:33]5[C:28](=[CH:29][C:30]([O:36]CC6C=CC=CC=6)=[C:31]([O:34][CH3:35])[CH:32]=5)[N:27]=[CH:26][CH:25]=4)=[C:19]([F:44])[CH:18]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.C1CC=CCC=1>CCO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[C:33]5[C:28](=[CH:29][C:30]([OH:36])=[C:31]([O:34][CH3:35])[CH:32]=5)[N:27]=[CH:26][CH:25]=4)=[C:19]([F:44])[CH:18]=3)=[O:15])[CH2:12][CH2:13]2)=[O:10])=[CH:4][CH:3]=1
Reactant: COc1cc2c(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ccnc2cc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCC=CC1
Product: COc1cc2c(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ccnc2cc1O
Temperature: 65 °C
Reaction time: 3 h

Procedure:
To a solution of the cyclopropane-1,1-dicarboxylic acid [4-(7-benzyloxy-6-methoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide (4-fluoro-phenyl)-amide (22.4 g, 37.6 mmol) in EtOH (340 mL) was added 1,4-cyclohexadiene (35 mL, 376 mmol) and 10% Pd/C (2.08 g). The reaction mixture was then heated at 65° C. with stirring for 3 h (Caution: H2 gas is released from the reaction). It was then allowed to cool to room temperature, and filtered through celite followed by a MeOH wash. The solution was then concentrated under reduced pressure. The yellow residue was taken into EtOAc (1 L). The EtOAc solution was washed with water (1×), brine (2×), dried over MgSO4 and concentrated in vacuo. Cyclopropane-1,1-dicarboxylic acid [3-fluoro-4-(7-hydroxy-6-methoxy-quinolin-4-yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide was obtained as a yellow solid (17.3 g, 91.1% yield), which were carried on to the next reaction without further purification. 1H NMR (400 MHz, DMSO, d6): 10.39 (s, 1H), 10.15 (s, 1H), 10.00 (s, 1H), 8.38 (d, 1H), 7.88 (dd, 1H), 7.63 (m, 2H), 7.50 (m, 2H), 7.40 (t, 1H), 7.27 (s, 1H), 7.14 (m, 2H), 6.33 (d, 1H), 3.95 (s, 3H), 1.47 (m, 4H). LC/MS Calcd for [M+H]+ 506.2, found 506.3. Anal. HPLC: 99.4% pure.
Reaction SMILES: [SH:1][C:2]1[S:3][CH2:4][CH2:5][N:6]=1.C(N(CC)CC)C.[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH2:19]Cl>C1(C)C=CC=CC=1>[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH2:19][S:1][C:2]1[S:3][CH2:4][CH2:5][N:6]=1
Reactant: ClCc1cccs1
Reactant: SC1=NCCS1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: c1csc(CSC2=NCCS2)c1
Temperature: 25 °C
Yield: 101.3 %

Procedure:
To a stirred solution of 1.3 grams (0.011 mole) of 2-mercaptothiazoline in 20 ml of toluene was added 1.1 grams (0.011 mole) of triethylamine, followed by 1.5 grams (0.011 mole) of 2-thienylmethyl chloride. Upon completion of addition the reaction mixture was heated under reflux for five hours. The reaction mixture was cooled to ambient temperature and filtered. The filtrate was concentrated under reduced pressure to give 2.4 grams of 2-(2-thienylmethylthio)-4,5-dihydrothiazole as an oil, Compound No. 22 of Table I.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:20][O:21][C:22](=[O:42])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]OS(C)(=O)=O>>[CH3:20][O:21][C:22](=[O:42])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][O:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)CCc1ccccc1OCCCCCOS(C)(=O)=O
Reactant: O=C1CCOc2c1ccc(O)c2Cc1ccccc1
Product: COC(=O)CCc1ccccc1OCCCCCOc1ccc2c(c1Cc1ccccc1)OCCC2=O
Yield: 91.5 %

Procedure:
Using the procedure of example 11 and starting with 1.2 g (4.72 mmol) of 2,3-dihydro-7-hydroxy-8-(phenylmethyl)-4H-1-benzopyran-4-one (from example 70) and 1.64 g (4.76 mmol) of 2-[[5-[(methylsulfonyl)oxy]pentyl]oxy]benzenepropanoic acid methyl ester (from example 72), 2-[5-[(3,4-dihydro-4-oxo-8-(phenylmethyl)-2H-1 -benzopyran-7-yl)oxy]pentyloxy]benzenepropanoic acid methyl ester was obtained in 91.5% yield (2.17 g) as a yellow oil. This diester (4.32 mmol) was saponified with 6.5 mL of 3N aqueous lithium hydroxide in 21 mL of tetrahydrofuran, at room temperature, for 48 hr. Work-up as in example 4 gave 2-[5-[(3,4-dihydro-4-oxo-8-(phenylmethyl)-2H-1-benzopyran-7-yl)oxy]pentyloxy]benzenepropanoic acid as an oil. This material was flash chromatographed on silica gel eluting with ethyl acetate-hexane mixtures giving 1.0 g (47.6%) of pure acid as a solid. Recrystallization from ethyl acetate-ether gave a colorless solid, mp 117°-118° C.
Reaction SMILES: [Cl-].[Li+].[CH2:3]([O:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][C@@H:17]([NH:23][C:24]([NH:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[S:25])[C:18](OCC)=[O:19])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[BH4-].[Na+]>C(O)C.O1CCCC1>[C:27]([NH:26][C:24](=[S:25])[NH:23][C@@H:17]([CH2:18][OH:19])[CH2:16][CH2:15][CH2:14][NH:13][C:11](=[O:12])[O:10][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CCOC(=O)[C@@H](CCCNC(=O)OCc1ccccc1)NC(=S)NC(C)(C)C
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)NC(=S)N[C@@H](CO)CCCNC(=O)OCc1ccccc1
Temperature: 20 °C
Reaction time: 20 h
Yield: 66.9 %

Procedure:
2.24 g of lithium chloride are added with stirring to a solution of 16 g of ethyl (2R)-5-{[(benzyloxy)carbonyl]amino}-2-(3-tert-butyl-thioureido)pentanoate in 200 cm3 of ethanol and 100 cm3 of tetrahydrofuran. After stirring for 15 minutes at a temperature in the region of 0° C., 2.24 g of sodium borohydride are added. After stirring for 20 hours at a temperature in the region of 20° C., a further 0.5 g of sodium borohydride is added. The reaction medium is filtered and the filtrates are concentrated under reduced pressure (1 kPa) at a temperature in the region of 40° C. The residue is chromatographed at atmospheric pressure on a column of silica gel (particle size 60-200μ; diameter 5.6 cm; height 40 cm), eluting with a mixture of dichloromethane/ethyl acetate (8/2 by volume) and a mixture of dichloromethane/ethyl acetate (6/4 by volume). The fractions containing the expected product are combined and then concentrated under the above conditions. 9.6 g of benzyl N-[(4R)-4-(3-tert-butylthioureido)-5-hydroxypentyl]carbamate are obtained in the form of a yellow oil [1H NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): from 1.30 to 1.60 (mt: 4H); 1.42 (s: 9H); 3.00 (mt: 2H); from 3.25 to 3.40 (mt: 1H); 3.45 (mt: 1H); 4.21 (unresolved complex: 1H); 4.76 (unresolved complex: 1H); 5.02 (s: 2H); 7.09 (d, J=8.5 Hz: 1H); 7.17 (broad s: 1H); 7.27 (t, J 5.5 Hz: 1H); from 7.30 to 7.45 (mt: 5H)].
Reaction SMILES: [OH:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.P(Cl)(Cl)(Cl)=O.O.CN([CH:21]=[O:22])C>>[OH:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH:21]=[O:22]
Reactant: Cn1nc(C(F)(F)F)cc1O
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cn1nc(C(F)(F)F)c(C=O)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.2 %

Procedure:
Into 16.6 g (100.0 mmol) of 5-hydroxy-1-methyl-3-trifluoromethyl-1H-pyrazole in 15.4 g of N,N-dimethylformaldehyde was added 16.2 g (105.0 mmol) of phosphorus oxychloride at 0° C., followed by 1 hour of stirring at room temperature. Furthermore, the whole was stirred at 100° C. for 1 hour. After the completion of the reaction was confirmed, the reaction solution was poured into water and the pH was made 10 or more with a 25% sodium hydroxide solution and then the aqueous layer was washed with ethyl acetate. The pH of the resulting aqueous layer was made about 4 with a saturated citric acid solution and then extracted with diethyl ether. The resulting organic layer was washed with water and saline, successively, and then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure and the residue was purified by silica gel column chromatography to obtain 4.5 g (yield: 23.2%) of 5-hydroxy-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C@H:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:3]1[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].Br[CH2:28][CH:29]1[CH2:31][CH2:30]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH:29]1([CH2:28][N:8]2[C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[O:5][C@H:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C@H:3]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])[C:2]2=[O:1])[CH2:31][CH2:30]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C(=O)Nc2ccccc2O[C@@H]1c1ccccc1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1C(=O)N(CC2CC2)c2ccccc2O[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.8 %

Procedure:
To a stirred solution of tert-butyl [(2R,3S)-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl]carbamate (67a) (190 mg, 0.536 mmol) in dry DMF (2 mL) under nitrogen was added (bromomethyl)cyclopropane (108 mg, 0.800 mmol) and powdered cesium carbonate (264 mg, 0.810 mmol). The mixture was stirred overnight at ambient temperature then diluted with ewater and extracted with ethyl acetate three times. The residue from the combined organic extracts was purified by flash chromatography on silica gel eluting with 6:1 (v/v) hexane:ethyl acetate to afford the title compound (201 mg, 92%) as a white solid. TLC Rf=0.31 (6:1 hexane:ethyl acetate). 1H NMR (300 MHz, CDCl3) δ0.19 (m, 1H), 0.35-0.62 (m, 3H), 1.15 (m, 1H), 1.37 (s, 9H), 3.50 and 3.55 (dd, 1H, J=7.0 Hz), 4.12 and 4.17 (dd, 1H, J=7.0 Hz), 4.93 (m, 2H), 5.65 (d, 1H, J=7.0 Hz), 7.29 (m, 4H), 7.41 (m, 5H). MS APCI, m/z=309 (M-BOC). LC/MS: 3.08 min.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:15][CH2:14][C:13](=[O:16])[NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.Br[CH2:20][CH2:21][CH:22]=[CH2:23].[H-].[Na+].O>CN(C=O)C>[CH2:23]([N:12]1[C:13](=[O:16])[CH2:14][CH2:15][N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:4]=2)[CH2:10][CH2:11]1)[CH2:22][CH:21]=[CH2:20]
Reactant: O=C1CCN(c2cccc(C(F)(F)F)c2)CCN1
Reactant: C=CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCCN1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Reaction time: 6 h
Yield: 28.8 %

Procedure:
To a solution of 1-(3-trifluoromethyl-phenyl)-[1,4]diazepan-5-one 0.29 g (1 mmol) and 4-bromobut-1-ene 0.3 g (2 mmol) in DMF (2 ml) was added NaH 0.1 g (2 mmol of 55% dispersion in oil) and the mixture stirred for 6 h. The reaction was then poured into water and extracted with EtOAc, dried (Na2SO4) and concentrated. Purification by flash column chromatography (EtOAc/n-heptane 1:1) afforded the title compound 0.09 g (25%) as a yellow gum. MS: 313.2 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:12][C:13]1[O:17][N:16]=[C:15]([C:18](Cl)=[O:19])[CH:14]=1>C(Cl)Cl>[CH3:12][C:13]1[O:17][N:16]=[C:15]([C:18]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=2)[C:7]([OH:9])=[O:8])=[O:19])[CH:14]=1
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Reactant: Cc1cc(C(=O)Cl)no1
Solvent: ClCCl
Product: Cc1cc(C(=O)Nc2ccc(Cl)c(C(=O)O)c2)no1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.8 %

Procedure:
To a solution of 5-amino-2-chlorobenzoic acid (342 mg, 2.0 mmol) and TEA (1.39 mL, 10 mmol), was added 5-methylisoxazole-3-carbonyl chloride (300 mg, 2.06 mmol) in DCM (5 mL). The reaction mixture was stirred at room temperature for 16 hr, and triturated with aqueous sodium bicarbonate. The organic layer was separated, dried (Na2SO4) and evaporated. The residue on filtered through a silica plug to give the title compound as a cream colored solid (330 mg, 57%).
Reaction SMILES: [NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20](O)=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([OH:48])=[O:47])[CH:43]([CH3:45])[CH3:44])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37].[C:49]([O:53][C:54]([CH2:56][CH2:57][CH2:58][CH2:59][NH-:60])=[O:55])([CH3:52])([CH3:51])[CH3:50].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>>[NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20]([NH:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([OH:48])=[O:47])[CH:43]([CH3:44])[CH3:45])=[O:40])[CH2:35][CH:36]([CH3:37])[CH3:38])=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:49]([O:53][C:54]([CH2:56][CH2:57][CH2:58][CH2:59][NH-:60])=[O:55])([CH3:52])([CH3:51])[CH3:50]
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O)OCc1ccccc1
Reactant: CC(C)C[C@H](N)C(=O)N[C@H](C(=O)O)C(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)(C)OC(=O)CCCC[NH-]
Agent: On1nnc2ccccc21
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)O)C(C)C

Procedure:
In a manner analogous to that described in Example 1, using as starting materials 144 mg of Z-Phe-His-OH, 138 mg of H-Leu-Val-4-tert.-butoxycarbonylbutyl amide, 51 mg of HOBt and 89 mg of DCCI, the title compound is obtained after flash chromatography (180 g of silica gel 60, 40-63 μm, system N10). Rf (B2)=0.40, Rf (N8)=0.41.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:7]=[CH:6][C:5]=1[O:14][C@@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17].[OH-].[Na+]>C(O)C>[CH3:13][S:10]([C:8]1[CH:7]=[CH:6][C:5]([O:14][C@@H:15]([CH3:20])[C:16]([F:17])([F:18])[F:19])=[C:4]([CH:9]=1)[C:3]([OH:21])=[O:2])(=[O:12])=[O:11]
Reactant: COC(=O)c1cc(S(C)(=O)=O)ccc1O[C@@H](C)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To 0.77 mmol 5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid methyl ester in 2.5 ml ethanol was added 1.53 mmol 2 N aq NaOH solution, and the reaction mixture was stirred at 80° C. for 30 minutes. After such time the solvent was removed in vacuo, the residue was taken in water and acidified by addition of 2 N HCl. After filtration, the title compound was obtained as a white solid (92% yield). MS (m/e): 311.0 ([M−H]−, 100%)
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.I[C:12]1[CH:13]=[C:14]([CH3:19])[CH:15]=[C:16]([CH3:18])[CH:17]=1>>[CH3:19][C:14]1[CH:13]=[C:12]([N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:10]=[C:2]2[CH3:1])[CH:17]=[C:16]([CH3:18])[CH:15]=1
Reactant: Cc1cc(C)cc(I)c1
Reactant: Cc1cc2ccccc2[nH]1
Product: Cc1cc(C)cc(-n2c(C)cc3ccccc32)c1
Yield: 94.8 %

Procedure:
Using general procedure A, 2-methylindole (165 mg, 1.26 mmol)) was coupled with 5-iodo-m-xylene (150 μL, 1.04 mmol). The crude product was purified by flash chromatography on silica gel (2×15 cm; hexane-ether 40:1; 15 mL fractions). Fractions 4-9 provided 232 mg (95% yield) of the product as a colorless oil. 1H NMR (300 MHz, CDCl3): δ 7.62-7.53 (m, 1H), 7.15-7.05 (m, 4H), 6.98 (s, 2H), 6.39 (s, 1H), 2.41 (s, 6H), 2.31 (d, J=1.0 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]=[C:14]4[CH2:17][CH2:18][C@@H:19]5[C@@H:24]([C@@:13]4([CH3:35])[CH2:12][C:11]=3[CH:10]=[N:9]2)[C@@H:23]([OH:25])[CH2:22][C@:21]2([CH3:34])[C@:26]([C:30](=[O:33])CO)([OH:29])[CH2:27][CH2:28][C@@H:20]52)=[CH:4][CH:3]=1.[OH-:36].[Na+].Cl>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]=[C:14]4[CH2:17][CH2:18][C@@H:19]5[C@@H:24]([C@@:13]4([CH3:35])[CH2:12][C:11]=3[CH:10]=[N:9]2)[C@@H:23]([OH:25])[CH2:22][C@:21]2([CH3:34])[C@@:26]([OH:29])([C:30]([OH:33])=[O:36])[CH2:27][CH2:28][C@@H:20]52)=[CH:4][CH:3]=1
Reactant: C[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)O
Temperature: 25 °C
Reaction time: 6 h
Yield: 85.7 %

Procedure:
In a 100 ml round-bottomed flask 1-[(1R,3aS,3bS,10aR,10bS,11S,12aS)-7-(4-fluorophenyl)-1,11-dihydroxy-10a,12a-dimethyl-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-tetradecahydrocyclopenta[5,6]naphtho[1,2-f]indazol-1-yl]-2-hydroxyethanone (Steroids 2003 (68) 177-191) (0.48 g, 1 mmol) was dissolved in MeOH (40 ml). NaOH (6 ml, 1M, 6 mmol) was added and the mixture was stirred vigorously for 6 hours at room temperature in an open vessel. The reaction was monitored by LC-MS. When the reaction was completed the solution was neutralised by the addition of 1M HCl (6 ml, 6 mmol) and the MeOH was removed in vacuo. Water was added to the precipitate (15 ml) and the mixture was stirred for 5 minutes. The solid was then collected by filtration and dried to give 0.4 g (86%) of the desired compound.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[N:10]3[CH:12]=[CH:13][CH:14]=[C:9]3[CH:8]=[N:7][C:6]=2[N:5](COCC[Si](C)(C)C)[C:4]=1[C:23]1[CH:28]=[CH:27][C:26]([C:29]2([CH3:34])OCC[O:30]2)=[CH:25][CH:24]=1)[CH3:2].Cl.C(O)(C(F)(F)F)=O.[NH4+].[OH-]>CC(C)=O.C(Cl)Cl>[CH2:1]([C:3]1[C:11]2[N:10]3[CH:12]=[CH:13][CH:14]=[C:9]3[CH:8]=[N:7][C:6]=2[NH:5][C:4]=1[C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:30])[CH3:34])=[CH:25][CH:24]=1)[CH3:2]
Reactant: CCc1c(-c2ccc(C3(C)OCCO3)cc2)n(COCC[Si](C)(C)C)c2ncc3cccn3c12
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC(C)=O
Product: CCc1c(-c2ccc(C(C)=O)cc2)[nH]c2ncc3cccn3c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.1 %

Procedure:
1-Ethyl-2-(4-(2-methyl-1,3-dioxolan-2-yl)phenyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-dipyrrolo[1,2-a:2′,3′-e]pyrazine (0.194 g, 0.406 mmol) was dissolved in acetone (6 mL) then treated with concentrated aqueous HCl (36 wt %, 0.170 mL, 2.08 mmol). The mixture was stirred at rt for 30 min. The solvents were evaporated under reduced pressure and then the material was treated with DCM (3 mL) and TFA (1.5 mL, 19 mmol). The mixture was stirred at rt for about 15 min then the solvents were evaporated under reduced pressure. The residue was dissolved in 1,4-dioxane (4 mL) then treated with concentrated aqueous NH4OH (26 wt %, 2 mL, 13.87 mmol). The mixture was stirred at rt for 30 min then warmed to about 50° C. for about 15 min. The mixture was cooled to rt and the solvents removed under reduced pressure. The material was treated with water (15 mL) then stirred for about 5 min at rt. The solids were collected by filtration then dried under vacuum at about 60° C. to a constant weight to give 1-(4-(1-ethyl-3H-dipyrrolo[1,2-a:2′,3′-e]pyrazin-2-yl)phenyl)ethanone (0.074 g, 60%): LC/MS (Table 2, Method b) Rt=2.37 min; MS m/z 304 (M+H)+.
Reaction SMILES: ClCC(Cl)=[O:4].[S:6]1[CH:10]=[C:9]2[C:11]([O:13][C:14](=[O:15])[C:8]2=[CH:7]1)=[O:12]>>[S:6]1[CH:10]=[C:9]([C:11]([OH:4])=[O:12])[C:8]([C:14]([OH:13])=[O:15])=[CH:7]1
Reactant: O=C(Cl)CCl
Reactant: O=C1OC(=O)c2cscc21
Product: O=C(O)c1cscc1C(=O)O

Procedure:
A 25.5 g. portion of 3,4-thiophenedicarboxylic acid {prepared by the method of Kornfeld and Jones [J. Org. Chem., 19, 1671 (1954)]} is suspended in 50 ml. of chloroacetyl chloride and is heated at reflux for 5.5 hours. Excess chloroacetyl chloride is distilled under reduced pressure. The residue is poured into 100 ml. of water and the resulting crystals are collected to yield 16.1 g. of 3,4-thiophenedicarboxylic anhydride.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[CH3:22])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:18])[CH:14]=2)[NH:9][CH:8]=1)=[O:6].C[Si](C)(C)[N-][Si](C)(C)C.[K+].[CH3:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37]Br>O1CCCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[CH3:22])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:18])[CH:14]=2)[N:9]([CH2:33][C:34]2[CH:41]=[CH:40][CH:39]=[C:36]([CH3:37])[CH:35]=2)[CH:8]=1)=[O:6]
Reactant: Cc1cccc(CBr)c1
Reactant: Cc1ccc(C(=O)c2c[nH]c3ccc(F)cc3c2=O)cc1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cccc(Cn2cc(C(=O)c3ccc(C)c(C)c3)c(=O)c3cc(F)ccc32)c1
Temperature: 60 °C
Yield: 77.3 %

Procedure:
Compound 4uu was prepared following the procedure outlined in Step 3 of Example 1. Briefly described here, 0.050 g (0.169 mmol) of 3-(3,4-dimethyl-benzoyl)-6-fluoro-1H-quinolin-4-one 3j, 0.4 mL of potassium hexamethyldisilazide (0.5 M in toluene, 0.203 mmol) and 37.6 mg (0.203 mmol) of 3-methylbenzyl bromide were combined in 1.5 mL of tetrahydrofuran and heated at 60° C. for 3 h. Purification of the crude product using flash chromatography (30-50% ethyl acetate in hexane) yielded 52.2 mg of 3-(3,4-dimethyl-benzoyl)-6-fluoro-1-(3-methyl-benzyl)-1H-quinolin-4-one as a white solid 4uu: LC-MSD, m/z for C26H22FNO2, [M+H]=400.5; Reverse phase HPLC gradient, 20-95% acetonitrile with 0.1% TFA in 4 minutes, retention time=2.9 min; 1H NMR (400 MHz, CDCl3): δ 8.26 (1H, s), 8.11 (1H, m), 7.64 (1H, s), 7.56 (1H, m), 7.38 (1H, m), 7.32-7.23 (2H, m), 7.18 (1H, m), 7.15 (1H, m), 6.97 (2H, m), 5.37 (2H, s), 2.33 (3H, s), 2.32 (3H, s), 2.31 (3H, s).