Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]1[CH2:20][CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:18][C:17](=[O:27])[CH2:16][CH2:15]1.N1C=CC=CC=1.[Br:34]Br>C(Cl)Cl>[Br:34][CH:16]1[CH2:15][CH:14]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH3:7])[CH2:20][CH:19]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:18][C:17]1=[O:27]
Reactant: BrBr
Reactant: Cc1ccccc1C1CCC(=O)NC(c2ccccc2)C1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccccc1C1CC(Br)C(=O)NC(c2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 46.5 %

Procedure:
To a 250 mL round-bottomed flask equipped with addition funnel and nitrogen inlet were added 3.5 grams (16.8 mol) phosphorus pentachloride and 25 mL dry methylene chloride. The mixture was cooled with stirring to 0° C., and a solution of 4.7 grams (16.8 mmol) 5-(2-methlphenyl)-7-phenyl-2,3,4,5,6,7-hexahydroazepin-2-one and 2.7 mL (33.6 mmol) pyridine in 50 mL methylene chloride was added drop wise over 20 minutes. The reaction was stirred 5 minutes at 0° C., then 1.9 mL (37.0 mmol) bromine in 5 mL methylene chloride was added drop wise over 5 minutes. The reaction was stirred 5 minutes at 0° C., then 1.8 hours at room temperature. The reaction was evaporated, taken up in 40 mL of 1:1 tetrahydrofuran: water, and stirred for 1.2 hours. The reaction was then poured into water and extracted into ethyl acetate. The organic layer was washed with aqueous sodium bisulfite solution and brine, dried over sodium sulfate, and evaporated to an oil. At this point, a little of the desired monobrominated product can be recovered by chromatography, as described below; the remainder, mostly dibromo adduct, is treated an follows. The oil was taken up in 20 mL methylene chloride and 20 mL ethanol, and hydrogenated under 42 p.s.i. hydrogen in the presence of 0.70 grams 10% palladium-on-carbon and 7 drops of quinoline for 1 hour. Tlc showed mostly desired monobromo product at Rf=0.5, with a little dibromo precursor at Rf=0.7 and starting lactam at Rf=0.15, in 1/1-ethyl acetate/hexane. The reaction was filtered through Celite with ethanol and methylene chloride, evaporated, and chromatographed on silica gel using 2/1-hexane/ethyl acetate as eluent to afford 2.8 grams (46%) of a foam, a mixture of diastereomers.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:7]2Cl.C(N(CC)CC)C.[H][H]>[Pd].O1CCOCC1>[NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7]2
Reactant: [H][H]
Reactant: CCOC(=O)c1cnc2c(N)cccc2c1Cl
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc2c(N)cccc2c1
Yield: 63.1 %

Procedure:
A mixture of 8-amino-4-chloro-3-ethoxycarbonylquinoline (45 mg), triethylamine (0.026 ml) and 10%o palladium on carbon (15 mg) in dioxane was stirred for 7 hours at ambient temperature under 3 atmospheric pressure of hydrogen. Insoluble material was filtered off and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (ethyl acetate-dichloromethane) to give 8-amino-3-ethoxycarbonylquinoline (24.5 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[C:18]([O:20][CH:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH:19]=2)[NH:16][C:15]([C:27](=[S:29])[NH2:28])=[CH:14]3)=[CH:6][CH:5]=1.[C:30]([O:35][CH2:36][CH3:37])(=[O:34])[C:31]#[C:32][CH3:33].C(P(CCCC)CCCC)CCC.C(OCC)(=O)C>O1CCCC1.C1(C)C=CC=CC=1.CCCCCC>[CH2:36]([O:35][C:30](=[O:34])[CH2:31][CH:32]1[S:29][C:27]([C:15]2[NH:16][C:17]3[C:13]([CH:14]=2)=[CH:12][C:11]([O:10][C:7]2[CH:8]=[N:9][C:4]([CH2:3][O:2][CH3:1])=[CH:5][CH:6]=2)=[CH:19][C:18]=3[O:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[N:28][CH2:33]1)[CH3:37]
Reactant: COCc1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C(N)=S)cc3c2)cn1
Reactant: CC#CC(=O)OCC
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(COC)nc4)cc(OC4CCOCC4)c3[nH]2)S1
Temperature: 90 °C
Reaction time: 1 h
Yield: 65.6 %

Procedure:
To a solution of 5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indole-2-carbothioamide (1.5 g) in tetrahydrofuran (10 mL) and toluene (15 mL) were added ethyl 2-butynoate (1.02 g) and tri-n-butylphosphine (0.73 g), and the mixture was stirred at 90° C. for 1 hr. The reaction mixture was cooled, and concentrated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate:hexane=0:100 to 100:0, volume ratio) to give the title compound (1.25 g, yield 66%) as a yellow amorphous solid.
Reaction SMILES: [C:1]1([CH:7]2[C:16]3[C:11]4=[C:12]([CH:18]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[CH2:19][CH2:20][N:10]4[CH2:9][CH2:8]2)[CH:13]=[C:14]([NH2:17])[CH:15]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:27]([N:30]=[C:31]=[S:32])[CH2:28][CH3:29]>ClCCl>[C:21]1([CH:18]2[C:12]3[C:11]4=[C:16]([CH:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH2:8][CH2:9][N:10]4[CH2:20][CH2:19]2)[CH:15]=[C:14]([NH:17][C:31]([NH:30][CH2:27][CH2:28][CH3:29])=[S:32])[CH:13]=3)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCCN=C=S
Reactant: Nc1cc2c3c(c1)C(c1ccccc1)CCN3CCC2c1ccccc1
Solvent: ClCCl
Product: CCCNC(=S)Nc1cc2c3c(c1)C(c1ccccc1)CCN3CCC2c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.3 %

Procedure:
To a solution 1,7-diphenyl-1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinolin-9-amine (Intermediate 4), (100 mg, 0.294 mmol) in dichloromethane (15 mL) was added propyl isothiocyanate (0.038 mL, 0.323 mmol) under argon at 0° C. The reaction mixture was then stirred at room temperature for overnight. The solvent was removed under reduced pressure and purified by MPLC (medium pressure liquid chromatography) using silica gel column with 15 to 20% EtOAc:Hexane to get 1-(1,7-diphenyl-1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinolin-9-yl)-3-propylthiourea (255) (64 mg 49%). 1H NMR (300 MHz, CDCl3) ppm 7.08-7.34 (m, 10H) 6.39 (s, 2H) 4.11 (t, J=6 Hz, 2H) 3.32-3.46 (m, 2H) 3.16-3.23 (m, 4H) 2.25-2.30 (m, 2H) 2.13-2.17 (m, 2H) 1.32-1.39 (m, 2H, 0.73 (t, J=6 Hz, 3H)
Reaction SMILES: N(/C(OC(C)C)=O)=N\C(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:34][C:35]1[C:44]([CH:45](O)[CH3:46])=[C:43]([F:48])[CH:42]=[C:41]2[C:36]=1[CH:37]=[CH:38][CH:39]=[N:40]2.[C:49]1(=[O:59])[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[C:51](=[O:58])[NH:50]1>C1COCC1>[F:34][C:35]1[C:44]([CH:45]([N:50]2[C:51](=[O:58])[C:52]3[C:57](=[CH:56][CH:55]=[CH:54][CH:53]=3)[C:49]2=[O:59])[CH3:46])=[C:43]([F:48])[CH:42]=[C:41]2[C:36]=1[CH:37]=[CH:38][CH:39]=[N:40]2
Reactant: CC(O)c1c(F)cc2ncccc2c1F
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(c1c(F)cc2ncccc2c1F)N1C(=O)c2ccccc2C1=O
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 48.6 %

Procedure:
A mixture of (E)-diisopropyl diazene-1,2-dicarboxylate (3.8 g, 18.9 mmol) and triphenylphosphine (5.4 g, 20.5 mmol) in THF (50 mL) was stirred for 30 min, and a solution of 1-(5,7-difluoroquinolin-6-yl)ethanol (3.3 g, 15.8 mmol) and isoindoline-1,3-dione (2.7 g, 17.4 mmol) in THF (50 mL) was added dropwise. The reaction mixture was heated at 50° C. overnight. After cooling and evaporating, the residue was purified by silica gel and eluted with hexane/EtOAc to give the title compound as a white solid (2.6 g, 49%). LCMS (method A): [MH]+=339, tR=5.81 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH:13]([C:20]2[CH:33]=[CH:32][C:23]([CH:24]=[C:25]([CH3:31])[C:26]([O:28]CC)=[O:27])=[CH:22][CH:21]=2)[C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH:13]([C:20]2[CH:21]=[CH:22][C:23]([CH:24]=[C:25]([CH3:31])[C:26]([OH:28])=[O:27])=[CH:32][CH:33]=2)[C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)=Cc1ccc(C(CNS(=O)(=O)c2ccc(Cl)cc2)c2cccnc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=Cc1ccc(C(CNS(=O)(=O)c2ccc(Cl)cc2)c2cccnc2)cc1)C(=O)O
Yield: 99.9 %

Procedure:
Ethyl 4-[2-(4-chlorobenzenesulfonamido)-1-(3-pyridyl)ethyl]-α-methylcinnamate (6.8 mg) was dissolved in 1 ml of methanol, followed by addition of 0.2 ml of aqueous 2N sodium hydroxide solution, and refluxed for 18 hours. The solvent was distilled off under reduced pressure. The crystalline deposited through neutralization of the resulting mixture with 2N hydrogen chloride was filtered, to obtain 6.4 mg of 4-[2-(4-chlorobenzenesulfonamido)-1-(3-pyridyl)ethyl]-α-methylcinnamic acid. The spectrometric data thereof supports the structural formula of [49] as follows.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C@H:16]([N:18]1[C:22]2[CH:23]=[C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]([C@H:35]4[CH2:39][CH2:38][CH2:37][N:36]4C(OC(C)(C)C)=O)=[O:34])[C@H:29]([CH3:47])[CH2:28]3)[CH:25]=[CH:26][C:21]=2[N:20]=[N:19]1)[CH3:17]>ClCCl>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C@H:16]([N:18]1[C:22]2[CH:23]=[C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]([C@H:35]4[CH2:39][CH2:38][CH2:37][NH:36]4)=[O:34])[C@H:29]([CH3:47])[CH2:28]3)[CH:25]=[CH:26][C:21]=2[N:20]=[N:19]1)[CH3:17]
Reactant: C[C@@H]1CN(c2ccc3nnn([C@H](C)c4ccc(Cl)cc4Cl)c3c2)CCN1C(=O)[C@H]1CCCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1CN(c2ccc3nnn([C@H](C)c4ccc(Cl)cc4Cl)c3c2)CCN1C(=O)[C@H]1CCCN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.5 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added to a solution of (R)-tert-butyl 2-((R)-4-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-2-methylpiperazine-1-carbonyl)pyrrolidine-1-carboxylate (0.075 g, 0.13 mol) in dichloromethane (1.5 mL) and the mixture was stirred at room temperature for 1 h. Excess solvent was removed in vacuo, and the residue was diluted with dichloromethane (15 mL). The organic layer was neutralized with saturated aqueous sodium bicarbonate, and the aqueous layer was further extracted with dichloromethane (2×15 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 0-30% methanol in dichloromethane) to give the title compound as a white solid (0.022, 0.037 mol, 30%). 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J=8.8 Hz, 1 H), 7.41 (dd, J=0.8, 0.8 Hz, 1 H), 7.15-7.14 (m, 2 H), 7.02 (dd, J=2.4, 9.2 Hz, 1 H), 6.53 (s, 1 H), 6.23 (q, J=7.2 Hz, 1 H), 4.90-4.84 (m, 1 H), 4.58-4.54 (m, 1 H), 4.32-4.28 (m, 1 H), 3.97-3.74 (m, 3 H), 3.56-3.44 (m, 3 H), 3.20-3.16 (m, 1 H), 2.97-2.94 (m, 1 H), 2.85-2.80 (m, 1 H), 2.14 (d, J=6.8 Hz, 3 H), 1.82-1.71 (m, 3 H), 1.47-1.25 (m, 2 H); MS: (ES) m/z calculated for C24H29Cl2N6O [M+H]+487.2 found 487.3.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=O)[CH3:13])=[CH:8][CH:7]=1)(=[O:4])=[O:3].Cl.[NH2:16][OH:17]>N1C=CC=CC=1.O>[CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[N:16][OH:17])[CH3:13])=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: NO
Reactant: CC(=O)c1ccc(NS(C)(=O)=O)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=NO)c1ccc(NS(C)(=O)=O)cc1
Temperature: 70 °C

Procedure:
A mixture of 4′-(Methylsulfonylamino)acetophenone (13-5, 5 mmol) and hydroxylamine hydrochloride (0.695 g, 10 mmol) in pyridine (5 mL) was heated at 70° C. for 3 h. The reaction mixture was cooled to room temperature, diluted with H2O, and extracted with EtOAc several times. The combined organic layers were washed with H2O and brine, dried over MgSO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAc:hexanes (1:1) as eluant to 4′-Methylsulfonylamino)acetophenone oxime (13-8, LJO-299).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:16]=[CH:15][C:7]2[CH2:8][CH:9]([CH3:14])[C:10](=[O:13])[NH:11][CH2:12][C:6]=2[CH:5]=1.[CH2:17]([O:19][CH2:20][C:21](Cl)=[O:22])[CH3:18]>CN(C)C=O>[Cl:3][C:4]1[CH:16]=[CH:15][C:7]2[CH2:8][CH:9]([CH3:14])[C:10](=[O:13])[N:11]([C:21](=[O:22])[CH2:20][O:19][CH2:17][CH3:18])[CH2:12][C:6]=2[CH:5]=1
Reactant: CC1Cc2ccc(Cl)cc2CNC1=O
Reactant: CCOCC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCC(=O)N1Cc2cc(Cl)ccc2CC(C)C1=O
Temperature: 80 °C
Yield: 52 %

Procedure:
0.018 moles of sodium hydride is added slowly, with stirring, to a solution of 3.4 g. (0.016 moles) of 8-chloro-4-methyl-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one in 60 ml. of dimethylformamide. The reaction mixture is heated to 80° C. for 15 minutes and then cooled in an ice bath. While cooling, 2.2 g. (0.018 moles) of ethoxyacetyl chloride are added dropwise and then the reaction mixture is gradually brought to a temperature of 80° C. and maintained at this temperature for 3 hours. The reaction mixture is then cooled, evaporated to dryness in vacuo and the residue extracted with chloroform. The organic solution is washed twice with water, dried over anhydrous sodium sulfate, filtered and then evaporated to dryness in vacuo. The residual solid is purified by chromatography on a silica column, using a mixture of benzene/ethanol (9:1 v/v) as eluent, and it is then recrystallized from 2-propanol. 2.5 g. (52% of theory) of 8-chloro-2-(ethoxyacetyl)-4-methyl-1,2,4,5-tetrahydro- 3H-2-benzazepin-3-one are obtained. M.P. 123°-124° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[C:11]([Si:13]([CH3:16])([CH3:15])[CH3:14])#[CH:12].O>CCN(CC)CC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([O:9][CH3:10])=[C:2]([C:12]#[C:11][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:7]=1
Reactant: COc1ccc(Cl)cc1Br
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(Cl)cc1C#C[Si](C)(C)C
Temperature: 80 °C
Reaction time: 6 h
Yield: 93.1 %

Procedure:
A mixture of 2-bromo-4-chloro-1-methoxybenzene (1 g, 4.5 mmol), CuI (43 mg, 0.23 mmol), Pd(PPh3)2Cl2 (0.16 g, 0.23 mmol) in NEt3 (10 mL) was degassed, Then ethynyltrimethylsilane (0.5 g, 5 mmol) was added to the solution, the mixture was stirred at 80° C. for 6 hours. Then the mixture was cooled to 25° C., and added to H2O (50 mL). The mixture was extracted with ethyl acetate and washed with brine, dried over Na2SO4. After the combined organic layers were concentrated, the resulting residue was purified using prep-TLC (petroleum ether:EtOAc=10:1) to provide the product of ((5-chloro-2-methoxyphenyl)ethynyl)trimethylsilane (1 g, yield: 90%). 1H-NMR (CDCl3, 400 MHz) δ 7.40 (s, 1H), 7.21˜7.23 (m, 1H), 6.76˜6.78 (d, J=9.2 Hz, 1H), 3.86 (s, 3H), 0.26 (s, 9H). MS (M+H)+: 239/241
Reaction SMILES: CC([C:4]1[CH:9]=[CH:8][CH:7]=[C:6](C(C)C)[C:5]=1[CH2:13][C:14]([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=[O:15])C.C(C1C=CC=C(C(C)C)C=1C[C:46](O)=[O:47])(C)C.COC1C=CC=CC=1CC(O)=O>>[CH3:46][O:47][C:6]1[CH:7]=[CH:8][CH:9]=[CH:4][C:5]=1[CH2:13][C:14]([C:16]1[C:17]([CH:30]([CH3:31])[CH3:32])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:23])[CH3:24])=[CH:20][CH:21]=1)=[O:15]
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)O
Agent: COc1ccccc1CC(=O)O
Product: COc1ccccc1CC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C

Procedure:
This compound was prepared in the same manner as for the title compound of Example 1, except that 2,6-diisopropylphenylacetic acid was replaced with 2-methoxyphenylacetic acid, mp 159°-161° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].C(=O)([O-])[O-].[K+].[K+].Br[CH:18]([CH3:24])[C:19]([O:21]CC)=[O:20]>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH:18]([CH3:24])[C:19]([OH:21])=[O:20])=[C:6]([CH:7]=[O:8])[CH:9]=1
Reactant: O=Cc1cc(Br)ccc1O
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(Oc1ccc(Br)cc1C=O)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
A solution of 5-bromo-2-hydroxybenzaldehyde (4.97 mmol) in acetonitrile (30 mL) was treated with potassium carbonate (14.92 mmol) and ethyl 2-bromopropanoate (5.97 mmol). The resulting mixture was stirred at room temperature overnight. Analysis by LCMS indicated the formation of the desired intermediate ester, and the reaction mixture was concentrated to dryness in vacuo. The crude material was dissolved in a 3:1 methanol:water mixture (20 mL) and was heated to 50° C. with stirring. The reaction was then cooled to room temperature and was acidified to pH˜3 using 1N aq HCl. The methanol was removed in vacuo and the resulting aqueous suspension was diluted with water (100 mL). The solution was extracted with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting beige solid was used without further purification (1.38 grams, 80% yield). MS(ES)+ m/e 273/275 [M+H]+ (bromide isotope pattern).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[OH:12].FC1C=CC(N)=CC=1.C(OC=C(C(OCC)=O)C(OCC)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:55][CH2:56][CH2:57][CH2:58]O.N(C(OC(C)C)=O)=NC(OC(C)C)=O.Br>O1CCCC1>[BrH:55].[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[O:12][CH2:58][CH2:57][CH2:56][Br:55]
Reactant: Oc1ccnc2ccc(F)cc12
Reactant: OCCCBr
Agent: Br
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: C1CCOC1
Product: Fc1ccc2nccc(OCCCBr)c2c1
Reaction time: 1 h
Yield: 32 %

Procedure:
To a suspension solution of 6-fluoroquinolin-4-ol (3.67 g, 22.5 mmol) (synthesized in overall yield of 32% starting from 4-fluoroaniline and diethyl ethoxymethylenemalonate according to a literature procedure (see Price et al., Organic Syntheses, Coll. Vol. 3, p. 272; Vol. 28, p. 38), triphenylphosphine (6.56 g, 25 mmol), and 3-bromo-1-propanol (2.3 mL, 25 mmol) in dry tetrahydrofuran (30 mL) was added diisopropyl azodicarboxylate (4.9 mL, 25 mmol) at 25° C. over 30 minutes under nitrogen and the reaction mixture was left stirring for one hour. Hydrobromic acid (2.8 mL of 48% aqueous solution, 25 mmol) was added, resulting in precipitation of the titled compound. The product was collected by suction filtration and washed with THF, acetone and ether to give a light yellow crystalline solid (4.17 g, 51%). 1H NMR (400 MHz, DMSO-d6): 2.45 (2H, m), 3.82 (2H, t, J=6.5 Hz), 4.61 (2H, t, J=5.7 Hz), 7.64 (1H, d, J=6.6 Hz), 8.40 (1H, dt, J=8.5, 2.7 Hz), 7.90 (m, 1H), 8.27 (1H, dd, J=9.4, 4.8 Hz), 9.24 (1H, d, J=6.6 Hz).
Reaction SMILES: O=[C:2]([C:6]1[C:14]2[C:9](=[CH:10][N:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)[C:3]([NH2:5])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[NH2:5][CH2:3][CH2:2][C:6]1[C:14]2[C:9](=[CH:10][N:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1
Reactant: NC(=O)C(=O)c1c[nH]c2cnccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: NCCc1c[nH]c2cnccc12
Temperature: 0 °C

Procedure:
A solution of 2-oxo-2-(1H-pyrrolo[2,3-c]pyridin-3-yl)acetamide (1 eq.) in ether is treated with lithium aluminum hydride (4 eq.), heated at reflux temperature for 8 h, cooled to 0° C. and quenched by addition of Rochelle's salt solution. The reaction mixture is extracted with CH2Cl2; the combined extracts are dried over MgSO4 and concentrated in vacuo to afford the title 6-azatryptamine product, which is used directly in step 4, below.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([O:11][C:12](=[O:23])[CH2:13][NH:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH3:10].Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[I:32]>O1CCCC1>[C:19]([O:18][C:16]([CH2:15][NH:14][CH:13]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[I:32])[C:12]([O:11][CH2:9][CH3:10])=[O:23])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CCOC(=O)CNCC(=O)OC(C)(C)C
Reactant: BrCc1ccccc1I
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccccc1I)NCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At −78° C., lithium diisopropylamide solution (2 M in THF/n-heptane, 17 ml, 34 mmol) was slowly added dropwise to ethyl(tert-butoxycarbonylmethylamino)acetate (7.4 g, 34 mmol) in tetrahydrofuran (abs., 50 ml). The mixture was stirred at this temperature for 2 h. 1-Bromomethyl-2-iodobenzene (10.0 g, 46 mmol) was then slowly added dropwise, and the mixture was stirred at −78° C. for 1 h. The reaction solution was slowly (12 h) warmed to room temperature and then concentrated on a rotary evaporator. The residue was taken up in ethyl acetate, washed, dried and concentrated. The residue obtained in this manner was then purified by column chromatography (SiO2, hexane/ethyl acetate). This gave 6.4 g (43%) of the target compound.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.Br[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=1>>[OH:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:23][CH2:24][CH2:25][O:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1
Reactant: COc1cccc(OCCCBr)c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Product: COc1cccc(OCCCOc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3O)cc2)c1

Procedure:
Analogously to Method I, 0.750 g of tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate and 0.808 g of 1-(3-bromopropoxy)-3-methoxybenzene are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.30 (1:2 EtOAc-heptane); Rt=5.18.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]=[C:10]([CH:20]([CH3:22])[CH3:21])[C:9]=2/[CH:23]=[CH:24]/[CH:25]([OH:34])[CH2:26][C:27](=[O:33])[CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:4][CH:3]=1.C(B(CC)CC)C.[BH4-].[Na+].CO>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]=[C:10]([CH:20]([CH3:21])[CH3:22])[C:9]=2/[CH:23]=[CH:24]/[C@@H:25]([OH:34])[CH2:26][C@@H:27]([OH:33])[CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:6][CH:7]=1
Reactant: COC(=O)CC(=O)CC(O)/C=C/c1c(-c2ccc(F)cc2)cc(-c2ccccc2)nc1C(C)C
Agent: CCB(CC)CC
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)C[C@H](O)C[C@H](O)/C=C/c1c(-c2ccc(F)cc2)cc(-c2ccccc2)nc1C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.7 %

Procedure:
A solution of (E)-7-[4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]-5-hydroxy-3-oxo-6-heptenoic acid, methyl ester (357 mg, 0.77 mmol) in THF (12 ml) was treated with triethylborane (1.0M in THF, 1.62 ml, 1.62 mmol). Twenty five milliliters of air was bubbled through the solution and the mixture was stirred at room temperature for 30 minutes. The solution was cooled to -78° C. and treated with NaBH4 (29.4 mg, 0.78 mmol) followed by dropwise addition of dry methanol (1.90 ml). After stirring at -78° C. for 1.5 hours, the mixture was quenched with 30% H2O2 (3.5 ml) in H2O (11 ml). The mixture was kept at -78° C. for 15 minutes, then warmed to room temperature and stirred for 30 minutes. The solution was poured into 50% saturated NaHCO3 and extracted with Et2O (3×). The Et2O extracts were combined, washed with H2O, saturated NaHCO3 and brine, then dried (Na2SO4). Filtration and removal of the solvent gave a yellow oil which was chromatographed (Flash, Merck SiO2, 40% EtOAc in hexane) to afford (3R, 5S, 6E)-7-[4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]-3,5-dihydroxy-6-heptenoic acid, methyl ester (320 mg, 89%) as a colorless oily foam.