Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9].[F:12][C:13]([F:20])([F:19])[C:14](OCC)=[O:15].C(N(CC)CC)C>CO>[F:12][C:13]([F:20])([F:19])[C:14]([NH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[O:15]
Reactant: CCOC(=O)C(F)(F)F
Reactant: COC(=O)CCCCCN
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)CCCCCNC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 19 h
Yield: 87 %

Procedure:
To a 2 liter round bottom flask, charged with 100.2 g (0.552 mol) of amine hydrochloride 2 and 1 liter of methanol was added 100 g (0.703 mol) of ethyl trifluoroacetate followed by 120 mL (0.861 mol) of triethylamine. The mixture was stirred at 20-30° C. for 19 h and then concentrated via rotary evaporation. The residue was diluted with 500 mL of diethyl ether and then filtered. The filtrate was washed with 3×300 mL aliquots of iN aqueous HCl, 200 mL of de-ionized water, 2×200 mL aliquots of saturated aqueous sodium bicarbonate and finally with 200 mL of de-ionized water. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was distilled under vacuum to afford 115.8 g of the product (3) as a colorless oil: b.p.=113-116° C. at 120 mm Hg: 1H NMR (d6 -DMSO) d 3.57 (3H, s), 2.75 (2H, m), 2.29 (2H, t), 1.60-1.40 (4H, m) and 1.37-1.19 (2H, m) ppm.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1.[C:19]([O:23][C:24]([NH:26][C:27]([CH3:45])([CH3:44])[CH2:28][C:29]([NH:31][C@@H:32]1[CH2:38][CH2:37][C:36]2[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=2[NH:34][C:33]1=[O:43])=[O:30])=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:16]([O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:34]2[C:35]3[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=3[CH2:37][CH2:38][C@@H:32]([NH:31][C:29](=[O:30])[CH2:28][C:27]([NH:26][C:24](=[O:25])[O:23][C:19]([CH3:21])([CH3:20])[CH3:22])([CH3:44])[CH3:45])[C:33]2=[O:43])=[CH:4][CH:5]=1)(=[O:18])[CH3:17]
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2NC1=O)NC(=O)OC(C)(C)C
Reactant: CC(=O)Oc1ccccc1-c1ccc(CBr)cc1
Product: CC(=O)Oc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)CC(C)(C)NC(=O)OC(C)(C)C)CCc3ccccc32)cc1

Procedure:
Prepared from 4'-bromomethyl-2-acetoxy-1,1'-biphenyl and 3-t-butoxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-butanamide (Example 57, Step A) by the procedure described in Example 69, Step D. 1H NMR (200 MHz,CDCl3): 1.38 (s,6H), 1.45 (s,9H), 1.85 (m,1H), 2.02 (s,3H), 2.35-2.65 (m,5H), 4.52 (m,1H), 4.84 (d,15 Hz,1H), 5.30 (d,15 Hz,1H), 6.71 (d,7 Hz,1H), 7.1-7.4 (m,12H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[O:4].O=[C:14]([CH2:20][CH3:21])[CH2:15][C:16]([O:18][CH3:19])=[O:17].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:20]([C:14]1[O:4][C:3]([C:5]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=2)=[CH:2][C:15]=1[C:16]([O:18][CH3:19])=[O:17])[CH3:21]
Reactant: CCC(=O)CC(=O)OC
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1oc(-c2ccc(OC)cc2)cc1C(=O)OC
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
To a solution of 2-bromo-4′-methoxyacetophenone (13.7 g) and methyl 3-oxopentanoate (7.8 g) in toluene (100 mL) was added dropwise 1,8-azabicyclo[5.4.0]-7-undecene (9.1 mL) over 30 min or more under ice-cooling. After the completion of the dropwise addition, the mixture was stirred for 30 min under ice-cooling, and then at room temperature for 2 hr. The resulting precipitate was filtered, and washed with toluene. The obtained toluene solution was passed through silica gel, and the silica gel was washed with ethyl acetate-hexane (1:1). The collected solutions were concentrated under reduced pressure to remove ethyl acetate-hexane to give a toluene solution. To this toluene solution was added 4-toluenesulfonic acid monohydrate (2.3 g), and the mixture was stirred at 100° C. for 2 hr. The reaction mixture was washed with aqueous sodium hydrogen carbonate solution, and the aqueous layer was extracted with ethyl acetate. The organic layers were collected, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 5% ethyl acetate/hexane) to give the title compound (9.2 g, 59%) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:21]([CH3:24])=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([N:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[CH:11]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](Cl)=[O:31]>CN1CCCC1=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:30](=[O:31])[C:29]5[CH:33]=[CH:34][CH:35]=[C:27]([C:26]([F:25])([F:36])[F:37])[CH:28]=5)[CH:23]=[CH:22][C:21]=4[CH3:24])=[CH:11][N:10]3[N:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Cc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)nn2c1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: CN1CCCC1=O
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Oc1ccc2nc(NC(=O)C3CC3)nn2c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 65.3 %

Procedure:
To a solution of N-[6-(3-amino-6-methylphenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (100 mg, 0.309 mmol) in 1-methylpyrrolidin-2-one (2.0 mL) was added 3-(trifluoromethyl)benzoyl chloride (78 mg, 0.371 mmol), and the mixture was stirred at room temperature for 10 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (100 mL), washed with 5% aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=50/50→0/100), and the obtained oil was triturated with ethyl acetate and hexane to give the title compound (100 mg, 65%) as a colorless powder.
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3Cl)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:33]1([NH2:38])[CH2:37][CH2:36][CH2:35][CH2:34]1.O>C(O)C>[C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3[NH:38][CH:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(Cl)ncnc32)[C@]1(C)F
Reactant: NC1CCCC1
Solvent: O
Solvent: CCO
Product: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(NC4CCCC4)ncnc32)[C@]1(C)F
Yield: 76 %

Procedure:
To a stirred solution of ((2R,4R)-3-acetoxy-5-(6-chloro-9H-purin-9-yl)-4-fluoro-3,4-dimethyl-tetrahydrofuran-2-yl)methyl benzoate (about 0.50 g, 1.08 mmol) in ethanol (about 5 ml) was added cyclopentylamine (about 1.28 ml, 12.9 mmol) and refluxed for about 30 minutes. Completion of the reaction mixture monitored by thin-layer chromatography, water added to the reaction mixture and the aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over sodium sulphate. Concentration under reduced pressure and purification by silica gel column chromatography using 6% methanol in dichloromethane as eluent furnished title compound (0.42 g) as a colorless solid. Yield: 76%; 1H-NMR: 1H NMR (300 MHz, CDCl3): δ 8.39 (s, 1H), 8.06-7.96 (m, 3H), 7.57-7.42 (m, 3H), 6.54 (d, 1H, J=23.1 Hz), 5.92 (d, 1H, J=7.5 Hz), 4.83-4.77 (m, 2H), 4.48-4.44 (m, 1H), 2.15 (s, 3H), 2.08-1.91 (m, 1H), 1.89-1.88 (d, 3H, J=2.1 Hz), 1.78-1.58 (m, 8H), 1.44 (d, 3H, J=23.1 Hz); ES Mass: [M+1]+ 526 (20%), [M+Na] 548 (100%); IR cm−: 3437, 2925, 2855, 1733, 1612, 1232, 1059, 951, 711; HPLC: 98%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=[O:14])[N:11]=[C:10]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([CH3:22])[CH:16]=3)[CH:9]=2)=[C:4]([CH3:23])[CH:3]=1.ClCCCl.C([N:35]1[CH2:40][CH2:39][CH:38]([CH:41]=O)[CH2:37][CH2:36]1)(OC(C)(C)C)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[OH:21][C:18]1[CH:19]=[CH:20][C:15]([C:10]2[CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][CH2:41][CH:38]4[CH2:39][CH2:40][NH:35][CH2:36][CH2:37]4)=[CH:3][C:4]=3[CH3:23])[NH:13][C:12](=[O:14])[N:11]=2)=[CH:16][C:17]=1[CH3:22]
Reactant: Cc1cc(-c2cc(-c3ccc(N)cc3C)[nH]c(=O)n2)ccc1O
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1cc(-c2cc(-c3ccc(NCC4CCNCC4)cc3C)[nH]c(=O)n2)ccc1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59 %

Procedure:
In a round bottom flask was added 6-(4-amino-2-methylphenyl)-4-(4-hydroxy-3-methylphenyl)pyrimidin-2(1H)-one (3) (30 mg, 0.10 mmol), 1,2 dichloroethane (2.0 mL), acetic acid (0.1 mL), and commercially available N-Boc-4-formyl piperidine (29 uL, 0.14 mmol). The reaction was stirred at room temperature for 15 minutes before adding sodium triacetoxy borohydride (30 mg, 0.14 mmol). Stirring was continued at room temperature overnight. The reaction was then quenched with saturated NaHCO3, extracted with EtOAc, dried over Na2SO4 and concentrated to dryness. The resultant oil was then dissolved in 4N HCl/dioxane (1.0 mL) and allowed to sit at RT for 30 min. or until Boc deprotection was complete. The 4N HCl/dioxane was decanted, and the residual solid product was rinsed with EtOAc 4×. The resulting orange solid was then dissolved in MeOH and purified by preparatory HPLC (5-85% gradient of AmAc/ACN, 15 min.) to give the product 4-(4-hydroxy-3-methylphenyl)-6-{2-methyl-4-[(piperidin-4 ylmethyl)amino]phenyl}pyrimidin-2(1H)-one as the acetate salt after lyopholyzation (24 mg, 59% yield).
Reaction SMILES: [C:1]([Si:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CN(C)[CH:24]=[O:25].O>O1CCCC1>[C:1]([Si:5]([CH3:7])([CH3:6])[O:8][C:9]1[C:10]([F:16])=[C:11]([C:12]([F:15])=[CH:13][CH:14]=1)[CH:24]=[O:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(F)cc1F
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(F)c(C=O)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To tert-butyl-(2,4-difluoro-phenoxy)-dimethyl-silane (36, 5.90 g, 24.1 mmol) in tetrahydrofuran (100 mL), under an atmosphere of nitrogen, cooled in a −78° C. acetone/dry ice bath, was added n-butyllithium (2.50 M in hexane, 10.6 mL, 26.5 mmol) slowly. The reaction was allowed to stir for 1 hour, then N,N-dimethylformamide (2.24 mL, 29.0 mmol) was added and the reaction was allowed to warm to room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The compound was isolated by silica gel column chromatography eluting with 10% ethyl acetate in hexane to give a colorless oil (37, 5.0 g, 76.0%). MS (ESI) [M+H+]+=272.2.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=1[O:21]C)[CH:6]=[CH:5]2.FC1C2C(=CC=C(O)C=2)N=C(C2C=CC(C(O)=O)=CC=2OC)C=1.B(Br)(Br)Br.O>C(Cl)Cl>[OH:21][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:12]=1[C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([OH:1])[CH:3]=2)[N:8]=1)[C:16]([OH:18])=[O:17]
Reactant: COc1cc(C(=O)O)ccc1-c1ccc2cc(O)ccc2n1
Agent: BrB(Br)Br
Agent: COc1cc(C(=O)O)ccc1-c1cc(F)c2cc(O)ccc2n1
Solvent: O
Solvent: ClCCl
Product: O=C(O)c1ccc(-c2ccc3cc(O)ccc3n2)c(O)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 43.5 %

Procedure:
70 mg of 4-(6-hydroxyquinolin-2-yl)-3-methoxybenzoic acid (Compound 48) was suspended in 10 ml DCM and 0.25 ml BBr3 was added. The mixture was stirred at room temperature for 2 days. 20 ml water was added to quench the reaction. DCM was removed by evaporation and the precipitate was filtered and washed with water and dried to obtain 29 mg of 3-hydroxy-4-(6-hydroxyquinolin-2-yl)benzoic acid. 1H NMR (DMSO-d6 300 MHz TMS): δ 10.34 (s, 1H), 8.45 (d, 1H), 8.30 (d, 1H), 8.24 (d, 1H), 7.97 (d, 1H), 7.46 (m, 3H), 7.26 (d, 1H), MS (ESI): m/z=282.30 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[CH:3]=1.[Cl:13][S:14](O)(=[O:16])=[O:15]>>[Cl:1][C:2]1[C:11]([S:14]([Cl:13])(=[O:16])=[O:15])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[CH:3]=1
Reactant: O=S(=O)(O)Cl
Reactant: COC(=O)c1ccc(Cl)cc1C
Product: COC(=O)c1cc(S(=O)(=O)Cl)c(Cl)cc1C
Temperature: 0 °C
Reaction time: 3 h
Yield: 75.6 %

Procedure:
A mixture of 15.8 g (0.086 mol) of methyl 4-chloro-2-methylbenzoate (2) and 25.8 ml (45.2 g, 0.39 mol) of chlorosulfonic acid was heated to a gentle reflux under nitrogen. After 3 hrs., the mixture was cooled and poured slowly into an ice-water mixture. After stirring for 1 hr., the mixture was filtered and rinsed well with ice cold water. Drying in a vacuum oven (60° C.) gave 17.4 g (0.065 mol, 75% yield) of the sulfonylated acid (off-white crystals). A mixture of 14.5 g of the acid and 2 drops of dimethylformamide in 50 ml of thionyl chloride was heated to reflux under nitrogen. After 11/2 hrs., the solvent was removed under reduced pressure. Methanol (125 ml) was added to residue material and the solution was cooled to 10° C. After 5 hrs., the solid was filtered and airdried, giving 12.8 g of off-white crystals (3); m.p. 94.5° -96° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([S:21](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:23])=[O:22])=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:36])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[Cl:8].[O:37]1[CH:41]=[CH:40][C:39]([NH2:42])=[N:38]1.C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([NH:42][C:39]4[CH:40]=[CH:41][O:37][N:38]=4)(=[O:22])=[O:23])=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:36])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[Cl:8]
Reactant: Nc1ccon1
Reactant: COc1nc(Cl)c(Cl)cc1-n1c(=O)ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1nc(Cl)c(Cl)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 133.5 %

Procedure:
A RBF was charged with perfluorophenyl 1-(5,6-dichloro-2-methoxypyridin-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (1.0 g, 1.763 mmol), isoxazol-3-amine (0.143 ml, 1.939 mmol), and THF (8.81 ml) to give a clear solution. The flask was cooled to 0° C. for 10 min, then lithium bis(trimethylsilyl)amide (1M in THF) (3.88 ml, 3.88 mmol) was added dropwise. The reaction was stirred for 30 minutes. The reaction was diluted with 1N aq. HCl and EtOAc. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with 1N aq. HCl, washed with brine, dried with sodium sulfate, filtered, and concentrated to afford crude 1-(5,6-dichloro-2-methoxypyridin-3-yl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (1.10 g, 2.354 mmol, 100% yield) as an orange solid. m/z (ESI) 467.0 (M+H)+.
Reaction SMILES: ClCCCCC1C2C(=CC=CC=2)NC=1.BrCCCCC1C2C(=CC=CC=2)NC=1.[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1C1CCNCC=1.Cl.[O:41]=[C:42]1[CH2:47][CH2:46][N:45]([C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:44][CH2:43]1>>[OH:41][C:42]1([C:30]2[S:29][CH:33]=[CH:32][CH:31]=2)[CH2:43][CH2:44][N:45]([C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:46][CH2:47]1
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: C1=C(c2cccs2)CCNC1
Agent: BrCCCCc1c[nH]c2ccccc12
Agent: Cl
Agent: ClCCCCc1c[nH]c2ccccc12
Product: CCOC(=O)N1CCC(O)(c2cccs2)CC1

Procedure:
A solution of 2.08 g of 3-(4-chlorobutyl)indole [or 2.52 g of 3-(4-bromobutyl)indole] and 1.65 g of 4-(2-thienyl)-1,2,3,6-tetrahydropyridine [hydrochloride, m.p. 242°; obtainable by reaction of 2-thienyl-Li with ethyl 4-oxo-1-piperidinecarboxylate to give ethyl 4-hydroxy-4-(2-thienyl)-1-piperidinecarboxylate, alkaline elimination of the protective group and dehydration with hydrochloric acid] in 10 ml of acetonitrile is stirred at 20° for 12 hours, worked up as usual and 3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)butyl]indole is obtained; hydrochloride ("T"), Rf 0.52.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[Cl:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][C:29]=1[Cl:30])[C:23]([NH:25][NH2:26])=[O:24].ClC1C(CC)=C(N[C@H]([C@@H](O)C)C(NNC(=O)C2C=CC=CC=2)=O)C=CC=1C#N>>[Cl:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][C:29]=1[Cl:30])[C:23]([NH:25][NH:26][C:12](=[O:14])[C@H:11]([NH:10][C:4]1[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[C:3]=1[CH3:18])[C@H:15]([OH:17])[CH3:16])=[O:24]
Reactant: Cc1c(N[C@@H](C(=O)O)[C@@H](C)O)ccc(C#N)c1Cl
Reactant: NNC(=O)c1ccc(Cl)c(Cl)c1
Agent: CCc1c(N[C@@H](C(=O)NNC(=O)c2ccccc2)[C@H](C)O)ccc(C#N)c1Cl
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(Cl)c(Cl)c2)[C@@H](C)O)ccc(C#N)c1Cl
Yield: 81 %

Procedure:
(2R,3R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (800 mg, 2.98 mmol) and 3,4-dichlorobenzohydrazide (615 mg, 2.98 mmol) were coupled together in a procedure analogous to that described for the preparation of intermediate 11c to furnish the title compound (1.10 g, 81%). 1H NMR (500 MHz, acetone d6, δ in ppm) 10.0 (br s, 2H), 8.17 (s, 1H), 7.87 (d, J=8 Hz, 1H), 7.68 (d, J=8 Hz, 1H), 7.47 (d, J=8 Hz, 1H), 6.79 (d, J=8 Hz, 1H), 5.61 (d, J=7 Hz, 1H), 4.29-4.22 (m, 1H), 4.17-4.19 (m, 1H), 2.39 (s, 3H), 1.40 (d, J=6 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](/[CH:9]=[CH:10]/[C:11]([OH:13])=O)[CH:6]=[CH:7][CH:8]=1)#[N:2].[NH:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[CH2:19][N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[O:13]=[C:11]([N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[CH2:19][N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)/[CH:10]=[CH:9]/[C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[C:1]#[N:2]
Reactant: N#Cc1cccc(/C=C/C(=O)O)c1
Reactant: C1CCN(C[C@@H]2CCCN2)CC1
Product: N#Cc1cccc(/C=C/C(=O)N2CCC[C@H]2CN2CCCCC2)c1

Procedure:
370 mg of the title compound were synthesized as described for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-3-(3-cyanophenyl)acrylic acid instead of (E)-4-bromocinnamic acid and 1-(((S)-pyrrolidin-2-yl)methyl)piperidine instead of (S)-2-((pyrrolidin-1-yl)methyl)pyrrolidine.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[Br:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[O:31][C:30](=[O:35])[CH:29]=[C:28]2OS(C(F)(F)F)(=O)=O>C(#N)C>[Br:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[O:31][C:30](=[O:35])[CH:29]=[C:28]2[NH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]=[CH:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:4][CH2:3]1
Reactant: NC1CCN(CC=Cc2ccccc2)CC1
Reactant: O=c1cc(OS(=O)(=O)C(F)(F)F)c2cc(Br)ccc2o1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=c1cc(NC2CCN(CC=Cc3ccccc3)CC2)c2cc(Br)ccc2o1
Temperature: 150 °C
Yield: 34.1 %

Procedure:
To a solution of 4-amino-1-cinnamylpiperidine (1.3 g, 6 mmol) and triethylamine (1.6 mL, 7.2 mmol) in dry acetonitrile (125 mL) was added trifluoromethanesulfonic acid 6-bromo-2-oxo-2H-chromen-4-yl ester (2.23 g, 6 mmol). About 5 mL of solution was added to each of 25 dry microwave vials equipped with stir bars. The vials were capped and each was heated at 150° C. for 5 minutes in the microwave. The solutions were combined, concentrated and dissolved in chloroform. The solution was washed with water and brine and dried over Na2SO4, and concentrated. The residue was purified by flash chromatography through a silica gel column with dichloromethane and methanol (95:5 v/v) to provide the desired compound (900 mg, 34%) as a yellow solid. MS (ESI(+)Q1MS m/z 440 (M+2H)+; 1H NMR (300 MHz, DMSO) δ ppm 1.57-1.67 (m, 2H), 1.89-1.95 (m, 2H), 2.13 (m, 2H), 2.92 (m, 2H), 3.13 (m, 2H), 3.50 (m, 1H), 5.28 (sd, 1H), 6.35 (dt, 1H), 6.56 (d, 1H), 7.24-7.47 (m. 7H), 7.74 (dd, 1H), 8.45 (d, 1H).
Reaction SMILES: [CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[CH:13][NH:12]4)[CH2:5][C@@H:4](O)[CH2:3]1.CS([Cl:23])(=O)=O>N1C=CC=CC=1>[CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[CH:13][NH:12]4)[CH2:5][C@@H:4]([Cl:23])[CH2:3]1
Reactant: CN1C[C@H](O)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CN1C[C@H](Cl)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Temperature: 80 °C

Procedure:
To a solution of 5 g of 6-methyl-8β-hydroxyergoline in 80 ml of pyridine, 3.2 ml of methanesulfonyl chloride were slowly added at room temperature. The mixture obtained was heated at 80° C. for about 3 hours and then evaporated. The residue was taken up with chloroform and washed with saturated aqueous sodium bicarbonate solution and then water. Evaporation of the organic solvent yielded a residue which was chromatographed over a silica gel column using cyclohexane:acetone 8:2 by volume as eluant. Fractions containing the product were combined and crystallized from methanol to give 3.8 g of 6-methyl-8β-chloro-ergoline, m.p. 195°-197° C.
Reaction SMILES: [C:1]1([C@@H:7]2[O:9][C@H:8]2[C:10]([O-:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[K+].ClC(OCC(C)C)=O.CN1CCOCC1.[NH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[OH:36]>C1COCC1>[OH:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[NH:29][C:10]([C@H:8]1[C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:9]1)=[O:12]
Reactant: O=C([O-])[C@@H]1O[C@H]1c1ccccc1
Reactant: Nc1ccccc1O
Agent: CC(C)COC(=O)Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: O=C(Nc1ccccc1O)[C@@H]1O[C@H]1c1ccccc1
Temperature: 10 °C
Yield: 77 %

Procedure:
To a stirred suspension of potassium (2R,3S)-3-phenyloxirane-2-carboxylate (64a) (4.040 g, 20.00 mmol) in dry THF (100 mL) under nitrogen cooled in an ice-water bath was added isobutyl chloroformate (2.730 g, 20.00 mmol) slowly via syringe. NMM (0.460 mg, 4.55 mmol) was added and the mixture stirred while gradually warming to 10° C. over 75 min. The mixture was cooled to 0° C. and 2-aminophenol was added, then the cooling bath was removed and the reaction stirred at ambient temperature for 24 h. The reaction was diluted with diethyl ether (100 mL) then filtered through diatomaceous earth to remove suspended solids. Rotary evaporation of the solution afforded a yellow solid that was triturated with diethyl ether and collected by filtration. The solid was rinsed on the filter with additional diethyl ether to afford pure title compound (3.920 g, 77%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ4.00 (d, 1H, J=1.8 Hz), 4.22 (d, 1H, J=1.8 Hz), 6.80 (m, 1H), 6.87-7.00 (m, 2H), 7.40 (s, 5H), 7.95 (d, 1H, J=7.9 Hz), 9.27 (s, 1H), 9.97 (s, 1H). 13C-DEPT NMR (75 MHz, DMSO-d6) δ57.7 (CH), 58.4 (CH), 115.5 (CH), 119.4 (CH), 121.6 (CH), 125.1 (CH), 125.8 (C), 126.5 (CH), 128.9 (CH), 129.1 (CH), 135.9 (C), 147.7 (C), 165.4 (C). MS APCI, m/z=256 (M+1). LC/MS: 2.12 min.