Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([N:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])=[CH:7][CH:6]=1)=[O:4].C(Cl)(Cl)[Cl:19].C1N2CN3CN(C2)C[N:23]1C3.Cl>C(O)C>[ClH:19].[CH3:16][N:15]([CH3:17])[S:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][NH2:23])=[CH:6][CH:7]=1)(=[O:14])=[O:13]
Reactant: CN(C)S(=O)(=O)Nc1ccc(C(=O)CBr)cc1
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: ClC(Cl)Cl
Agent: Cl
Solvent: CCO
Product: CN(C)S(=O)(=O)Nc1ccc(C(=O)CN)cc1
Reaction time: 8 h

Procedure:
N-[4-(Bromoacetyl)phenyl]-N', N'-dimethylsulfamide (32 g., 0.10 mole) is added dropwise to a chloroform solution of hexamethylenetetramine (21.0 g., 0.15 mole) and the mixture is stirred overnight to give 42.6 g. of the complex. This is hydrolyzed by heating 0.5 hr. with 40 ml. conc. HCl and 500 ml. abs. ethanol. The mixture is cooled and the insoluble ammonium chloride is removed. The solution is concentrated in vacuo and the residue is triturated with isopropanol to give 27.3 g. of intermediate which is washed with water and recrystallized from methanol-isopropyl ether, m.p. 159-159.5° C. (dec.)
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[NH2:11][CH2:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([F:31])([F:30])[F:29])[CH2:17][CH2:16]1)=[O:14].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH:54]1[C:62]2[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=2)[C:56]([C:63](O)=[O:64])=[CH:55]1>CN(C=O)C.O>[O:14]=[C:13]([N:15]1[CH2:16][CH2:17][N:18]([C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([F:31])([F:29])[F:30])[CH2:19][CH2:20]1)[CH2:12][NH:11][C:63]([C:56]1[C:57]2[C:62](=[CH:61][CH:60]=[CH:59][CH:58]=2)[NH:54][CH:55]=1)=[O:64]
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: O=C(O)c1c[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 12.35 %

Procedure:
DIPEA (143 mg, 0.193 mL, 1.11 mmol) was added to a stirred solution of 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (prepared by the method described above) (157 mg, 0.44 mmol) in DMF (2 mL). HOBT (60 mg, 0.44 mmol) and EDCI (85 mg, 0.44 mmol) were then added at room temperature. After 2 minutes, 1H-Indole-3-carboxylic acid (60 mg, 0.37 mmol) was added and the resulting mixture was stirred at room temperature for 4 hrs. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to the residue. The residue was purified by preparative HPLC to afford 21.3 mg (12.35% yield) of 1H-Indole-3-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 95.81%. 1H NMR (CDCl3): δ 9.1 (s, 1H), 8.1 (d, 1H), 7.9-7.5 (m, 4H), 7.4-7.1 (m, 4H), 4.4-4.2 (m, 2H), 4.1-3.8 (m, 2H), 3.8-3.4 (m, 4H), 3.4-3.1 (m, 3H).
Reaction SMILES: [CH2:1]([C@@:4]1([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22](=[O:25])[N:21]([CH3:26])[CH:20]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=C.C1C[O:37]CC1.O>CCOC(C)=O.O=[Os](=O)(=O)=O>[F:33][C:30]1[CH:31]=[CH:32][C:27]([C@:4]2([CH2:1][CH2:2][OH:37])[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]3[CH:14]=[CH:15][C:16]([C:19]4[CH:24]=[CH:23][C:22](=[O:25])[N:21]([CH3:26])[CH:20]=4)=[CH:17][CH:18]=3)[CH3:12])[CH2:6][CH2:5]2)=[CH:28][CH:29]=1
Reactant: C1CCOC1
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(=O)n(C)c3)cc2)C(=O)O1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@@H](c1ccc(-c2ccc(=O)n(C)c2)cc1)N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one (0.064 g, 0.144 mmol, 1.0 equiv) in THF-H2O (1:1, 6 mL) were added NalO4 (0.145 g, 0.678 mmol, 4.7 equiv) and OsO4 (2.5 wt. % solution in t-BuOH, 0.048 g, 0.0047 mmol, 0.033 equiv), and the mixture was stirred at rt for 1 h. The mixture was diluted with EtOAc, dried over Na2SO4, and concentrated under reduced pressure. The residue was dissolved in MeOH (3 mL) and NaBH4 (0.100 g) was added. After the mixture was stirred for 0.5 h at rt, acetone was added. The solvents were removed in vacuo, the residue was treated with saturated brine, extracted with CH2Cl2, and dried over Na2SO4. After the solvent was evaporated, the residue was purified by reversed-phase HPLC (SunFire™ Prep O18 OBD™ 5 μm 19×50 mm column, 10%→90% CH3CN/H2O, 0.1% CF3COOH over 8 min and then 90% CH3CN/H2O, 0.1% CF3COOH over 2 min, flow rate 20 mL/min) to afford (S)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one. LC-MS Method 1 tR=1.21 min, m/Z=451 (M+1); 1H NMR (400 MHz, CD3OD) δ 7.80 (m, 1H), 7.69 (d, J=9.4 Hz, 1H), 7.22-7.19 (m, 4H), 7.00-6.92 (m, 4H), 6.52 (d, J=9.4 Hz, 1H), 5.45 (q, J=7.0 Hz, 1H), 3.60-3.52 (m, 1H), 3.52 (s, 3H), 3.24-3.18 (m, 1H), 3.02-2.98 (m, 1H), 2.39-2.35 (m, 1H), 2.23-2.12 (m, 2H), 2.01 (t, J=7.3 Hz, 2H), 1.43 (d, J=7.0 Hz, 3H); 19F NMR (376 MHz, CD3OD) 8-117.19 (m).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:15])([F:14])[C:5]1[N:10]=[CH:9][C:8]([CH2:11][C:12]#[N:13])=[CH:7][CH:6]=1.Br[CH2:17][CH2:18][CH2:19]Br.O>CS(C)=O.C1COCC1>[F:15][C:4]([F:14])([F:3])[C:5]1[N:10]=[CH:9][C:8]([C:11]2([C:12]#[N:13])[CH2:19][CH2:18][CH2:17]2)=[CH:7][CH:6]=1
Reactant: BrCCCBr
Reactant: N#CCc1ccc(C(F)(F)F)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: N#CC1(c2ccc(C(F)(F)F)nc2)CCC1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a suspension of NaH (567 mg, 14.2 mmol, 60%) in DMSO (30 mL) was added dropwise a solution of Example 85D (1.2 g, 6.45 mmol) in THF (5 mL) at room temperature and then the mixture was stirred for 30 minutes, followed by the addition of a solution of 1,3-dibromopropane (1.4 g, 7.10 mmol) in THF (5 mL) at room temperature. The mixture was stirred for additional 2 hours. After addition of water (30 mL) carefully, the resulting mixture was extracted with EtOAc (30 mL×2). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over Na2SO4, filtered, and concentrated to provide the title compound (1.45 g, 6.45 mmol, yield 100%) as a oil. The crude product was used in the next step without further purification. LC-MS: m/z 227.2 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Br:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[F:13].[Cl-].[Cl-].[Cl-].[Al+3].Cl>>[Br:5][C:6]1[C:7]([F:13])=[CH:8][C:9]([C:1](=[O:3])[CH3:2])=[C:10]([F:12])[CH:11]=1
Reactant: CC(=O)Cl
Reactant: Fc1ccc(F)c(Br)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)c1cc(F)c(Br)cc1F
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
Acetyl chloride (17 ml) is slowly dropped into a stirred mixture of 1-bromo-2,5-difluorobenzene (30 g) and aluminium trichloride (53 g) heated at 60° C. and kept under argon. The reaction mixture is then stirred 90 minutes at 95° C. The mixture is cooled at 40° C. and carefully poured into crushed ice (400 g) and concentrated hydrochloric acid (35 ml). The resulting mixture is stirred a few minutes and then extracted with ethyl ether (2×250 ml). The ethereal solution is washed to neutral with brine, dried over sodium sulfate and the solvent is evaporated. The distillation of the oily residue gives 4'-bromo-2 ',5'-difluoroacetophenone (21.2 g) b.p. (0.05 mm)=60° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([CH3:26])=[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[C:10](=[O:17])[NH:11]2.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Cl[C:40](OC(=O)C)([F:42])[F:41]>O>[CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([CH3:26])=[C:9]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)[C:10]([O:17][CH:40]([F:42])[F:41])=[N:11]2
Reactant: COC(=O)COc1ccc(F)c2[nH]c(=O)c(Cc3ccc(F)cc3)c(C)c12
Reactant: CC(=O)OC(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccc(F)c2nc(OC(F)F)c(Cc3ccc(F)cc3)c(C)c12
Temperature: 70 °C
Reaction time: 120 h

Procedure:
A mixture of [8-fluoro-3-(4-fluorobenzyl)-4-methyl-2-oxo-1,2-dihydroquinolin-5-yloxy]acetic acid methyl ester (0.48 g), N,N-dimethylformamide (6.0 mL), potassium carbonate (0.72 g) and acetic acid chlorodifluoromethyl ester (1.7 mL) was stirred at 70° C. for 5 days. The mixture was diluted with Water, extracted with ethyl acetate and the combined extracts washed with water and then dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (1:6 by volume), followed by washing with diethyl ether gave title compound as a white solid, 0.29 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:5]([CH3:17])[CH:4]=1.[CH:18]([Li])(CC)[CH3:19].O.Cl.[O:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[C:12]([O:11][C:10](=[O:16])[NH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH2:17][CH:29]([CH:28]1[CH2:19][CH2:18][CH2:26][CH2:27]1)[OH:25])([CH3:13])([CH3:14])[CH3:15]
Reactant: [Li]C(C)CC
Reactant: COc1ccc(NC(=O)OC(C)(C)C)c(C)c1
Reactant: C1CCOC1
Agent: Cl
Solvent: O
Product: COc1ccc(NC(=O)OC(C)(C)C)c(CC(O)C2CCCC2)c1
Reaction time: 0.25 h

Procedure:
To a solution of tert-butyl (4-methoxy-2-methylphenyl)carbamate (475 mg) in tetrahydrofuran (7 mL) was added dropwise sec-butyllithium (1.04 mol/L hexane-cyclohexane solution, 4.3 mL) at −40° C. under an argon atmosphere, and the mixture was stirred for 15 minutes. Then a solution of cyclopentanecarboxyaldehyde (0.256 mL) in tetrahydrofuran (1 mL) was added dropwise, and the mixture was stirred at −40° C. for 15 minutes and at room temperature for additional one hour. Water and 1 mol/L hydrochloric acid were added to the reaction mixture and this resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (535 mg).
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[C:5]=1[Br:14])[CH:2]=C.[O:15]=[O+][O-].CSC>CO.CCOC(C)=O>[Br:14][C:5]1[C:6]2[CH2:10][O:9][C:8](=[O:11])[C:7]=2[CH:12]=[CH:13][C:4]=1[CH2:1][CH:2]=[O:15]
Reactant: C=CCc1ccc2c(c1Br)COC2=O
Reactant: O=[O+][O-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CSC
Product: O=CCc1ccc2c(c1Br)COC2=O
Temperature: 25 °C

Procedure:
To a solution of 5-allyl-4-bromo-2-benzofuran-1(3H)-one (120 mg, 0.47 mmol) in methanol (20 mL) was bubbled ozone at −78° C. until the solution turned light blue. Excess ozone was removed by bubbling nitrogen through, which was followed by addition of dimethyl sulfide (0.35 mL, 4.7 mmol). The reaction was allowed to warm to RT, diluted with EtOAc, washed with brine, adsorbed onto silica gel, and purified by MPLC. Removal of solvent gave rise to (4-bromo-1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([NH:13][C:14](SC)=[C:15]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:16]#[N:17])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH:32]1([NH2:37])[CH2:36][CH2:35][CH2:34][CH2:33]1>>[F:31][C:2]([F:30])([F:1])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([NH:37][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[C:15]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)(=[O:19])=[O:20])[C:16]#[N:17])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CSC(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1
Reactant: NC1CCCC1
Product: N#CC(=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)NC1CCCC1)S(=O)(=O)c1ccc(Cl)cc1
Yield: 71 %

Procedure:
3-(3,5-Bis(trifluoromethyl)phenylamino)-2-(4-chloro-phenylsulfonyl)-3-methylsulfanyl-2-propenenitrile (0.400 g, 0.8 mmol) was stirred in cyclopentylamine (2 ml) at 80° C. for 2 h and at room temperature for 16 h under nitrogen. Work up as descriped in Example 1, 2) gave 305 mg (71%) of the title compound as pale yellow crystals. Mp 199-200° C. 1H NMR (300 MHz, CDCl3): δ=1.4-1.65 (m, 4H), 1.65-1.85 (m, 4H), 3.56 (sextet, 1H), 7.42 (s, 2H), 7.49 (d, 2H), 7.67 (s, 1 H), 7.78 (d, 2H); MA calc for C22H18ClF6N3O2S: C, 49.12%; H, 3.37%; N, 7.18%. Found: C, 48.93%; H, 3.31%; N, 7.58%.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH2:11][CH2:12][CH2:13][C:3]=12.[CH:14]1([C@H:17]2[CH2:22][NH:21][CH2:20][C@@H:19]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C@@H:18]2[OH:31])[CH2:16][CH2:15]1.C(N(CC)CC)C>C(O)(C)C>[CH:14]1([C@H:17]2[CH2:22][N:21]([C:2]3[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]4[CH2:11][CH2:12][CH2:13][C:3]=34)[CH2:20][C@@H:19]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])[C@@H:18]2[OH:31])[CH2:15][CH2:16]1
Reactant: O=[N+]([O-])c1cnc2c(c1Cl)CCC2
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNC[C@H](C2CC2)[C@H]1O
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1CN(c2c([N+](=O)[O-])cnc3c2CCC3)C[C@H](C2CC2)[C@H]1O
Temperature: 90 °C
Yield: 40.7 %

Procedure:
A mixture of 4-chloro-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridine (0.094 g, 0.47 mmol), tert-butyl [(3R,4R,5S)-5-cyclopropyl-4-hydroxypiperidin-3-yl]carbamate (0.13 g, 0.51 mmol), and triethylamine (0.26 mL, 1.9 mmol) in isopropyl alcohol (2 mL) was heated at 90° C. for 2 days. The desired product partially precipitated from the reaction mixture and was collected by filtration, washed with hexanes and dried under reduced pressure to afford pure sub-title compound (0.080 g). The filtrate was concentrated under reduced pressure and purified by flash column chromatography (20 g silica gel column, eluting with 0-15% MeOH/DCM) to afford further sub-title compound (0.034 g, total 0.114 g, 58%). LCMS (ESI) m/z calc. for C21H31N4O5 419.2 [M+H]+. found 419.1.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:22]3[CH2:23][CH2:24][CH2:25][C:26](=[O:27])[C:21]=3[O:20][N:19]=2)=[CH:14][C:13]=1[O:28][CH3:29]>C1COCC1>[CH3:29][O:28][C:13]1[CH:14]=[C:15]([C:18]2[C:22]3[CH2:23][CH2:24][CH2:25][C:26](=[O:27])[C:21]=3[O:20][N:19]=2)[CH:16]=[CH:17][C:12]=1[NH:11][CH:1]=[O:3]
Reactant: O=CO
Reactant: COc1cc(-c2noc3c2CCCC3=O)ccc1N
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: COc1cc(-c2noc3c2CCCC3=O)ccc1NC=O
Reaction time: 1 h

Procedure:
To formic acid (6.24 g, 135.6 mmol) was added dropwise 3.96 g (38.8 mmol) of acetic anhydride (exothermic, cooling with tap water was used). The reaction mixture was stirred for 1 hr. The resulting mixture was transferred via cannula into another reaction flask containing a solution of 3-(4-amino-3-methoxyphenyl)-5,6-dihydrobenzo[d]isoxazol-7(4H)-one in 50 ml of THF (Cooling with tap water was used). The mixture was stirred for 2 hr, extracted with DCM, washed with water and brine, dried over sodium sulfate and concentrated to furnish 2.65 g of the title compound, MS(M+H)+=287.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH2:18][C@H:19]1[CH2:23][C:22](=[O:24])[N:21]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C@@H:20]1[CH3:34])(=O)=O>CN(C=O)C.O>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:18][CH:19]2[CH:20]([CH3:34])[N:21]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=3)[C:22](=[O:24])[CH2:23]2)[CH:6]=1
Reactant: Ic1cn[nH]c1
Reactant: COc1ccc(CN2C(=O)C[C@H](COS(C)(=O)=O)[C@H]2C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)CC(Cn3cc(I)cn3)C2C)cc1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
4-Iodo-1H-pyrazole (0.93 g, 4.77 mmol) and cesium carbonate (2.59 g, 7.95 mmol) were added to a solution of [(2R,3S)-1-(4-methoxybenzyl)-2-methyl-5-oxopyrrolidin-3-yl]methyl rac-methanesulfonate (1.3 g, 3.98 mmol) in DMF (26 mL). The mixture was stirred at 90° C. under a nitrogen atmosphere for 3 hours. After cooling to room temperature, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (100 mL×3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (ethyl acetate/petroleum ether) to afford rac-(4R,5R)-4-[(4-iodo-1H-pyrazol-1-yl)methyl]-1-(4-methoxybenzyl)-5-methylpyrrolidin-2-one. MS ESI calc'd. for C17H21IN3O2 [M+H]+ 426. found 426. 1H NMR (400 MHz, CDCl3): δ 7.47 (s, 1H), 7.17 (d, J=8.5 Hz, 2H), 6.95 (s, 1H), 6.90 (d, J=8.5 Hz, 2H), 4.99-4.94 (m, 1H), 4.02-3.99 (m, 1H), 3.90-3.85 (m, 1H), 3.85 (s, 3H), 3.82-3.79 (m, 1H), 3.15-3.06 (m, 1H), 2.69-2.63 (m, 1H), 2.58-2.48 (m, 1H), 2.18-2.09 (m, 1H), 1.06 (d, J=6.5 Hz, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)=[C:4]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[CH:3]=1.[CH2:33]([Zn]CC)[CH3:34]>C1COCC1>[CH2:33]([C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:11]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=2)=[C:4]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[CH:3]=1)[CH3:34]
Reactant: CC[Zn]CC
Reactant: Cc1ccccc1-c1cc(Cl)ncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: C1CCOC1
Product: CCc1cc(-c2ccccc2C)c(N(C)C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1

Procedure:
To a solution of N-(6-chloro-4-o-tolylpyridin-3-yl)-N-methyl-3,5-bis(trifluoromethyl)-benzamide (0.1 g, 212 μmol, example 12) in THF (1 mL) were added tetrakis(triphenyl-phosphine)palladium(0) (12.2 mg, 10.6 μmol) and diethylzinc (1M solution in n-hexane, 137 μL, 137 μmol) and the brown solution was stirred at reflux for 16 hours. The solvent was evaporated and the brown gum was diluted with 1M aqueous HCl and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were washed with brine, dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 10 g column using an MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 30:70). Light yellow solid (0.051 g; 51%). MS (ESI): m/z=467.16 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[NH:19][C:18]2[C:20]3[C:3]=1[CH2:4][C@@H:5]1[C:13]([C:14]=3[CH:15]=[CH:16][CH:17]=2)=[CH:12][C@@H:8]([C:9](=[O:11])[OH:10])[CH2:7][N:6]1[CH3:21].Cl.CO.[CH3:25]COCC.CCCCCC>CO>[CH3:25][O:11][C:9]([C@@H:8]1[CH:12]=[C:13]2[C@@H:5]([CH2:4][C:3]3[C:20]4[C:18](=[CH:17][CH:16]=[CH:15][C:14]2=4)[NH:19][C:2]=3[CH3:1])[N:6]([CH3:21])[CH2:7]1)=[O:10]
Reactant: CCOCC
Reactant: Cc1[nH]c2cccc3c2c1C[C@@H]1C3=C[C@@H](C(=O)O)CN1C
Agent: Cl
Solvent: CCCCCC
Solvent: CO
Product: COC(=O)[C@@H]1C=C2c3cccc4[nH]c(C)c(c34)C[C@H]2N(C)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a suspension of 25 g 2-methyl-lysergic acid in 500 ml CH3OH are added 253 ml 3.5N HCl/CH3OH. The reaction mixture is then stirred at room temperature for 15 hours, then diluted with 500 ml CH3OH and stirred 2 days. The mixture is evaporated and partitioned between ethyl acetate and 5% K2CO3 solution. After drying and evaporating the heading compound is obtained as crystals, which are then rubbed with ether/hexane (1:1), m.p. 154° (sintering 150°).
Reaction SMILES: [H-].[Na+].[C:3]([O:8][CH2:9][CH:10]([CH3:12])[CH3:11])(=[O:7])[C@@H:4]([CH3:6])[OH:5].Cl[CH2:14][O:15][CH3:16]>C1(C)C=CC=CC=1>[CH3:14][O:15][CH2:16][O:5][C@H:4]([CH3:6])[C:3]([O:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[O:7]
Reactant: COCCl
Reactant: CC(C)COC(=O)[C@@H](C)O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COCO[C@H](C)C(=O)OCC(C)C
Yield: 94.7 %

Procedure:
2.0 g of 60% sodium hydride was suspended in 50 ml of toluene. The suspension was cooled on an ice bath. Thereto was dropwise added 7.3 g of isobutyl (R)-(+)-lactate with stirring, followed by stirring for 1 hour. Thereto was dropwise added 5.0 g of chloromethoxymethane, followed by stirring for 3 hours. The reaction mixture was washed with 50 ml of a saturated aqueous sodium hydrogen carbonate solution and 30 ml of water in this order. The washed material was subjected to vacuum distillation to remove the solvent, whereby was obtained 9.0 g (yield: 86.6%) of an oily title compound.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[CH:3]=1.F[C:12]1[C:13]([F:18])=[N:14][CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[O:6]1[C:5]2[CH:9]=[CH:10][C:2]([O:1][C:15]3[CH:16]=[CH:17][CH:12]=[C:13]([F:18])[N:14]=3)=[CH:3][C:4]=2[O:8][CH2:7]1
Reactant: Fc1cccnc1F
Reactant: Oc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Fc1cccc(Oc2ccc3c(c2)OCO3)n1
Temperature: 50 °C

Procedure:
To DMSO (5 mL) was added 5-hydroxy-1,3-benzodioxolane (1.09 g, 7.9 mmol), difluoropyridine (0.72 mL, 7.9 mmol), and cesium carbonate (2.62 g, 8.0 mmol). After heating at 50° C. for 18 hours, the reaction was partitioned with water and ethyl acetate. The organic layer was washed with water, brine, and dried (Na2SO4). The solvent was removed to give 2-(1,3-benzodioxol-5-yloxy)-6-fluoropyridine.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[S:7][CH:8]=1.[O:17]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18]1.[NH+]1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[O:17]1[CH2:22][CH2:21][CH:20]([O:1][CH2:2][CH2:3][C:4]2[N:5]=[C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[S:7][CH:8]=2)[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)Nc1nc(CCO)cs1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1nc(CCOC2CCOCC2)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
To a solution of Example 3B (6.3 g, 27.4 mmol) in dichloromethane (100 mL) were added commercially available 3,4-dihydro-2H-pyran (purchased from Aldrich) (21 g, 250 mmol) and pyridinium-p-toluenesulfonic acid (purchased from Aldrich) (3.5 g, 14.0 mmol). The reaction mixture was stirred overnight at room temperature and then diluted with dichloromethane, washed with water, dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography using an Analogix® IT280™ (SiO2, 0-100% ethyl acetate in hexanes) to afford 7.4 g (82%) of the title compound. MS (ESI+) m/z 329 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH:12]([CH3:14])[CH3:13])=[C:6]([N+:15]([O-])=O)[CH:5]=1>CO.CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH:12]([CH3:13])[CH3:14])=[C:6]([NH2:15])[CH:5]=1
Reactant: COC(=O)c1ccc(NCC(C)C)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(NCC(C)C)c(N)c1
Yield: 94.4 %

Procedure:
3-Amino-4-isobutylamino-benzoic acid methyl ester (790.0 mg) was prepared by following General Procedure B starting from 4-isobutylamino-3-nitro-benzoic acid methyl ester (950.0 mg) and Pd/C (20% by weight, 190.0 mg) in MeOH:EtOAc (1:1, 10.0 mL). The crude product was used in the next step without further purification.