Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:14]2[C:5](=[C:6]3[C:11](=[CH:12][CH:13]=2)[CH2:10][CH2:9][C@H:8]([CH2:15]OS(C2C=CC(C)=CC=2)(=O)=O)[O:7]3)[CH:4]=[CH:3][CH:2]=1.[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[C:37]1[CH2:38][CH2:39][NH:40][CH2:41][CH:42]=1.C(Cl)(Cl)Cl>CS(C)=O>[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[C:37]1[CH2:38][CH2:39][N:40]([CH2:15][C@H:8]2[CH2:9][CH2:10][C:11]3[C:6](=[C:5]4[C:14](=[CH:13][CH:12]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)[O:7]2)[CH2:41][CH:42]=1
Reactant: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCc3ccc4ncccc4c3O2)cc1
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Product: Fc1ccc2[nH]cc(C3=CCN(C[C@H]4CCc5ccc6ncccc6c5O4)CC3)c2c1
Yield: 56.6 %

Procedure:
A solution of (6R)-toluene-4-sulfonic acid 7,8-dihydro-6H-5-oxa-1-aza-phenanthren-6-ylmethyl ester (0.17 g, 0.47 mmole) and 5-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.20 g, 0.94 mmole) in anhydrous DMSO (25 mL) was stirred at 80° C. for 2 hours. The reaction mixture was then poured into chloroform (100 mL) and washed with water (3×40 mL). The organic layer was dried over sodium sulfate and filtered, and the solvent was removed under vacuum. Column chromatography on silica gel (5% methanol/ethyl acetate) afforded 0.11 g (55%) of the title compound. The fumarate salt was prepared in ethyl acetate and isopropyl alcohol and had mp 210° C. and [α]25D=−60.030° (c=4.5, DMSO).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=O)=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2].CC[N:18](CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH4+].[Cl-]>C(Cl)Cl>[CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([NH2:18])=[O:15])=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1ccc(CC(=O)O)cc1
Reactant: CCN(CC)CC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: ClCCl
Product: CCS(=O)(=O)c1ccc(CC(N)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
To a mixture of 2-(4-(ethylsulfonyl)phenyl)acetic acid (3 g, 13.2 mmol), Et3N (4.0 g, 39.6 mmol) and HATU (5.93 g, 15.6 mmol) in anhydrous CH2Cl2 (100 mL) was added NH4Cl (1.54 g, 26.4 mmol). The resulting mixture was stirred at rt overnight. The mixture was diluted with CH2Cl2 (100 mL) and washed with water (3×80 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluting with 50% EtOAc in petroleum ether, gradient to 100%) to afford crude 2-(4-(ethylsulfonyl)phenyl)acetamide. The crude product was added to petroleum ether/ethyl acetate (20 mL, 1/1), then the mixture was stirred for 0.5 h. The mixture was filtered and the filter cake was dried under vacuum to give 2-(4-(ethylsulfonyl)phenyl)acetamide (1.5 g, 50%) as a white solid. LC-MS tR=0.900 min in 0-30AB—2 min chromatography (Welch Xtimate C18, 2.1*30 mm, 3 um), MS (ESI) m/z 269.0 [M+H+CH3CN]+. 1H NMR (DMSO-d6, 400 MHz): δ 7.80 (d, J=8.0 Hz, 2H), 7.58 (broad s, 1H), 7.51 (d, J=8.0 Hz, 2H), 7.00 (broad s, 1H), 3.50 (s, 2H), 3.25 (q, J=7.2 Hz, 2H), 1.08 (t, J=7.2 Hz, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[F:13][C:14]1[CH:23]=[CH:22][C:17]([CH:18]=[CH:19][CH:20]=O)=[CH:16][CH:15]=1.C1C=CC=CC=1>O>[F:13][C:14]1[CH:23]=[CH:22][C:17](/[CH:18]=[CH:19]/[CH2:20][NH:1][CH2:2][C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=[CH:5][CH:4]=2)=[CH:16][CH:15]=1
Reactant: O=CC=Cc1ccc(F)cc1
Reactant: NCc1cccc2ccccc12
Solvent: O
Solvent: c1ccccc1
Product: Fc1ccc(/C=C/CNCc2cccc3ccccc23)cc1

Procedure:
A mixture of 10 g of 1-aminomethylnaphthalene, 9.55 g of p-fluorocinnamaldehyde and 150 ml of benzene is heated in a reaction vessel equipped with a water separator, at reflux, until the theoretical amount of water has been separated. The mixture is cooled and evaporated to dryness. 5.78 g of the resulting Schiff's base in 60 ml of methanol, after warming to 50°, is mixed, with vigorous stirring, with 1.51 g of solid NaBH4, portionwise, and the mixture is refluxed for 20 minutes. The resulting mixture may be used as such in the next stage. The title compound can be isolated as an oil, however, by evaporation and dividing the residue between aqueous NaHCO3 solution and chloroform, drying the organic phase and evaporation.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11](O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[N+:50]([C:53]1[CH:54]=[N:55][NH:56][CH:57]=1)([O-:52])=[O:51]>C1COCC1>[N+:50]([C:53]1[CH:54]=[N:55][N:56]([CH:11]2[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]2)[CH:57]=1)([O-:52])=[O:51]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2cc([N+](=O)[O-])cn2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 53.7 %

Procedure:
1-Boc-4-hydroxy piperidine (2.6 g, 0.0132 mol), triphenylphosphine (4.1 g, 0.015 mol) and di-tert-butyl azodicarboxylate (3.9 g, 0.0172 mol) are added in portions to a solution of 4-nitro-1H-pyrazole (1.5 g, 0.0132 mol) in THF (40 ml) at 10-15° C. The reaction mixture is stirred at room temperature for 48 h. The mixture is evaporated in a rotary evaporator, and the crude material is chromatographed, giving 2.1 g of a white solid;
Reaction SMILES: [C:1]([O:4][CH:5]1[O:22][C@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)[CH3:2].[CH:28]1C(O)=C[CH:31]=[C:30]([CH3:35])[CH:29]=1>[Cl-].[Cl-].[Zn+2]>[C:8]([O:7][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:22][C@@H:5]1[O:4][C:1]1[CH:28]=[CH:29][C:30]([CH3:35])=[CH:31][CH:2]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)OC[C@H]1OC(OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: Cc1ccc(O)cc1
Agent: [Cl-]
Agent: [Zn+2]
Product: CC(=O)OC[C@H]1O[C@H](Oc2ccc(C)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Yield: 37.2 %

Procedure:
According to scheme XIV, the coupling of penta-O-acetyl-D-galactopyranose (36 g, 92 mmoles) with p-cresol (30 g, 280 mmoles) is carried out by fusion in the presence of anhydrous ZnCl2 (1.8 g) at 160° C. for 30 minutes, according Helferich technique. After cooling, a chromatography on a column of 60H silica (solvent:hexane-ethyl acetate: 90/10-v/v) is directly performed on the mixture and gives 15 g, yield=40% of 4-methylphenyl 2,3,4,6-tetra-O-acetyl-α-D-galactopyranoside, which crystallises in ethanol. Its analytical characteristics are identical as the one described before.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][OH:8].Br[CH2:10][C:11]#[CH:12].O>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:12][C:11]#[CH:10]
Reactant: C#CCBr
Reactant: COCCOCCO
Solvent: C1CCOC1
Solvent: O
Product: C#CCOCCOCCOC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2 g 2-(2-Methoxy-ethoxy)-ethanol in 20 ml THF 1.8 g KOt-Bu were added at 0° C. After stirring for 10 min 8.1 ml 3-Bromo-propyne (75% in toluene) were added and the mixture was warmed to RT and stirred for 4 h. Then 10 ml of water were added and the mixture was filtered through a Chem Elut® cartridge by elution with CHCl3. This solution containing the desired product was subjected to the next reaction step.
Reaction SMILES: I[C:2]1[S:3][CH:4]=[C:5]([C:7]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]2[CH3:15])=[O:8])[N:6]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:2]1[S:3][CH:4]=[C:5]([C:7]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]2[CH3:15])=[O:8])[N:6]=1
Reactant: COc1ccccc1B(O)O
Reactant: CC1CCCCN1C(=O)c1csc(I)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COc1ccccc1-c1nc(C(=O)N2CCCCC2C)cs1
Temperature: 78 °C

Procedure:
A mixture of (2-iodo-thiazol-4-yl)-(2-methyl-piperidin-1-yl)-methanone (Step 3; 200 mg, 0.59 mmol), 2-methoxyphenylboronic acid (Combi-Blocks, Inc., San Diego, Calif.; 135 mg, 0.89 mmol), potassium carbonate (201 mg, 1.45 mmol), and PdCl2dppf (Strem Chemicals, Inc., Newburyport, Mass.; 22 mg, 0.03 mmol) in dimethoxyethane (3 mL) in a scintillation vial was heated at ˜78° C. for 72 h with shaking. The reaction mixture was cooled to room temperature, concentrated in vacuo using a Genevac evaporator, and purified using automated mass-directed LC-MS purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[N+:11]([O-])([OH:13])=[O:12]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=[O:6]
Reactant: O=Cc1ccc(O)c(Cl)c1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=Cc1cc(Cl)c(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 58.4 %

Procedure:
To a solution of 3-chloro-4-hydroxybenzaldehyde (400 mg, 2.55 mmol) in acetic acid (5 mL) was added concentrated nitric acid (0.1 mL) and at 0° C., the resulting suspension was stirred at 25° C. for 6 h. The mixture was poured into ice water; the solid was collected by filtration, washed with water (30 mL) and dried in vacuo to give Intermediate 59 (300 mg, 58.4%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([F:14])[CH:12]=2)[N:7]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:6]=1[CH3:24])=[O:4].[Br:25]N1C(C)(C)C(=O)N(Br)C1=O>ClCCCl>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([F:14])[CH:12]=2)[N:7]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:6]=1[CH2:24][Br:25])=[O:4]
Reactant: COC(=O)c1c(C)n(S(=O)(=O)c2ccccc2)c2ncc(F)cc12
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: ClCCCl
Product: COC(=O)c1c(CBr)n(S(=O)(=O)c2ccccc2)c2ncc(F)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.3 %

Procedure:
A mixture of 1-benzenesulfonyl-5-fluoro-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid methyl ester (13.9 g, 39.9 mmol), 1,3-dibromo-5,5-dimethylhydantoin (12.6 g, 39.9 mmol) and 1,1-azobis(cyclohexanecarbonitrile) (1.95 g, 8.0 mmol) in 1,2-dichloroethane (150 mL) was heated under reflux for 90 minutes then stirred at ambient temperature for 16 hours. The reaction mixture was washed with saturated aqueous sodium thiosulfate solution. The organic layer was dried (Na2SO4) then filtered. The filtrate was stirred with flash silica gel, filtered and the filtrate evaporated under reduced pressure. The resultant residue was triturated with diethyl ether/pentane (1:1) to afford the title compound as a cream solid (15.9 g, 93%). 1H NMR (400 MHz, CDCl3): 8.47-8.44 (m, 2H), 8.32 (dd, J=2.8, 1.1 Hz, 1H), 8.04 (dd, J=8.5, 2.8 Hz, 1H), 7.64-7.64 (m, 1H), 7.54-7.53 (m, 2H), 5.68 (s, 2H), 4.00 (s, 3H).
Reaction SMILES: [BH4-].[Na+].[CH3:3][C@H:4]1[CH2:9][C@@H:8]([OH:10])[C@H:7]([C:11]([CH3:13])=[CH2:12])[CH2:6][CH2:5]1.B(F)(F)F.CC[O:20]CC.OO>COCCOCCOC>[OH:20][CH2:12][CH:11]([C@@H:7]1[CH2:6][CH2:5][C@@H:4]([CH3:3])[CH2:9][C@H:8]1[OH:10])[CH3:13]
Reactant: C=C(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Reactant: CCOCC
Agent: FB(F)F
Agent: OO
Agent: [BH4-]
Solvent: COCCOCCOC
Product: CC(CO)[C@@H]1CC[C@@H](C)C[C@H]1O
Reaction time: 0.25 h
Yield: 200.9 %

Procedure:
5.1 g (0.13 mol) of sodium borohydride, 700 ml of diglyme and 50.0 g (0.32 mol) of (-)-isopulegol were charged into a 1λ three-necked flask equipped with a condenser, a dropping funnel, a thermometer and a magnetic stirrer. 23.0 ml (0.13 mol) of boron trifluoride etherate was put in the flask on a water bath, and the contents thereof were agitated well for 15 min (precipitated). Further, the contents were agitated at room temperature for 1 hr, and then 50 ml of water was added to thereby decompose any excess hydroxide. 40 ml of a 3M aqueous sodium hydroxide solution was added to the organic borane formed by the above reaction on the water bath heated at 30° to 50° C. Further, 40 ml of a 30% aqueous hydrogen peroxide solution was added and agitated well for 30 mins. The reaction product was extracted with 1λ of ether and washed with the same amount of chilled water 5 times to thereby remove the diglyme. The resultant ether phase was dried over anhydrous magnesium sulfate, and the solvent was distilled off, thereby obtaining 45.0 g (yield: 80.8%) of (1R, 2S, 5R)-2-(2-hydroxy-1-methylethyl)-5-methylcyclohexanol in the form of white crystals (reference: Helv. Chim. Acta., 50(21), 153 (1967)).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[N:5]([CH2:8][CH2:9][O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[C:6]=1Br.C([Li])CCC.C(O)(C)C>O1CCCC1.[Cl-].[NH4+]>[Br:1][C:2]1[N:3]=[C:4]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[N:5]([CH2:8][CH2:9][O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(Br)c(Br)n2CCOC2CCCCO2)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2nc(Br)cn2CCOC2CCCCO2)CC1
Temperature: -78 °C
Reaction time: 1.08 h
Yield: 109.6 %

Procedure:
Add tert-butyl 4-(4,5-dibromo-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate (46.00 g 85.61 mmol) in tetrahydrofuran (1 L). Cool to −78° C. under nitrogen. Add 1.6 M butyllithium in hexanes (90.97 mL, 1.7 eq) dropwise over 15 minutes. Maintain the internal temperature below −65° C. After 65 minutes, add isopropyl alcohol (50 mL). Allow to warm to room temperature over 2 hr. Dilute with saturated aqueous ammonium chloride, then extract with ethyl acetate three times. Wash the organics with saturated aqueous sodium chloride. Dry over anhydrous magnesium sulfate, filter, and concentrate in vacuo to give the title compound (43.00 g, 100%). MS (ES) m/z=460 [M]+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:21])[N:10]([CH:12]1[CH2:17][CH2:16][C:15](=[CH:18][O:19]C)[CH2:14][CH2:13]1)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C1COCC1>[CH2:1]([O:8][C:9](=[O:21])[N:10]([CH:12]1[CH2:17][CH2:16][CH:15]([CH:18]=[O:19])[CH2:14][CH2:13]1)[CH3:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC=C1CCC(N(C)C(=O)OCc2ccccc2)CC1
Agent: Cl
Solvent: C1CCOC1
Product: CN(C(=O)OCc1ccccc1)C1CCC(C=O)CC1
Temperature: 25 °C

Procedure:
A solution of 495 g (1710.6 mmol) of (4-Methoxymethylene-cyclohexyl)-methyl-carbamic acid benzyl ester in 1.7 l THF was treated with 3.42 l of aqueous 1N HCl at RT and heated at reflux for 2 h. The reaction was cooled to RT and extracted with TBME (1.7 and 0.9 l). The organic phase was washed with aqueous 1M NaHCO3, dried (Na2SO4), filtered and evaporated to give 457.4 (97%) of crude (4-Formyl-cyclohexyl)-methyl-carbamic acid benzyl ester (trans:cis ca 70:30).
Reaction SMILES: [CH:1]([C:4](=[CH2:19])[C:5]([C:7]1[S:8][CH:9]=[C:10]([C:12]2[CH:17]=[C:16](C)[CH:15]=[CH:14][CH:13]=2)[CH:11]=1)=[O:6])([CH3:3])[CH3:2].[CH3:20]S(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>O>[CH3:20][C:9]1[S:8][C:7]2[C:5](=[O:6])[CH:4]([CH:1]([CH3:2])[CH3:3])[CH2:19][C:11]=2[C:10]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C=C(C(=O)c1cc(-c2cccc(C)c2)cs1)C(C)C
Reactant: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Product: Cc1sc2c(c1-c1ccccc1)CC(C(C)C)C2=O
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
A mixture of 2-(isopropyl)-1-(5-methyl-4-phenyl(2-thienyl))prop-2-en-1-one (98 g crude product) and Eaton's reagent (200 mL) was heated to 90° C. with stirring. After 10 minutes, the reaction mixture was poured slowly into water (500 mL). The product was extracted with dichloromethane, washed with a saturated aqueous solution of NaHCO3, and dried (MgSO4). Rotoevaporation of solvent gave 98 g of crude product (˜70% product by GC/MS). A portion of the product was further refined by chromatography on silica. 1H-NMR δ (CDCl3): 7.15–7.4 (m, 5H), 2.7 (m, 2H), 2.5 (m, 1H), 2.38 (s, 3H), 2.3 (m, 1H), 0.9 (d, 3H). EIMS: m/z (%) 270 (M+, 10), 255 (4), 228 (100), 213 (5), 195 (5), 184 (10), 165 (7), 152 (6).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:11])=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[OH-].[K+].ClC(OC(Cl)(Cl)Cl)=[O:16]>O>[CH3:11][C:4]1[S:3][C:2]2[NH:1][C:10](=[O:16])[O:9][C:7](=[O:8])[C:6]=2[CH:5]=1
Reactant: COC(=O)c1cc(C)sc1N
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1cc2c(=O)oc(=O)[nH]c2s1
Temperature: 90 °C
Reaction time: 2 h
Yield: 53.8 %

Procedure:
Methyl 2-amino-5-methyl-thiophene-3-carboxylate (16.8 g, 299 mmol) was added to a solution of potassium hydroxide (25 g, 146 mmol) in 300 mL water. The solution was heated at 90° C. until to yield a clear solution. The solution was heated at same temperature for another 30 min and then cooled to 0° C. Trichloromethyl chloroformate (26.42 mL, 219 mmol) was added slowly without allowing the temperature to rise beyond 10° C. The solution was further stirred for 2 h. The precipitated solid was collected by vacuum filtration to yield 21.6 g (83%) of 6-methyl-1H-thieno[2,3-d][1,3]oxazine-2,4-dione. 1H-NMR (DMSO-d6) δ 2.38 (d, J=1.2 Hz, 3H), 6.90 (q, J=1.2 Hz, 1H), 12.44 (b, 1H) ppm; EIMS m/z 184 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16]C(=O)C)=[CH:12][CH:11]=1.Cl.[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[O:31][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[C:25](Cl)=O>>[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[O:31][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[CH2:25][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]1[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=1
Reactant: O=C(Cl)c1ccc(OCCN2CCCCC2)c(F)c1
Reactant: CC(=O)Oc1ccc(C=Cc2ccccc2N)cc1
Agent: Cl
Product: Oc1ccc(C=Cc2ccccc2NCc2ccc(OCCN3CCCCC3)c(F)c2)cc1
Yield: 63.1 %

Procedure:
Synthesized from acetic acid 4-[2-(2-aminophenyl)vinyl]phenyl ester (328 mg) and 3-fluoro-4-(2-piperidin-1-ylethoxy)benzoyl chloride hydrochloride (500 mg) according to an analogous synthetic method to Example 152, the title compound (365 mg) was obtained.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH2:12]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClS([N:23]=[C:24]=[O:25])(=O)=O>O1CCCC1>[C:1]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:24]([NH2:23])=[O:25])[C:13](=[O:18])[CH2:12]2)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: O=C1Cc2cc(C(=O)c3ccccc3)ccc2N1
Solvent: C1CCOC1
Product: NC(=O)N1C(=O)Cc2cc(C(=O)c3ccccc3)ccc21

Procedure:
A mixture of 10.1 g. (42 mmole) of 5-benzoyl-2-oxindole, 4.4 ml. (51 mmole) of chlorosulfonyl isocyanate and 300 ml. of tetrahydrofuran was stirred at room temperature for 6 hours, and then the solvent was removed by evaporation in vacuo. The residue was added to 150 ml. of glacial acetic acid and 300 ml. of water and the resulting mixture was heated under reflux for 2 hours. The reaction mixture was cooled and the supernatant liquid was removed by decantation. The remaining gummy residue was triturated under acetonitrile to give a solid which was recovered by filtration and then recrystallized from a 1:1 mixture of n-propanol and acetonitrile. This gave 4.1 g. of the title compound as a solid, mp. 210°-211° C.
Reaction SMILES: [CH:1]1([C:7]2[CH:35]=[CH:34][C:10]([C:11]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([N:20]4[CH2:24][CH2:23][CH:22]([CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21]4)=[N:18][CH:19]=3)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:36][C:37]([CH3:41])=[CH:38][CH2:39]Br>>[CH:1]1([C:7]2[CH:35]=[CH:34][C:10]([C:11]([N:13]([CH2:39][CH:38]=[C:37]([CH3:41])[CH3:36])[C:14]3[CH:15]=[CH:16][C:17]([N:20]4[CH2:24][CH2:23][CH:22]([CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:31])[CH3:32])[CH2:21]4)=[N:18][CH:19]=3)=[O:12])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)=CCBr
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2ccc(NC(=O)c3ccc(C4CCCCC4)cc3)cn2)C1
Product: CC(C)=CCN(C(=O)c1ccc(C2CCCCC2)cc1)c1ccc(N2CCC(CNC(=O)OC(C)(C)C)C2)nc1

Procedure:
tert-Butyl {1-[5-(4-cyclohexylbenzoylamino)pyridin-2-yl]pyrrolidin-3-yl}methylcarbamate was reacted with 3-methyl-2-butenyl bromide by method F-a. This resulted in the product with the molecular weight of 546.76 (C33H46N4O3); MS (ESI): 547 (M+H+).
Reaction SMILES: [C:1]1([CH2:7][NH:8][C@@H:9]2[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]2[OH:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C.[Br-].[CH3:30][CH:31]1[O:35][C:34](=[N+:36]([CH3:38])[CH3:37])[C:33]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:32]1>O>[OH:15][C@H:10]1[C@H:9]([NH:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:14][CH2:13][N:12]([CH:31]([CH3:30])[CH2:32][C:33]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:34]([N:36]([CH3:37])[CH3:38])=[O:35])[CH2:11]1
Reactant: CC1CC(c2ccccc2)(c2ccccc2)C(=[N+](C)C)O1
Reactant: O[C@@H]1CNCC[C@H]1NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: CC(CC(C(=O)N(C)C)(c1ccccc1)c1ccccc1)N1CC[C@@H](NCc2ccccc2)[C@H](O)C1
Reaction time: 24 h
Yield: 45 %

Procedure:
A mixture of 17.6 parts of trans-4-[(phenylmethyl)amino]-3-piperidinol, 27 parts of sodium carbonate and 680 parts of 4-methyl-2-pentanone was stirred and refluxed for 45 minutes using a water separator. After cooling, 33.8 parts of N-(dihydro-5-methyl-3,3-diphenyl-2(3H)-furanylidene)-N-methylmethanaminium bromide were added and stirring was continued for 24 hours at reflux. The mixture was cooled and washed with water. The organic layer was dried, filtered and evaporated. The residue was dissolved in 1,1'-oxybisethane and acidified with 2-propanol, saturated with hydrogen chloride. The liquid was decanted and the half solid precipitated product was dissolved in water and treated with ammonium hydroxide. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (90:10 by volume) as eluent. The desired fractions were collected and the eluent was evaporated. The residue was solidified on scratching in petroleum ether. The product was filtered off and crystallized twice from acetonitrile. The product was filtered off and dried, yielding 18.8 parts (45%) of trans-3-hydroxy-N,N,γ-trimethyl-α,α-diphenyl-4-[(phenylmethyl)amino]-1-piperidinebutanamide; mp. 134.5° C. (interm. 18).