Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([OH:16])=[C:4]([CH2:11][CH:12]([OH:15])CO)[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[BH4-].[Na+].Cl>O.CC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH2:11][CH2:12][OH:15])[C:3]=1[OH:16]
Reactant: O=[N+]([O-])c1cc(F)c(O)c(CC(O)CO)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=[N+]([O-])c1cc(F)c(O)c(CCO)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
Compound 4 (3.7 g, 16 mmol) was suspended in water and dissolved by adding a few drops of acetone. NaIO4 (3.42 g, 16 mmol) was added portionwise at 0° C. After 7 min NaBH4 (4.84 g, 128 mmol) was added slowly. The solution was stirred for 1 h at room temperature, the acidified with dilute hydrochloric acid and extracted with ethyl acetate. The filtrate was concentrated to yield the desired compound 5 (2.4 g, yield 75%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[C:9]=2[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:39][C:40]#[N:41]>CN(C=O)C>[C:40]([CH2:39][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[C:9]=2[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]3[CH2:28][CH2:29][CH2:30][CH2:31]3)=[CH:20][CH:19]=2)=[CH:4][CH:3]=1)#[N:41]
Reactant: Oc1ccc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#CCOc1ccc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1
Temperature: 25 °C

Procedure:
A suspension of 2-(4-hydroxyphenyl)-3-[4-[2-(1-pyrrolidinyl)ethoxy]benzyl]benzo[b]thiophene (102 mg) and cesium carbonate (386 mg) in DMF (3.0 mL) was treated with bromoacetonitrile (20 uL) while stirring at ambient temperature.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][S:9]([C:12]1[C:13]([O:28][CH3:29])=[C:14]([CH:25]=[CH:26][CH:27]=1)[C:15]([O:17]CC1C=CC=CC=1)=[O:16])(=[O:11])=[O:10]>>[Cl:8][S:9]([C:12]1[C:13]([O:28][CH3:29])=[C:14]([CH:25]=[CH:26][CH:27]=1)[C:15]([OH:17])=[O:16])(=[O:11])=[O:10]
Reactant: COc1c(C(=O)OCc2ccccc2)cccc1S(=O)(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1c(C(=O)O)cccc1S(=O)(=O)Cl
Yield: 68.7 %

Procedure:
A trifluoroacetic acid (95 mL) solution of benzyl 3-(chlorosulfonyl)-2-methoxybenzoate (12.9 g) was stirred at 70° C. for 5 hours. The solution part was decanted and evaporated under reduced pressure. Toluene was added to the residue, and this was again evaporated. The resulting solid was collected by filtration, washed with toluene and dried to obtain 3-(chlorosulfonyl)-2-methoxybenzoic acid (6.52 g).
Reaction SMILES: I.[Cl:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:4]=1[CH:5]=[N:6][NH:7][C:8](=[NH:11])SC.[NH2:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1.[ClH:25]>C(O)C>[ClH:2].[ClH:25].[Cl:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:4]=1[CH:5]=[N:6][NH:7][C:8]([NH:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)=[NH:11]
Reactant: CSC(=N)NN=Cc1c(Cl)cccc1Cl
Reactant: NCc1cccnc1
Agent: Cl
Agent: I
Solvent: CCO
Product: N=C(NCc1cccnc1)NN=Cc1c(Cl)cccc1Cl

Procedure:
A solution of 5.85 g. of methyl 3-(2,6-dichlorobenzylidene)thiocarbazimidate hydriodide and 1.62 g. of 3-(aminomethyl)pyridine in 25 ml. of absolute ethanol is heated under reflux for 47 hours. To the resulting solution is added 3.00 ml. of 5N sodium hydroxide and evaporation under reduced pressure gives a light brown crystalline residue. The residue is dissolved in 100 ml. of dichloromethane:methanol (95:5) and chromatographed on a column (2.8 × 35 cm.) of silica gel; 200 ml. cuts are taken. Evaporation under reduced pressure of combined cuts 2-4 gives 4.70 g. of crude product as a light tan foam. The foam is dissolved in 25 ml. of absolute ethanol and 7.5 ml. of 5.25N methanolic hydrogen chloride is added. The resulting solution is evaporated under reduced pressure and the residual gum is crystallized from absolute ethanol-acetone. After chilling, filtration gives 3.83 g. of light tan crystals. Recrystallization from 1:1 methanol:acetonitrile gives the desired product as colorless crystals, m.p. 235°-239° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([N+:10]([O-:12])=[O:11])[C:5]([O:13][CH3:14])=[CH:4][C:3]=1[O:15][CH3:16].[CH:17](O)=[O:18]>O>[CH:17]([NH:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([N+:10]([O-:12])=[O:11])[C:5]([O:13][CH3:14])=[CH:4][C:3]=1[O:15][CH3:16])=[O:18]
Reactant: COc1cc(OC)c([N+](=O)[O-])c(OC)c1N
Reactant: O=CO
Solvent: O
Product: COc1cc(OC)c([N+](=O)[O-])c(OC)c1NC=O

Procedure:
A mixture comprising 0.11 mole (26.6 g) of 2-amino-4-nitro-1,3,5-trimethoxybenzene and 55 ml of formic acid are refluxed during three hours. The reaction mixture is cooled and diluted with iced water. The expected product precipitates and is separated by filtration. After drying it is recrystallized from ethanol. It melts at 98° C.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:7])[CH2:4][CH:5]=O.[C:8]([O:11][C@@H:12]([C@:23]12[CH2:58][C:57](=[O:59])[C:56]([CH:60]([CH3:62])[CH3:61])=[C:24]1[C@@H:25]1[C@@:38]([CH3:41])([CH2:39][CH2:40]2)[C@@:37]2([CH3:42])[C@@H:28]([C@:29]3([CH3:55])[C@@H:34]([CH2:35][CH2:36]2)[C:33]([CH3:44])([CH3:43])[C@@H:32]([O:45][C:46](=[O:54])[CH2:47][C:48]([CH3:53])([CH3:52])[C:49]([OH:51])=[O:50])[CH2:31][CH2:30]3)[CH2:27][CH2:26]1)[CH2:13][NH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)(=[O:10])[CH3:9].C([BH3-])#N.[Na+]>CO>[C:8]([O:11][C@@H:12]([C@:23]12[CH2:58][C:57](=[O:59])[C:56]([CH:60]([CH3:62])[CH3:61])=[C:24]1[C@@H:25]1[C@@:38]([CH3:41])([CH2:39][CH2:40]2)[C@@:37]2([CH3:42])[C@@H:28]([C@:29]3([CH3:55])[C@@H:34]([CH2:35][CH2:36]2)[C:33]([CH3:44])([CH3:43])[C@@H:32]([O:45][C:46](=[O:54])[CH2:47][C:48]([CH3:52])([CH3:53])[C:49]([OH:51])=[O:50])[CH2:31][CH2:30]3)[CH2:27][CH2:26]1)[CH2:13][N:14]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=1)[CH2:5][CH2:4][N:3]([CH3:7])[CH3:2])(=[O:10])[CH3:9]
Reactant: CN(C)CC=O
Reactant: CC(=O)O[C@H](CNCc1ccc(Cl)cc1)[C@@]12CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)C1=C(C(C)C)C(=O)C2
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(=O)O[C@H](CN(CCN(C)C)Cc1ccc(Cl)cc1)[C@@]12CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)C1=C(C(C)C)C(=O)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.6 %

Procedure:
To a solution of 2-(dimethylamino)acetaldehyde, hydrochloride (238 mg, 1.922 mmol) in methanol (12 mL) was added 4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-1-acetoxy-2-((4-chlorobenzyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid (50) (150 mg, 0.192 mmol). The reaction mixture was stirred at rt for 2 h then sodium cyanoborohydride (121 mg, 1.922 mmol) was added and the mixture was stirred overnight. Upon completion, the mixture was purified preparative-HPLC to provide the title compound (50 mg, 24%). 1H NMR (400 MHz, CHLOROFORM-d) δ=7.35-7.12 (m, 4H), 5.65 (d, J=9.3 Hz, 1H), 4.49 (dd, J=5.8, 10.0 Hz, 1H), 3.83 (d, J=13.6 Hz, 1H), 3.55 (d, J=13.6 Hz, 1H), 3.25-2.91 (m, 7H), 2.91-2.73 (m, 7H), 2.73-2.52 (m, 3H), 2.33 (d, J=18.1 Hz, 1H), 1.99-0.72 (m, 48H); LC/MS: m/z calculated 850.5. found 851.4 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14]O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Br)(Br)(Br)[Br:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][Br:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCOC(CO)C1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCOC(CBr)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 37.3 %

Procedure:
To a cooled (0° C.) solution of 2-hydroxymethylmorpholine-4-carboxylic acid tert-butyl ester (1.04 g, 4.79 mmol, see Step 1) in dichloromethane (20 mL) was added CBr4 (1.98 g, 5.98 mmol). After stirring the mixture for 10 minutes, triphenylphosphine (2.20 g, 8.38 mmol) was added portion-wise. The reaction mixture was stirred at 0° C. for 6 hours and then allowed to warm to room temperature and stirred for 60 hours. The mixture was concentrated under reduced pressure and then diluted with ether. The crude mixture was filtered and the filtrate was concentrated to afford the crude product, which was chromatographed on Biotage eluting with dichloromethane. The desired fractions were combined and concentrated to yield 0.50 g of product (37% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=1.[CH2:16]([O:23][NH:24][CH3:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:23][N:24]([C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=1)[CH3:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CNOCc1ccccc1
Reactant: CCCNc1nc(Cl)nc(NCCC)n1
Product: CCCNc1nc(NCCC)nc(N(C)OCc2ccccc2)n1
Yield: 29 %

Procedure:
2-Chloro-N-(4,6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV) and O-benzyl-N-methyl-hydroxylamine (LII) were reacted as described in Example 13 to yield O-benzyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-methyl-hydroxylamine (LIII) (29% yield). 200 MHz 1H NMR (DMSO-d6, ppm) 7.52-7.28 (5H, m), 7.07-6.67 (2H, m), 4.93 (2H, s), 3.26-3.03 (7H, m), 1.58-1.39 (4H, m), 0.85 (6H, t, J=7.2 Hz). ESI-MS (m/z): 331 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([NH:5][NH2:6])(=[O:4])=[O:3].CCN(C(C)C)C(C)C.C[O:17][C:18](=O)[C:19]1[CH:24]=[C:23]([C:25]2[N:26]([CH3:30])[CH:27]=[CH:28][CH:29]=2)[C:22]([C:31]([F:34])([F:33])[F:32])=[CH:21][C:20]=1[NH:35][C:36](OC1C=CC(Cl)=CC=1)=[O:37]>O1CCOCC1>[CH3:30][N:26]1[CH:27]=[CH:28][CH:29]=[C:25]1[C:23]1[CH:24]=[C:19]2[C:20](=[CH:21][C:22]=1[C:31]([F:32])([F:33])[F:34])[NH:35][C:36](=[O:37])[N:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[C:18]2=[O:17]
Reactant: COC(=O)c1cc(-c2cccn2C)c(C(F)(F)F)cc1NC(=O)Oc1ccc(Cl)cc1
Reactant: CS(=O)(=O)NN
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cccc1-c1cc2c(=O)n(NS(C)(=O)=O)c(=O)[nH]c2cc1C(F)(F)F
Temperature: 95 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
CH3SO2NHNH2 (25.5 mg, 1.5 equiv) and i-Pr2NEt (26.5 μL, 1 equiv) were added to a solution of 2-(4-chloro-phenoxycarbonylamino)-5-(1-methyl-1H-pyrrol-2-yl)-4-trifluoromethyl-benzoic acid methyl ester (70 mg, 0.155 mmol) in dioxane (2 mL). The mixture was stirred for 2 h (TLC control) at 95° C. CH3SO2NHNH2 (25.5 mg, 1.5 equiv) and i-Pr2NEt (26.5 μL, 1 equiv) were then added. The mixture was stirred for 48 h at 95° C. The mixture was evaporated to dryness. The crude product was purified by column chromatography (silica gel 60, EtOAc/hexanes 7/3) to give N-[6-(1-methyl-1H-pyrrol-2-yl)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl]-methanesulfonamide (50 mg, 80%) as a yellow solid. ESI-MS: m/z 420 [M+NH4]+, rt: 4.83 min. 1H-NMR (DMSO-d6, 400 MHz) 7.91 (s, 2H), 7.57 (s, 1H), 7.54 (s, 1H), 3.88 (s, 3H), 3.14 (s, 3H).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][CH2:15][CH2:16][CH:17]2[CH2:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[CH2:21][NH:20][C:19]3[CH:29]=[CH:30][CH:31]=[CH:32][C:18]2=3)[CH2:7]1)=[O:5])C.[OH-].[Na+].[ClH:35]>C(O)C>[ClH:35].[CH:32]1[C:18]2[CH:17]([CH2:16][CH2:15][O:14][CH2:13][CH2:12][N:8]3[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]3)[CH2:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[CH2:21][NH:20][C:19]=2[CH:29]=[CH:30][CH:31]=1
Reactant: CCOC(=O)[C@@H]1CCCN(CCOCCC2Cc3ccccc3CNc3ccccc32)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@@H]1CCCN(CCOCCC2Cc3ccccc3CNc3ccccc32)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The above ester (0.4 g, 0.9 mmol) was dissolved in ethanol (7 ml) and a 2 N aqueous sodium hydroxide solution (1.8 ml) was added. The reaction mixture was stirred at room temperature for 16 h. The mixture was placed on an ice-bath and a concentrated aqueous hydrochloric acid solution (0.37 ml) was added. The volatiles were evaporated in vacuo, the residue suspended in dichloromethane and the solid removed by filtration. The solvent was evaporated from the filtrate in vacuo to give a residue which was re-evaporated with dichloromethane to give 0.30 g of the title compound as an amorphous solid.
Reaction SMILES: [C:1]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:2][C:3]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=O.N1CCCCC1.[NH2:20][C:21]1[C:22]([CH:27]=O)=[N:23][CH:24]=[CH:25][N:26]=1>C1(C)C=CC=CC=1>[N:23]1[CH:24]=[CH:25][N:26]=[C:21]2[N:20]=[C:3]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:2]([C:1]([O:11][CH2:12][CH3:13])=[O:10])=[CH:27][C:22]=12
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Reactant: Nc1nccnc1C=O
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CCOC(=O)c1cc2nccnc2nc1C(=O)OCC
Yield: 27.9 %

Procedure:
Diethyl oxalacetate, (4.7 g, 0.025 mol) and piperidine (1.66 g, 1.93 mL) are added to 3-aminopyrazine-2-carboxaldehyde (2.4 g, 0.0195 mol) dissolved in 250 mL of toluene. After the reaction mixture is refluxed for two hours, the toluene is removed under reduced pressure to give a dark red oily residue. The product is purified by column chromatography on silica gel (hexane:EtOAc, 4:1), affording 3.1 g (58% yield), of the crude desired product. Crystallization from ether-hexane (4:1) gives analytically pure compound 1.5 g (28%) having a melting point 83°-85° C.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[NH2:9][C:10]1[N:15]=[C:14]([S:16][CH3:17])[CH:13]=[N:12][CH:11]=1>C(Cl)(Cl)Cl>[NH2:9][C:10]1[C:11]([Br:8])=[N:12][CH:13]=[C:14]([S:16][CH3:17])[N:15]=1
Reactant: CSc1cncc(N)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: CSc1cnc(Br)c(N)n1

Procedure:
NBS (3.28 G, 18.4 MMOL) WAS SLOWLY ADDED TO A STIRRED SOLUTION OF 6-AMINO-2-METHYLTHIOPYRAZINE (2.6 G, 18.4 MMOL) IN CHLOROFORM (100 ML). AFTER 1 H THE REACTION MIXTURE WAS PARTITIONED BETWEEN 10% SODIUM METABISULFITE SOLUTION AND CHLOROFORM. THE ORGANIC LAYER WAS DRIED (NA2SO4) AND EVAPORATED IN VACUO. THE CRUDE PRODUCT WAS PURIFIED BY FLASH COLUMN CHROMATOGRAPHY ON SILICA GEL (20% ETHYL ACETATE/HEXANES) TO GIVE THE TITLE COMPOUND AS A CRYSTALLINE SOLID: 1H NMR (CDCL3): Δ 2.49 (S, 3H), 4.97 (BR S, 2H), 7.59 (S, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][C:12](=[O:14])[CH3:13])=[CH:5][CH:4]=1.[N+:15]([O-])([OH:17])=[O:16]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][NH:11][C:12](=[O:14])[CH3:13])=[CH:7][C:8]=1[N+:15]([O-:17])=[O:16]
Reactant: COc1ccc(CCNC(C)=O)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: COc1ccc(CCNC(C)=O)cc1[N+](=O)[O-]
Temperature: 32.5 °C
Reaction time: 1 h

Procedure:
A solution of 70 g of N-[2-(4-methoxyphenyl)ethyl]acetamide in 330 mL of acetic acid was introduced slowly into 350 mL of 70% nitric acid so that the temperature was between 30-35° C. The addition process took 1 hour. The mixture was stirred at 30-35° C. for additional 40 minutes and was then poured into 1500 mL of ice water. The resulting slurry was extracted with chloroform (2×400 mL). The organic phase was extracted with a saturated aqueous solution of NaHCO3 (2×400 mL) and then with water (2×400 mL). The solvent was then removed by rotary evaporation to produce 65 g of N-[2-(4-methoxy-3-nitrophenyl)ethyl]acetamide, which was further purified by recrystallization from ethyl acetate to yield 48 g (55.6% yield) of yellow crystals. 1HNMR (DMSO-d6) spectrum was consistent with the desired product.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][C:26]4([C:29]([OH:31])=O)[CH2:28][CH2:27]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][CH:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:32])[NH:6]2.C[CH2:34][N:35](C(C)C)[CH:36](C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.CNC>C(Cl)Cl>[F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][C:26]4([C:29]([N:35]([CH3:36])[CH3:34])=[O:31])[CH2:28][CH2:27]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][CH:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:32])[NH:6]2
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ccnc2cc1OCC1(C(=O)O)CC1
Agent: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ccnc2cc1OCC1(C(=O)N(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product of Example 10 (100 mg) was mixed with DIPEA (1.5 eq), EDC (1.25 eq), HOBt (1 eq) and dimethylamine hydrochloride (3 eq) in DCM (20 ml). The reaction was stirred at RT overnight and washed with NaHCO3 solution, dried. The solution was evaporated and purified with silica gel column to give the titled product (80 mg). Mass: (M+1), 464
Reaction SMILES: C([O:5][C:6](=[O:22])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:21])[CH:13]([CH3:20])[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])(C)(C)C>FC(F)(F)C(O)=O>[CH3:19][O:18][C:16]([CH2:15][CH2:14][CH:13]([CH3:20])[C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:6]([OH:22])=[O:5])=[O:21])=[O:17]
Reactant: COC(=O)CCC(C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CCC(C)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 1 h

Procedure:
1-(4-Methoxycarbonyl-2-methylbutanoyl)-L-proline tert.-butyl ester (3.4 g.) is dissolved in trifluoroacetic acid (25 ml.) and the solution kept at room temperature for one hour. The trifluoroacetic acid is removed in vacuo and the residue is reprecipitated from ethyl-hexane several times. The residue is dissolved in acetonitrile (12 ml.) and 2 ml. of dicyclohexylamine is added. The crystalline salt is isolated by filtration and recrystallized from acetonitrile to yield 18 g. of 1-(4-methoxycarbonyl-2-D-methylbutanoyl)-L-proline dicyclohexylamine salt, m.p. 174°-175°. From the mother liquors the 1-(4-methoxycarbonyl-2-L-methylbutanoyl)-L-proline isomer is also separated as the dicyclohexylamine salt. The salts are converted to the acids by treatment with Dowex 50.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH:22]=1)[C:7]([NH:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([S:18]([NH2:21])(=[O:20])=[O:19])[CH2:14][CH2:13]1)=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].[CH:31]1([N:37]=[C:38]=[S:39])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH:22]=1)[C:7]([NH:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([S:18]([NH:21][C:38]([NH:37][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[S:39])(=[O:20])=[O:19])[CH2:14][CH2:13]1)=[O:8]
Reactant: COc1ccc(Cl)cc1C(=O)NCCC1CCN(S(N)(=O)=O)CC1
Reactant: S=C=NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COc1ccc(Cl)cc1C(=O)NCCC1CCN(S(=O)(=O)NC(=S)NC2CCCCC2)CC1
Yield: 44.5 %

Procedure:
376 mg (1 mmol) of 4-(2-(5-chloro-2-methoxybenzamido)ethyl)piperidine-1-sulfonamide and 652 mg (2.0 mmol) of cesium carbonate were heated in 5 ml of N-methyl-2-pyrrolidone with 0.3 ml (2 mmol) of cyclohexyl isothiocyanate at 80° C. for 10 minutes. The reaction mixture was poured onto ice/2 M hydrochloric acid, and the precipitated solid was filtered off with suction, washed with water until neutral, dissolved in methanol, filtered after addition of activated carbon and crystallized using diethyl ether. 230 mg (45%) of the title compound were obtained as a colorless solid.
Reaction SMILES: [CH2:1]([S:4][C:5]1[C:9]([Br:10])=[CH:8][S:7][CH:6]=1)[CH:2]=[CH2:3].N1C=CC=CC=1>C1(C)C=CC=CC=1>[Br:10][C:9]1[C:5]2[S:4][CH2:1][CH2:2][CH2:3][C:6]=2[S:7][CH:8]=1
Reactant: C=CCSc1cscc1Br
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Brc1csc2c1SCCC2
Yield: 89 %

Procedure:
A solution of 30.2 g (0.13 mol) of 3-allylthio-4-bromothiophene and 10.3 mls (0.13 mol) of pyridine in 250 mls of toluene was refluxed for 68 hours, cooled, washed with 1N HCl solution, 1N NaOH solution, water and brine and dried over MgSO4 and concentrated to give 27.2 g of an amber oil. The oil was chromatographed on 500 g of SiO2 eluting with hexane to give 16.2 g of the desired product as a colorless oil (90% purity).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:6](=[O:7])[CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:16])=[O:15])=[CH:10][CH:9]=2)[O:3]1.FC(F)(F)C(O[I:23](C1C=CC=CC=1)OC(=O)C(F)(F)F)=O.II>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:17])[C:6](=[O:7])[C:5]([I:23])=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:16])=[O:15])=[CH:10][CH:9]=2)[O:3]1
Reactant: CS(=O)c1ccc(C2=CC(=O)C(C)(C)O2)cc1
Reactant: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Agent: II
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CS(=O)c1ccc(C2=C(I)C(=O)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.9 %

Procedure:
To a stirred solution of 6 g of 2,2-dimethyl-5-{4-(methylsulfinyl)phenyl}-3(2H)-furanone in 200 ml carbon tetrachloride and 100 ml chloroform, were added 5.15 g of [bis(trifluoroacetoxy)iodo]benzene (BTI) and 6.5 g of iodine. The reaction solution was stirred at room temperature. After 4 hours, the reaction was quenched by adding saturated aqueous sodium thiosulfate until the characteristic color of iodine disappeared. The quenched solution was extracted with water and dichloromethane (100 ml×3). The organic layer was concentrated in vacuo and the resulting crude product was recrystallized from hexane/ethylacetate to yield 4.5 g of 2,2-dimethyl-4-iodo-5-{4-(methylsulfinyl)phenyl}-3(2H)-furanone. NMR: δ1.53 (s, 6H), 2.79 (s, 3H), 7.81 (d, J=8.1 Hz, 2H), 8.38 (d, J=8.1 Hz, 2H). IR (cm−1): 2975, 2929, 1699, 1595, 1404, 1319, 1150, 969, 766, 552.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][CH:9]2[CH2:10][CH2:11][N:12]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]3[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=3)[CH2:13][CH2:14]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C(=C(c1ccccc1)c1ccccc1)C1CCNCC1
Reactant: ClCCCCCCCCc1cccnc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C(=C(c1ccccc1)c1ccccc1)C1CCN(CCCCCCCCc2cccnc2)CC1
Temperature: 75 °C

Procedure:
The title compound was prepared in a manner similar to that employed for the compound of Example 23 above starting with 8.64 g of 4-(2,2-diphenylethenyl)piperidine, 7.4 g of 3-(8-chlorooctyl)pyridine, 4.92 g of sodium iodide, 3.48 g of sodium carbonate, and 50 mL of dimethylformamide. The mixture was stirred an heated at 75° C. for 18 hours and then evaporated to dryness. The residue was partitioned between ethyl acetate and 1N sodium hydroxide and the organic layers were dried over sodium sulfate and evaporated to give 11.0 g (74%) of crude free base. Recrystallization from hexane gave the analytically pure, 3-[8-[4-(2,2-diphenylethenyl)-1-piperidinyl]octyl]pyridine, mp 54°-55° C. Analysis Calculated for C32H40N2 : C, 84.91; H, 8.91; N, 6.19. Found: C, 84.81; H, 8.74; N, 6.14. The fumaric acid salt was crystallized from ethanol/acetone, mp 128° -129° C. Analysis Calculated for C32H40N2.C4H4O4 : C, 76.02; H, 7.80; N, 4.93. Found: C, 76.15, H, 7.79, N, 4.89.