Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[N:9])[C:3]=1[CH2:10][C:11]([OH:13])=O.C(N(CC)CC)C.[B-](F)(F)(F)F.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.Cl.[OH:44][CH2:45][C@H:46]1[CH2:55][C:54]2[C:49](=[CH:50][CH:51]=[CH:52][C:53]=2[CH2:56][CH2:57][C:58]([CH3:61])([OH:60])[CH3:59])[C@H:48]([CH3:62])[NH:47]1>C(#N)C>[Cl:1][C:2]1[C:3]([CH2:10][C:11]([N:47]2[C@@H:46]([CH2:45][OH:44])[CH2:55][C:54]3[C:49](=[CH:50][CH:51]=[CH:52][C:53]=3[CH2:56][CH2:57][C:58]([OH:60])([CH3:59])[CH3:61])[C@@H:48]2[CH3:62])=[O:13])=[C:4]([CH:5]=[CH:6][CH:7]=1)[C:8]#[N:9]
Reactant: C[C@@H]1N[C@@H](CO)Cc2c(CCC(C)(C)O)cccc21
Reactant: N#Cc1cccc(Cl)c1CC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[C@H]1c2cccc(CCC(C)(C)O)c2C[C@H](CO)N1C(=O)Cc1c(Cl)cccc1C#N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 21.6 %

Procedure:
In a vial slurry 2-(2-chloro-6-cyano-phenyl)acetic acid (75.4 mg, 0.37 mmol) in acetonitrile (0.3 mL). Add triethylamine (114 μL, 0.82 mmol) and stir until the solids dissolve. Add 0-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (165 mg, 0.51 mmol) and stir at ambient temperature for 10 min. In a separate flask slurry 4-[(1S,3R)-3-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl]-2-methyl-butan-2-ol hydrochloride (102 mg, 0.34 mol) in acetonitrile (0.3 mL). Add triethylamine (227 μL, 1.63 mmol) and a precipitate forms. Stir 10 min at ambient temperature. Transfer the 2-(2-chloro-6-cyano-phenyl)acetic acid, acetonitrile, triethylamine, and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate reaction mixture from the vial to the flask containing the 4-[(1S,3R)-3-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl]-2-methyl-butan-2-ol hydrochloride, acetonitrile and triethylamine reaction mixture. Rinse with acetonitrile (0.9 mL) and stir the homogeneous reaction mixture at ambient temperature overnight. Dilute the reaction mixture with water and extract with ethyl acetate. Wash the ethyl acetate extracts with water, saturated sodium bicarbonate solution and brine. Dry the extracts over sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue by silica gel chromatography, eluting with ethyl acetate: hexanes (0-60% gradient) to give a residue. Purify by reverse phase chromatography on C18 modified silica to yield the title compound as a green oil (34 mg, 0.08 mmol): (m/z): 441.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:9][C:8]2[N:4]([C:5]3[CH2:16][CH2:15][NH:14][C:13](=[O:17])[C:6]=3[C:7]=2C(O)=O)[CH2:3]1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.N1C2C(=CC=CC=2)C=CC=1.Cl>O.CN1C(=O)CCC1>[CH3:1][C:2]1([CH3:18])[CH2:9][C:8]2[N:4]([C:5]3[CH2:16][CH2:15][NH:14][C:13](=[O:17])[C:6]=3[CH:7]=2)[CH2:3]1
Reactant: CC1(C)Cc2c(C(=O)O)c3c(n2C1)CCNC3=O
Agent: Cl
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: CN1CCCC1=O
Solvent: c1ccc2ncccc2c1
Solvent: O
Product: CC1(C)Cc2cc3c(n2C1)CCNC3=O
Yield: 60.7 %

Procedure:
A microwave vial was charged with 137m (900 mg, 3.63 mmol), Cu2O (26 mg, 0.18 mmol), phenanthroline (66 mg, 0.36 mmol), quinoline (3 g, 23 mmol) and NMP (8 mL). The reaction mixture was microwaved at 200° C. for 3 h. See FIG. 2. Water was added and the mixture was neutralized to pH 7 by addition of 1N HCl and extracted with EA (50 mL×3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM/MeOH=10/1) to give 7,7-dimethyl-2,3,4,6,7,8-hexahydro-1H-pyrido[3,4-b]pyrrolizin-1-one 137n (450 mg, 61%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 6.18 (t, J=1.2 Hz, 1H), 5.16 (s, 1H), 3.57 (s, 4H), 2.76 (t, J=6.9 Hz, 2H), 2.64 (d, J=1.1 Hz, 2H), 1.25 (s, 6H); MS-ESI [M+H]+=205.1.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].O.[C:10](=O)(O)[O-:11].[Na+].C(C(C(Cl)=O)C(Cl)=O)C.[C:24]([O:27][CH2:28][CH3:29])(=[O:26])[CH3:25]>>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:10](=[O:11])[CH2:25][C:24]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CCOC(C)=O
Reactant: O=C([O-])O
Reactant: Nc1ccccc1F
Agent: CCC(C(=O)Cl)C(=O)Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CC(=O)Nc1ccccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-fluoroaniline (8.67 ml) in ethyl acetate (266 ml) was added water (200 ml) and sodium bicarbonate (15.12 g). Ethyl malonyl chloride (13.82 ml) was added and the solution was stirred at room temperature for 1 hour. The two layers were separated and the organic phase was washed with a saturated aqueous solution of sodium bicarbonate, water and brine, dried over sodium sulfate and evaporated to provide a brownish oil. The crude reaction mixture was used directly in the next step. LRMS (ES+) m/z 226.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:32])[N:6]2[C@H:21]1[C:30]2[C:25](=[C:26]([F:31])[CH:27]=[CH:28][CH:29]=2)[O:24][CH2:23][CH2:22]1.[CH2:33](O)[CH2:34][CH2:35][CH3:36].[C:38](#N)[CH3:39]>>[F:20][C:17]1[CH:18]=[CH:19][C:14]2[N:13]=[CH:12][N:11]([C:9]3[N:8]=[C:7]4[C:3]([NH:4][C:5](=[O:32])[N:6]4[C@H:21]4[C:30]5[C:25](=[C:26]([F:31])[CH:27]=[CH:28][CH:29]=5)[O:24][CH2:23][CH2:22]4)=[C:2]([C:33]4[CH:39]=[CH:38][CH:36]=[CH:35][CH:34]=4)[N:10]=3)[C:15]=2[CH:16]=1
Reactant: CCCCO
Reactant: O=c1[nH]c2c(Cl)nc(-n3cnc4ccc(F)cc43)nc2n1[C@@H]1CCOc2c(F)cccc21
Reactant: CC#N
Product: O=c1[nH]c2c(-c3ccccc3)nc(-n3cnc4ccc(F)cc43)nc2n1[C@@H]1CCOc2c(F)cccc21
Temperature: 110 °C
Reaction time: 1.5 h

Procedure:
General procedure for displacement reactions of 6-chloropurinones with aliphatic amines. To 10 mg (0.022 mmol) of 6-chloro-2-(6-fluoro-1H-benzo[d]imidazol-1-yl)-9-((R)-8-fluorochroman-4-yl)-7H-purin-8(9H)-one was added 0.6 mL of 1-butanol, followed by an aliphatic amine (0.1 mL), and the reaction mixture was stirred at 110° C. for 1-2 h (HPLC monitoring). Upon completion of the reaction, the mixture was left to cool to room temperature, was diluted with acetonitrile and filtered through a Nylon 0.45 μm filter. Preparative HPLC purification afforded, after solvent evaporation and drying, the desired product.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][C:12]2=[O:17])=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:25][CH:26]([CH3:32])/[CH:27]=[CH:28]/[C:29](Cl)=[O:30]>ClCCl>[CH3:25][CH:26]([CH3:32])/[CH:27]=[CH:28]/[C:29]([N:14]1[CH2:15][CH2:16][N:11]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=[CH:2][CH:3]=2)[C:12](=[O:17])[CH2:13]1)=[O:30]
Reactant: CC(C)/C=C/C(=O)Cl
Reactant: O=C1CNCCN1c1ccnc2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)/C=C/C(=O)N1CCN(c2ccnc3ccccc23)C(=O)C1

Procedure:
1-(4-Quinolyl)piperazin-2-one (23 mg, 0.1 mmol) was dissolved in dichloromethane (1 ml), triethylamine was added (21 μl, 0.15 mmol) followed by a solution of (E)-4-methylpent-2-enoyl chloride in 0.5 ml dichloromethane. The mixture was shaken briefly, washed with 5% sodium bicarbonate solution (2×), water and evaporated to dryness. The raw product was purified by preparative HPLC (gradient of water containing 0.1% ammonia and acetonitrile). 14.4 mg of a solid residue were obtained (0.044 mmol, 44%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].CC(C)(CCCCI)CC(OC)=[O:17].[O:26]1CCC[CH2:28][CH:27]1[O:32][CH:33]([CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH2:34][CH2:35][CH2:36][N:37]([CH2:41][CH2:42][CH2:43]CC(C)(C)CC(OC)=O)C(=O)C>>[C:27]([O:32][CH:33]([CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH2:34][CH2:35][CH2:36][N:37]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:41](=[O:17])[CH:42]=[CH2:43])(=[O:26])[CH3:28]
Reactant: CCCCCC(CCCN(CCCCC(C)(C)CC(=O)OC)C(C)=O)OC1CCCCO1
Reactant: COC(=O)CC(C)(C)CCCCI
Reactant: CCOC(=O)CCCCCCBr
Product: C=CC(=O)N(CCCCCCC(=O)OCC)CCCC(CCCCC)OC(C)=O

Procedure:
The synthesis of this compound is carried out as described in Example 1 except that, in Step A, the ethyl 7-bromoheptanoate is replaced by an equimolar amount of methyl 3,3-dimethyl-7-iodoheptanoate. The product of Step A is methyl 7-{N-[4-(2-tetrahydropyranyloxy)nonyl]-acetamido}-3,3-dimethylheptanoate. The subsequent step yields 7- [N-(4-hydroxynonyl)acetamido]-3,3-dimethylheptanoic acid (B).
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)([O:3][CH3:4])=[O:2].C(COC)OC.C(Cl)[Cl:37]>>[ClH:37].[C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([Cl:37])=[O:26])=[CH:23][CH:22]=1)([O:3][CH3:4])=[O:2]
Reactant: ClCCl
Reactant: COC(=O)CCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Solvent: COCCOC
Product: COC(=O)CCCCCCCCCCCCCCCNc1ccc(C(=O)Cl)cc1
Product: Cl

Procedure:
A cold solution of 25 g. of 4-(15-carbomethoxypentadecylamino)benzoic acid in 500 ml. of dimethoxyethane-methylene chloride (4:1) is prepared and dry hydrochloric acid is bubbled through the solution until no more precipitate forms. The solution is treated with 25 ml. of thionyl chloride and refluxed until all of the precipitate has redissolved. The solvents are evaporated to yield an orange, semi-crystalline mass.
Reaction SMILES: [C:1]([C:6]1[C:7](=[O:16])[O:8][C:9]2([CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:10]=1)(=O)[CH:2]([CH3:4])[CH3:3].[NH2:17][C:18]1[CH2:23][C:22]([CH3:25])([CH3:24])[CH2:21][C:20](=[O:26])[CH:19]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.O=C1O[C@H]([C@H](CO)O)C(O)=C1O>ClCCl.CCOCC.C(OC(=O)C)C>[CH:2]([C:1]1[C:6]2[C:7](=[O:16])[O:8][C:9]3([CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[C:10]=2[C:19]2[C:20](=[O:26])[CH2:21][C:22]([CH3:25])([CH3:24])[CH2:23][C:18]=2[N:17]=1)([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)C1=CC2(CCOCC2)OC1=O
Reactant: CC1(C)CC(=O)C=C(N)C1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)c1nc2c(c3c1C(=O)OC31CCOCC1)C(=O)CC(C)(C)C2
Temperature: 200 °C
Reaction time: 0.5 h

Procedure:
3.12 g 3-Isobutyryl-1,8-dioxaspiro[4.5]dec-3-en-2-one and 2.13 g 3-amino-5,5-dimethylcyclohex-2-enone are mixed and heated to 200° C. for 10 minutes under a vacuo of 20 mbar. The mixture is cooled to room temperature, 15 ml ethylacetate are added and the mixture is stirred for 30 minutes. Then 15 ml petrole ether are added and the precipitate is isolated by filtration. The crude product is dissolved in 350 ml dichloromethane, treated with 2.46 g 2,3dichloro-5,6-dicyano-p-benzoquinone and stirred for 18 hours. 2 g Ascorbic acid are added and the mixture is stirred for 10 minutes. The it is washed for three times with water. The organic phase is dried with sodium sulphate and the solvents are evaporated in vacuo. The residue is chromatographed on silica gel (petrole ether/ethylacetate 100:0 to 50:50).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[Na]>ClCCl.C(O)(=O)C.FC(F)(F)C(O)=O>[F:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1ccc(F)cc1
Agent: [Na]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC(=O)O
Product: Fc1ccc(NC2CCNCC2)cc1

Procedure:
Was synthesised in the same way as (A) from 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (3.59 g, 18.0 mmol), 4-fluoro-phenylamine (1.0 g, 9.0 mmol) and sodium triacetoxyborhydride (5.34 g, 25.2 mmol) in dichloromethane (40 ml) and acetic acid (3.1 ml). The deprotection was run in dichloromethane (37 ml) and trifluoro acetic acid (18 ml). Yield 1.1 g, 63%.
Reaction SMILES: [Na].[CH2:2]([O:4][C:5](=[O:16])[CH2:6][S:7][CH2:8][CH2:9][CH2:10][C:11](OCC)=[O:12])[CH3:3].CC(O)=O>CCO.CCOCC>[O:12]=[C:11]1[CH2:10][CH2:9][CH2:8][S:7][CH:6]1[C:5]([O:4][CH2:2][CH3:3])=[O:16]
Reactant: CCOC(=O)CCCSCC(=O)OCC
Agent: [Na]
Solvent: CCOCC
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C1SCCCC1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.2 %

Procedure:
To a solution of 5 g (219 mmol) of sodium in 13 mL of anhydrous EtOH and 88 mL of ether are added dropwise, at 0° C. and under argon, 20.5 g (87.5 mmol) of ethyl 4-[(2-ethoxy-2-oxoethyl)sulfanyl]butanoate. After stirring for 18 hours at room temperature, the reaction mixture is poured into a mixture of AcOH (12 mL)/ice (70 g). The medium is then concentrated under reduced pressure, and the residue obtained is taken up in 100 mL of ether, washed with brine (2×50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue obtained is purified by chromatography on silica gel, eluting with a cyclohexane/EtOAc gradient of from 0 to 10% EtOAc. 5.64 g of ethyl 3-oxotetrahydro-2H-thiopyrane-2-carboxylate are obtained in the form of a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[NH:14][C:13]([O:15][CH3:16])=[N:12][C:11]([CH2:17][CH3:18])=[C:10]2[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH:5]=[CH:6][C:7]=1[F:8].N1C=CC=CC=1.Cl[C:36]([O:38][C:39]1[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=1)=[O:37]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[N:14]([C:36]([O:38][C:39]3[CH:40]=[CH:41][C:42]([N+:45]([O-:47])=[O:46])=[CH:43][CH:44]=3)=[O:37])[C:13]([O:15][CH3:16])=[N:12][C:11]([CH2:17][CH3:18])=[C:10]2[C:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:20])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCC1=C(C(=O)OCc2ccccc2)C(c2ccc(F)c(F)c2)NC(OC)=N1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC1=C(C(=O)OCc2ccccc2)C(c2ccc(F)c(F)c2)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(OC)=N1
Reaction time: 4 h

Procedure:
Into a well-stirred solution of benzyl 6-(3,4-difluorophenyl)-4-ethyl-2-methoxy-1,6-dihydro-5-pyrimidinecarboxylate (27.5 g, 68.75 mmol) and pyridine (9.2 mL) in CH2Cl2 (300 mL) was added 4-nitrophenyl chloroformate (14.49 g, 82.5 mmol) at room temperature. The reaction mixture was stirred for 4 h and then washed with 10% aqueous KOH solution (2×150 mL). The organic layer was separated and dried over Na2SO4. The solvent was removed in vacuo and the residue was used in the next step without further purification: 1H NMR (CDCl3) δ 1.24 (t, J=7.2 Hz, 3H), 2.81-2.98 (m, 3H), 3.97 (s, 3H), 5.14 (ABq, 2H), 6.28 (s, 3H), 7.03-7.29 (m, 8H), 7.35 (d, J=9.2 Hz, 2H), 8.26 (d, J=9.2 Hz, 2H).
Reaction SMILES: Cl[S:2]([OH:5])(=[O:4])=O.[CH3:6][S:7]([C:10]1[CH:22]=[CH:21][C:13]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8].[CH3:23][NH:24][CH3:25]>O>[CH3:23][N:24]([CH3:25])[S:2]([C:18]1[CH:19]=[CH:20][C:15]([O:14][C:13]2[CH:21]=[CH:22][C:10]([S:7]([CH3:6])(=[O:8])=[O:9])=[CH:11][CH:12]=2)=[CH:16][CH:17]=1)(=[O:5])=[O:4]
Reactant: CNC
Reactant: O=S(=O)(O)Cl
Reactant: CS(=O)(=O)c1ccc(Oc2ccccc2)cc1
Solvent: O
Product: CN(C)S(=O)(=O)c1ccc(Oc2ccc(S(C)(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.6 %

Procedure:
To 15 ml (0.227 mole) of chlorosulfonic acid was added 10.0 g (0.0403 mole) of 1-(4-(methylsulfonyl)phenoxy)benzene in small portions keeping the temperature below 55° C. After the addition was complete and the mixture had stirred at ambient temperature for 10 minutes, the mixture was slowly poured over ice and water. The crystalline 4-(4-(methylsulfonyl)phenoxy)benzenesulfonyl chloride was collected by filtration, washed with water and dried. The material was dissolved in 350 ml of CH2Cl2 and 26.6 g (0.177 mole) of 30% aqueous dimethylamine was added dropwise. The reaction mixture was heated at reflux temperature for 1.5 hrs and cooled. The mixture was extracted with 3N aqueous hydrogen chloride, dried (Na2SO4) and solvent removed in vacuo, which gave 13.4 g (93.7% yield) of product. Recrystallization from ethanol, followed by purification using column chromatography with silica gel as the support and chloroform as the eluent gave purified N,N-dimethyl-4-(4-(methylsulfonyl)phenoxy)benzenesulfonamide, mp 127.5°-130° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])[CH3:2].[C:10]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:11]=1.C(O)C.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[CH2:10]([O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:1][CH3:2])[CH3:11]
Reactant: CCc1ccccc1O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1ccccc1CC
Reaction time: 18 h
Yield: 84.8 %

Procedure:
To a solution of 2-ethylphenol (6.9 g, 56.5 mmol), triphenylphosphine (15.7 g, 60 mmol) and ethanol (6 mL, excess) in tetrahydrofuran (100 mL) was added dropwise DIAD (12.1 g, 60 mmol). After stirring for 18 hours, mixture was evaporated and the residue was chromatographed on silica gel (heptane/ethyl acetate 9/1) to give 1-ethoxy-2-ethyl benzene (7.2 g) as a clear liquid. GC-MS shows one peak, RT=5.6 minutes. MS 150 (M+).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH2:19])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:20]1([C:26]2[O:30][N:29]=[C:28]([C:31](O)=[O:32])[CH:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([C:26]2[O:30][N:29]=[C:28]([C:31]([NH:19][CH2:18]/[CH:17]=[CH:16]\[CH2:15][O:14][C:10]3[CH:9]=[C:8]([CH2:7][N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH:13]=[CH:12][N:11]=3)=[O:32])[CH:27]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: O=C(O)c1cc(-c2ccccc2)on1
Product: O=C(NC/C=C\COc1cc(CN2CCCCC2)ccn1)c1cc(-c2ccccc2)on1
Yield: 50 %

Procedure:
Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenylamine and 5-phenyl-3-isoxazolecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound, melting at 105°-106° C., was obtained as colorless prisms in a 50% yield.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[CH2:15]([O:22][C:23]([C:25]1([C:56](Cl)=[O:57])[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]3[N:42]=[C:41]([C:43]4[CH:48]=[CH:47][C:46]([C:49]5[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=5)=[C:45]([F:55])[CH:44]=4)[O:40][N:39]=3)=[CH:34][CH:33]=2)[CH2:27][CH2:26]1)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>ClCCl>[CH2:15]([O:22][C:23]([C:25]1([C:56](=[O:57])[NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:26][CH2:27][N:28]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]3[N:42]=[C:41]([C:43]4[CH:48]=[CH:47][C:46]([C:49]5[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=5)=[C:45]([F:55])[CH:44]=4)[O:40][N:39]=3)=[CH:34][CH:33]=2)[CH2:29][CH2:30]1)=[O:24])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Nc1ccccn1
Reactant: O=C(Cl)C1(C(=O)OCc2ccccc2)CCN(Cc2ccc(-c3noc(-c4ccc(-c5ccccc5)c(F)c4)n3)cc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1ccccn1)C1(C(=O)OCc2ccccc2)CCN(Cc2ccc(-c3noc(-c4ccc(-c5ccccc5)c(F)c4)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of triethyl amine (0.34 g, 0.0034 mol) in dichloromethane (20 mL), 2-amino pyridine (0.152 g, 0.0016 mol) is added. A solution of 4-chlorocarbonyl-1-{4-[5-(2-fluorobiphenyl-4-yl)-[1,2,4]oxadiazol-3-yl]benzyl}-piperidine-4-carboxylic acid benzyl ester in dichloromethane (10 mL) is added slowly into the reaction mixture at 0-50 C. It is then stirred at room temperature for 1 hr. Demineralized water (15 mL) is added to the reaction mixture, organic layer is separated and the aqueous layer is extracted with (1×20 mL) dichloromethane. Combined organic layer is dried over sodium sulphate and concentrated under reduced pressure to get the crude material, which is purified by column chromatography (silica gel 230-400 mesh, n-hexane:ethyl acetate 60:40) to furnish 1-{4-[5-(2-fluorobiphenyl-4-yl)-[1,2,4]oxadiazol-3-yl]benzyl}-4-(pyridin-2-ylcarbamoyl)piperidine-4-carboxylic acid benzyl ester (138) (BS6.555).
Reaction SMILES: CS(C)=O.[C:5](Cl)(=O)[C:6](Cl)=O.[O:11]([C:19]1[CH:32]=[CH:31][C:30]2[N:29]([C:33]([O-:35])=[O:34])[CH:28]([C:36]#[C:37]/[CH:38]=[CH:39]\[C:40]#[CH:41])[C:27]34[O:42][C:22]3([CH:23]([OH:48])[C:24]([O:46][CH3:47])([O:44][CH3:45])[CH2:25][CH:26]4[CH3:43])[C:21]=2[CH:20]=1)[Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].[CH2:49](N(CC)CC)C.P([O-])([O-])([O-])=O>ClCCl>[O:11]([C:19]1[CH:32]=[CH:31][C:30]2[N:29]([C:33]([O:35][CH2:49][CH:5]=[CH2:6])=[O:34])[C@@H:28]([C:36]#[C:37]/[CH:38]=[CH:39]\[C:40]#[CH:41])[C@:27]34[O:42][C@:22]3([C:23](=[O:48])[C:24]([O:46][CH3:47])([O:44][CH3:45])[CH2:25][C@@H:26]4[CH3:43])[C:21]=2[CH:20]=1)[Si:12]([C:15]([CH3:18])([CH3:16])[CH3:17])([CH3:14])[CH3:13]
Reactant: CCN(CC)CC
Reactant: O=C(Cl)C(=O)Cl
Reactant: C#C/C=C\C#CC1N(C(=O)[O-])c2ccc(O[Si](C)(C)C(C)(C)C)cc2C23OC12C(C)CC(OC)(OC)C3O
Agent: O=P([O-])([O-])[O-]
Solvent: CS(C)=O
Solvent: ClCCl
Product: C#C/C=C\C#C[C@@H]1N(C(=O)OCC=C)c2ccc(O[Si](C)(C)C(C)(C)C)cc2[C@@]23O[C@@]12[C@@H](C)CC(OC)(OC)C3=O
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 91.6 %

Procedure:
Dimethyl sulfoxide (4.22 mL, 59.5 mmol, 15.0 equiv) was added to a solution of oxalyl chloride (3.46 mL, 39.7 mmol, 10.0 equiv) in dichloromethane (75 mL) at -78° C. After stirring at -78° C. for 20 min, a solution of allyl (6S, 6aS, 7S, 10R, 10aS)-2-(tert-butyldimethylsiloxy)-6-[(Z)-3-hexene-1,5-diynyl]-7,8,9,10-tetrahydro-10-hydroxy-9,9-dimethoxy-7-methyl-6a,10a-epoxyphenanthridine-5 (6H)-carboxylate (23, 2.30 g, 3.97 mmol, 1 equiv) in dichloromethane (75 mL) was added over 10 min via cannula to the cold reaction solution. The reaction mixture was warmed to -40° C. and was held at that temperature for 10 h. The reaction mixture was then cooled to -78° C., triethylamine (16.6 mL, 119 mmol, 30.0 equiv) was added, and the resulting solution was stirred in an ice bath for 30 min. The product solution was poured into aqueous phosphate buffer solution (pH 7, 0.05M in sodium hydrogen phosphate and 0.05M in potassium dihydrogen phosphate, 150 mL). The aqueous layer was separated and extracted further with dichloromethane (2×150 mL). The combined organic layers were dried over sodium sulfate and were concentrated. The residue was purified by flash column chromatography (2% ethyl acetate-dichloromethane initially, grading to 5% ethyl acetate-dichloromethane) to afford allyl (6S, 6aS, 7S, 10aR)-2-(tert-butyldimethylsiloxy)-6-[(Z)-3-hexene-1,5-diynyl]-7,8,9,10-tetrahydro-9,9-dimethoxy-7-methyl-10-oxo-6a,10a-epoxyphenanthridine-5 (6H)-carboxylate (24) as a light brown foam (2.10 g, 92%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:23])=[C:11]([N:15]4[CH2:22][C:21]5[CH2:20][NH:19][CH2:18][C:17]=5[CH2:16]4)[C:12]=3[F:14])[C:7](=[O:24])[C:6]([C:25]([OH:27])=[O:26])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:28](I)[CH3:29].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:23])=[C:11]([N:15]4[CH2:22][C:21]5[CH2:20][N:19]([CH2:28][CH3:29])[CH2:18][C:17]=5[CH2:16]4)[C:12]=3[F:14])[C:7](=[O:24])[C:6]([C:25]([OH:27])=[O:26])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCI
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(N3CC4=C(CNC4)C3)c(F)cc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN1CC2=C(C1)CN(c1c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c1F)C2
Temperature: 25 °C
Reaction time: 24 h
Yield: 52.8 %

Procedure:
To a solution of 1-cyclopropyl 6,8-difluoro-7-[3,7-diazabicyclo [3.3.0]-oct-1(5)-en-3-yl]-1,4-dihydro-4-oxoquinoline-3-carboxyl-ic acid (0.37 g) in dimethyl formamide (30 ml), which was prepared in Example 11, ethyliodide (0.17 g) and potassium carbonate (powder, 1 g) were added and stirred at room temperature for 24 hours. To the reaction mixture, water (100 ml) was added and the precipitate was filtered. The filter cake was purified by silica gel column chromatography (CHCl3 :methanol:acetic acid=6:3:1) to give the title compound (0.21 g, yield 52%).