Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18](O)[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].[S:29]=[C:30]1[CH:38]=[CH:37][CH:36]=[C:32]([C:33]([O-:35])=[O:34])[C:31]1=S.COC1C=CC([Te](C2C=CC(OC)=CC=2)=O)=CC=1>>[CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([SH:29])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].[C:33]([O-:35])(=[O:34])[C:32]1[CH:36]=[CH:37][CH:38]=[CH:30][CH:31]=1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=C([O-])C1=CC=CC(=S)C1=S
Agent: COc1ccc([Te](=O)c2ccc(OC)cc2)cc1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](S)CC[C@]4(C)[C@H]3CC[C@]12C
Product: O=C([O-])c1ccccc1
Yield: 67.2 %

Procedure:
5-Cholesten-3β-ol-dithionobenzoate (130 mg, 0.25 mmol) was reacted with bis-(p-methoxyphenyl)-telluroxide for 27 h. 5-Cholesten-3β-thiol-benzoate (88 mg, 70%), m.p. 160°-162° was obtained after p.l.c. (petroleum ether-ethyl acetate 20:1). The product obtained was recrystallised from ethyl acetate (65 mg, 52%), m.p. 164.5-166 (lit., 167°), νmax. (CCl4) 2800,2750,1670,1550,1250,1210,1180,920,865,810-740 (broad) and 700 cm-1, m/e 506 (M+ weak), 369, and 368 (100%).
Reaction SMILES: Br[C:2]1[C:3](Cl)=NC(Cl)=N[CH:7]=1.[Br:10][C:11]1[C:12]([NH:18][CH:19](C(C)C)[CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[N:13][C:14]([Cl:17])=[N:15][CH:16]=1>>[Br:10][C:11]1[C:12]([NH:18][CH2:19][C@@H:20]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH:2]([CH3:3])[CH3:7])=[N:13][C:14]([Cl:17])=[N:15][CH:16]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CC(C)C(CNC(=O)OC(C)(C)C)Nc1nc(Cl)ncc1Br
Product: CC(C)[C@@H](CNc1nc(Cl)ncc1Br)NC(=O)OC(C)(C)C

Procedure:
tert-butyl N-[(1S)-1-[[(5-bromo-2-chloro-pyrimidin-4-yl)amino]methyl]-2-methyl-propyl]carbamate was synthesized using 5-bromo-2,4-dichloro-pyrimidine and Intermediate E using analogous reaction conditions as described for tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamate. 1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.95-1.02 (m, 6H) 1.35-1.45 (m, 9H) 1.75-1.90 (m, 1H) 3.35-3.48 (m, 1H) 3.52-3.61 (m, 1H) 3.64-3.76 (m, 1H) 4.56 (d, J=8.49 Hz, 1H) 6.47 (s, 1H) 8.07 (s, 1H). LCMS (ESI) 393 (M+H).
Reaction SMILES: [N:1]1[C:6]2[S:7][CH:8]=[CH:9][C:5]=2[C:4](=[O:10])[NH:3][CH:2]=1.[Br:11]Br>C(O)(=O)C>[Br:11][C:8]1[S:7][C:6]2[N:1]=[CH:2][NH:3][C:4](=[O:10])[C:5]=2[CH:9]=1
Reactant: O=c1[nH]cnc2sccc12
Reactant: BrBr
Solvent: CC(=O)O
Product: O=c1[nH]cnc2sc(Br)cc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of 3H-thieno[2,3-d]pyrimidin-4-one (7.68 g, 0.056 mol) in glacial acetic acid (75 ml) was treated with bromine (7.5 ml) and stirred at ambient temperature for 4 hours. The resulting solid was collected by filtration, washed with water and dried in vacuo to give 6-bromo-3H-thieno[2,3-d]pyrimidin-4-one as a light brown solid (11.64 g), which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[N:7]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][NH2:26])=[CH:21][C:20]=1[CH2:27][OH:28])[CH:8]1[C:17]2[N:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:30][C:31](OC(C)=O)=[O:32].CCN(CC)CC.N#N>C(Cl)Cl>[C:1]([O:5][C:6](=[O:29])[N:7]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][NH:26][C:31](=[O:32])[CH3:30])=[CH:21][C:20]=1[CH2:27][OH:28])[CH:8]1[C:17]2[N:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(CN)cc1CO)C1CCCc2cccnc21
Reactant: CC(=O)OC(C)=O
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCc1ccc(CN(C(=O)OC(C)(C)C)C2CCCc3cccnc32)c(CO)c1
Yield: 99.6 %

Procedure:
To a solution of (4-aminomethyl-2-hydroxymethyl-benzyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-carbamic acid tert-butyl ester (0.86 g, 2.17 mmol) dissolved in CH2Cl2 (15 mL) was added Ac2O (0.21 mL, 2.17 mmol) and Et3N (0.31 mL, 2.17 mmol). The solution was stirred for 30 minutes under a positive pressure of N2. The reaction mixture was quenched with saturated aqueous NaHCO3 (25 mL) and extracted with CH2Cl2 (2×25 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated to afford [4-(acetylamino-methyl)-2-hydroxymethyl-benzyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-carbamic acid tert-butyl ester as a white solid (0.95 g, 99%). 1H NMR (CDCl3) δ 1.06 (s, 9H), 1.65 (m, 1H), 2.01 (m, 3H), 2.08 (m, 1H), 2.70 (m, 2H), 3.87 (d, 1H, J=15.0 Hz), 4.09 (m, 1H), 4.41 (d, 3H, J=6.0 Hz), 5.07 (d, 1H, J=12.0 Hz), 5.56 (d, 1H, J=12.0 Hz), 5.96 (m, 1H), 6.98 (m, 1H), 7.15 (s, 2H), 7.32 (d, 1H, J=6.0 Hz), 7.41 (s, 1H), 8.15 (d, 1H, J=3.0 Hz). Deprotection with TFA following General Procedure F gave N-{3-hydroxymethyl-4-{(5,6,7,8-tetrahydro-quinolin-8-ylamino)-methyl}-benzyl}-acetamide as an off-white solid. 1H NMR (CDCl3) δ 1.79 (m, 2H), 1.94 (m, 1H), 2.00 (s, 3H), 2.26 (m, 1H), 2.77 (m, 2H), 3.89 (m, 2H), 4.13 (d, 1H, J=12.0 Hz), 4.41 (m, 3H), 4.79 (d, 1H, J=12.0 Hz), 7.05 (m, 1H), 7.20 (m, 1H), 7.31 (m, 1H), 7.40 (m, 2H), 8.33 (d, 1H, J=3.0 Hz).
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]([OH:20])=O)[CH:15]=[CH:14][C:12]=2[N:13]=1)[CH2:6][CH2:7][CH3:8].[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1O.[OH-].[Na+]>CN1CCCC1=O>[CH2:5]([C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]3[O:20][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=3)[CH:15]=[CH:14][C:12]=2[N:13]=1)[CH2:6][CH2:7][CH3:8]
Reactant: CCCCc1nc2ccc(C(=O)O)cc2[nH]1
Reactant: Nc1ccccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O=S(Cl)Cl
Product: CCCCc1nc2ccc(-c3nc4ccccc4o3)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1.43 g (12 mMol) of thionyl chloride are added dropwise at 10° C. with stirring to a suspension of 2.52 g (10 mMol) of 2-n-butyl-benzimidazole-5-carboxylic acid in 15 ml of N-methylpyrrolidinone. The mixture is stirred for a further 15 minutes at ambient temperature, then 1.31 g (11 mMol) of 2-aminophenol are added and the mixture is heated to 140° C. for 2 hours. The mixture is then poured onto about 50 g of ice and 5 ml of 30% sodium hydroxide solution are added with stirring. The crude product precipitated is suction filtered and purified by column chromatography (300 g of silica gel; eluant:methylene chloride+3% ethanol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[C:12]([C:14]1[CH:15]=[C:16]([F:22])[C:17]([F:21])=[C:18]([F:20])[CH:19]=1)#[CH:13].N>>[Cl:1][C:2]1[CH:11]=[C:6]([C:7]2[CH:13]=[C:12]([C:14]3[CH:15]=[C:16]([F:22])[C:17]([F:21])=[C:18]([F:20])[CH:19]=3)[O:9][N:8]=2)[CH:5]=[N:4][CH:3]=1
Reactant: C#Cc1cc(F)c(F)c(F)c1
Reactant: ON=C(Cl)c1cncc(Cl)c1
Agent: N
Product: Fc1cc(-c2cc(-c3cncc(Cl)c3)no2)cc(F)c1F

Procedure:
The titled compound was prepared according to Method CB using the product of Example 69B (57 mg, 0.3 mmol) and 5-ethynyl-1,2,3-trifluorobenzene (Apollo, 47 mg, 0.3 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.87 (s, 1H), 7.92 (dd, J=8.6, 6.6 Hz, 2H), 8.39 (t, J=2.0 Hz, 1H), 8.82 (d, J=2.4 Hz, 1H), 9.04 (d, J=1.7 Hz, 1H) ppm; MS (DCI/NH3) m/z 311 (M+H)+, 313 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][C@H:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[N:12]4[C:23](=[O:25])[NH:24][C:10]([C:11]=34)=[C:9]([CH:26]=C)[CH:8]=2)=[C:5]([CH3:28])[O:4][N:3]=1.I([O-])(=O)(=O)=[O:30].[Na+]>O.O1CCCC1.C(OCC)(=O)C>[CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][C@H:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[N:12]4[C:23](=[O:25])[NH:24][C:10]([C:11]=34)=[C:9]([CH:26]=[O:30])[CH:8]=2)=[C:5]([CH3:28])[O:4][N:3]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1cc(-c2c(C)noc2C)c2c3c1[nH]c(=O)n3[C@@H](c1ccccn1)CO2
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1cc(C=O)c2[nH]c(=O)n3c2c1OC[C@@H]3c1ccccn1
Temperature: 60 °C
Yield: 47 %

Procedure:
A mixture of (4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-9-vinyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (1690 mg, 4.51 mmol) in water (7.8 mL) and tetrahydrofuran (104 mL) was treated with sodium metaperiodate (2.90 g, 13.5 mmol) and heated at 60° C. for 1 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over magnesium sulfate, filtered, and concentrated to give the crude product. Purification by flash column chromatography (50% ethyl acetate/hexanes to 100% ethyl acetate/hexanes) gave the desired product (0.797 g, 47%) as a single enantiomer. LCMS calculated for C20H17N4O4 (M+H)+: m/z=377.1. found: 376.9.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][OH:11].N1C=CC=CC=1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>CCOCC>[S:24]([C:21]1[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=1)([O:11][CH2:10][CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])(=[O:26])=[O:25]
Reactant: OCCCc1ccccc1F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)OCCCc2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
17.75 gm of the compound prepared in (3) above was dissolved into 200 ml of dry pyridine. To this was slowly added 24.25 gm of p-toluenesulfonyl chloride at 0° C. and the mixture was stirred for 3 hours at room temperature. After the addition of 300 ml of ether, the mixture was washed with water, followed by the addition of 6 N hydrochloric acid to acidify it and washing with saturated brine. The product was dried over anhydrous sodium sulfate and the solvent was evaporated to obtain 31.3 gm of the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([CH:9]1[O:11][CH2:10]1)Cl.CC(C)([O-])C.[K+]>C(O)(C)(C)C.O1CCCC1>[O:11]1[CH2:10][CH:9]1[CH2:7][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: ClCC1CO1
Reactant: C1CCNCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: C1CCN(CC2CO2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Piperidine (3 ml) was dissolved in t-butyl alcohol (1.2 ml), and the solution was added dropwise with (±)-epichlorohydrin (2.45 ml) on an ice bath. The mixture was slowly warmed to room temperature as it was, and stirred for 18 hours. Then, the mixture was added dropwise with a solution of potassium t-butoxide (3.39 g) in tetrahydrofuran (18 ml) under ice cooling so that the internal temperature should not exceed 15° C. After the addition, the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, the resulting residue was added to distilled water, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, then dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform:methanol=50:1) to obtain the title compound (1.55 g).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.I[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu].CN(C)C=O>[C:15]1([CH3:18])[CH:16]=[CH:17][C:12]([N:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)=[CH:13][CH:14]=1
Reactant: Cc1ccc(I)cc1
Reactant: c1ccc2c(c1)CCCN2
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(N2CCCc3ccccc32)cc1

Procedure:
Under the atmosphere of nitrogen, 4 parts of 1,2,3,4-tetrahydroquinoline, 20 parts of 4-iodotoluene, 20 parts of dimethylformamide (DMF), 10 parts of potassium carbonate, and 1 part of copper powder (200 mesh) were stirred at 160° C. for 10 hours. After the reaction, the resultant was extracted with water/ethyl acetate, and the ethyl acetate phase was dried over magnesium sulfate. Ethyl acetate was distilled off, and the residue was separated and purified by column chromatography to yield 5 parts of a precursor of the compound (303), 1,2,3,4-tetrahydro-1-p-tolylquinoline as a colorless crystal. Next, 1.7 parts of phosphorus oxychloride were dropwise added to 10 parts of chloroform and 1 part of N,N-dimethylacrolein, the temperature of which was adjusted to 5° C., while the temperature of the reaction solution was kept at 10° C. or lower. The reaction solution was then stirred at 5° C. for 1 hour. Thereafter, 2.0 parts of 1,2,3,4-tetrahydro-1-p-tolylquinoline described above were added thereto, and then the reactive components were caused to react at 25° C. for 1 hour. The reaction solution was then stirred at 70° C. for 1 hour. Thereafter, a 20% solution of sodium hydroxide in water was added to the reaction solution until the pH turned to 12. The precipitated crystal was filtrated, and the resultant crystal was washed with water. The crystal was then separated by column chromatography (hexane/ethyl acetate), and recrystallized from ethanol to yield 1.8 parts of the compound (303) as a yellow crystal.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:25])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[NH:6][C:5]1=[O:24])[CH:2]=[CH2:3].Cl[C:27]1[C:32]([CH3:33])=[CH:31][C:30]([N+:34]([O-:36])=[O:35])=[CH:29][N:28]=1>>[CH2:1]([C@@:4]1([CH3:25])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C:27]2[C:32]([CH3:33])=[CH:31][C:30]([N+:34]([O-:36])=[O:35])=[CH:29][N:28]=2)[C:5]1=[O:24])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)NC1=O
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(c2ncc([N+](=O)[O-])cc2C)C1=O

Procedure:
The title compound was prepared from (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one (Example 71, Step D) and 2-chloro-3-methyl-5-nitropyridine as described in Example 111, Step A to provide a light-yellow solid.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1)(=O)[CH3:2].[CH2:13](Br)C=C>>[CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1)[CH:2]=[CH2:13]
Reactant: C=Cc1ccc(OC(C)=O)cc1
Reactant: C=CCBr
Product: C=CCOc1ccc(C=C)cc1
Yield: 82 %

Procedure:
The reaction described in Example 1 was repeated on the same scale but with the reaction temperature maintained in the range of 4°-6° C., rather than 10° C., during the addition of 4-acetoxystyrene and allyl bromide. In this case, 4-allyloxystyrene was obtained in 82% yield following vacuum distillation. Residual concentrations of 4-acetoxystyrene and 4-vinylphenol were 4 and 9% respectively.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][C:4]([NH:16]C(=O)C2C(C)=CC=CC=2C)=[N:3]1.[I-].[Na+].B(F)(F)F.CCOCC>C(#N)C>[NH2:16][C:4]1[CH:5]=[C:6]([CH2:7][O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:2]([CH3:1])[N:3]=1
Reactant: Cc1cccc(C)c1C(=O)Nc1cc(COCc2ccccc2)n(C)n1
Agent: FB(F)F
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOCC
Product: Cn1nc(N)cc1COCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.8 %

Procedure:
To a cooled (0° C.) suspension of N-(1-methyl-5-benzyloxymethylpyrazol-3-yl)-2,6-dimethyl benzamide (9 g, 0.025M) and sodium iodide (19 g, 0.125M) in acetonitrile (250 ml) was added boron trifluoride etherate (18,3 g, 0,125M) in acetonitrile (60 ml) under nitrogen atmosphere. After being stirred for 2 hours at room temperature and usual work-up, the crude material was purified by column chromatography on silica gel using CH2Cl2, then CH2Cl2 /CH3OH=97.5/2.5 and 95/5 as eluents to give 1.5 g (23%) of a white solid.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH2:12]1[C:15]2([C@H:19]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:18][NH:17][CH2:16]2)[CH2:14][CH2:13]1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.O>[C:23]([O:22][C:21]([NH:20][C@H:19]1[C:15]2([CH2:14][CH2:13][CH2:12]2)[CH2:16][N:17]([C:2]([O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:3])[CH2:18]1)=[O:27])([CH3:26])([CH3:24])[CH3:25]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNCC12CCC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)CC12CCC2
Reaction time: 0.75 h

Procedure:
Benzyl chloroformate (0.224 mL, 1.569 mmol) was added dropwise to a stirred solution of (S)-tert-butyl 6-azaspiro[3.4]octan-8-ylcarbamate (0.2368 g, 1.046 mmol) in dichloromethane (7 mL) and a solution of sodium carbonate (69.1 mg, 0.652 mmol) in Water (1.05 mL) @ 0° C. Stirring of the biphasic reaction was continued @ 0° C. for 45 minutes. +/−MS analysis after 16 hrs indicated that essentially no starting material remained (m/e 361.3, M+H for desired product). A small amount of water was added and the layers were separated. The CH2Cl2 layer was washed with brine, dried over Na2SO4, and concentrated under vacuum to yield 0.433 g of the desired product as a viscous yellow oil. Flash chromatography on silica gel (Teledyne-Isco RediSep Rf 12 g column), eluting with 100 mL ea of 95:5, 90:10, and 200 mL of 80:20 hexane:EtOAc yielded 0.324 g of the title compound as a viscous colorless oil that slowly solidifies upon standing under vacuum to a white solid. +/−MS: m/e 361.3 (M+H), 305.2 (M+H-56 isobutylene), 261.2 (M+H-Boc). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.45-7.32 (m, 5H), 5.15 (s, 2H), 4.53 (br. s., 1H), 4.14-4.01 (m, 1H), 3.70-3.50 (m, 2H), 3.47-3.24 (m, 2H), 2.19-2.09 (m, 1H), 2.05-1.83 (m, 5H), 1.49 (s, 9H).
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:8]([O:18][CH2:19][CH2:20][CH2:21]OS(C)(=O)=O)=[CH:9][C:10]3[O:15][C:14](=[O:16])[CH:13]=[CH:12][C:11]=3[CH:17]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:27]1([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CC(OC)(C)C.C([O-])(=O)/C=C/C([O-])=O>CC(C)=O.C(O)(C)C>[CH:1]1([O:6][C:7]2[C:8]([O:18][CH2:19][CH2:20][CH2:21][N:36]3[CH2:35][CH2:34][CH:33]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:38][CH2:37]3)=[CH:9][C:10]3[O:15][C:14](=[O:16])[CH:13]=[CH:12][C:11]=3[CH:17]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: CS(=O)(=O)OCCCOc1cc2oc(=O)ccc2cc1OC1CCCC1
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CC(C)=O
Solvent: CC(C)O
Solvent: COC(C)(C)C
Product: O=c1ccc2cc(OC3CCCC3)c(OCCCN3CCC(c4ccccc4)CC3)cc2o1
Yield: 48 %

Procedure:
Method B (30 h at 45° C.); starting materials: 6-(cyclo-pentyloxy)-7-[3-(methanesulfonyloxy)propoxy]-2H-1-benzopyran-2-one (example 72) and 4-phenylpiperidine; yield 48%; fusion point 96°-97° C. (from TBME and isopropanol). Fumarate: method E; yield 83%; fusion point 171°-173° C. (from acetone).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:35](Cl)(Cl)=[O:36].CC1(C)[O:44][C@@H:43]([CH2:45][CH2:46][NH2:47])[CH2:42][O:41]1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C(Cl)Cl.CO>[OH:44][C@H:43]([CH2:42][OH:41])[CH2:45][CH2:46][NH:47][C:35]([N:9]1[CH2:10][CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[F:22])([C:13]#[N:14])[CH:8]1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)=[O:36]
Reactant: CC1(C)OC[C@H](CCN)O1
Reactant: O=C(Cl)Cl
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1F
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)CC1CN(C(=O)NCC[C@H](O)CO)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 43.8 %

Procedure:
To a mixture of rac-(2S,3S,4S)-2-(3-chloro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (40.5 mg, 0.10 mmol) and triethylamine (TEA, 20.0 mg, 0.20 mmol) in CH2Cl2 (1 mL) was added phosgene solution (Aldrich, 20% in toluene, 0.12 mL, 0.12 mmol) by injection, and the reaction mixture was stirred at rt for 20 min. 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (29.4 mg, 0.20 mmol) was then added. The reaction mixture was stirred at rt for another 30 min then concentrated to give the crude product (checked by LCMS) which was diluted with MeOH and treated with PPTS (cat.) at 120° C. for 5 min with CEM microwave reactor. The reaction mixture was concentrated and diluted with CH2Cl2 and washed with water and brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by RP-HPLC to give rac-(2S,3S,4S)-2-(3-chloro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide (23.5 mg, 43.8%, 2 steps) as a white amorphous. HRMS (ES+) m/z Calcd for C27H32Cl2FN3O3+H [(M+H)+]: 536.1878; Found: 536.1879.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[S:7])([CH3:3])[CH3:2].[OH:13][CH:14]1[CH2:17][O:16][CH2:15]1.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([O:13][CH:14]1[CH2:17][O:16][CH2:15]1)=[S:7])([CH3:3])[CH3:2]
Reactant: OC1COC1
Reactant: CC(C)c1ccccc1C(=S)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)c1ccccc1C(=S)OC1COC1
Reaction time: 3 h
Yield: 89 %

Procedure:
##STR16## A mixture of 12.9 g of 2-isopropylthiobenzoyl chloride and 20 ml of absolute toluene is added dropwise to a mixture of 4.44 g of 3-hydroxyoxetane, 6.64 g of pyridine and 60 ml of absolute toluene at a temperature of 15° to 20° C. The suspension formed is stirred at a temperature of 20°-25° C. for 2 hours and at a temperature of 40°-45° C. for a further 3 hours. Adding water to the reaction mixture, washing the organic phase with water and drying and evaporating it gives 12.6 g of oxetan-3-yl 2-isopropylthiobenzoate as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:29][CH3:30])[C:5]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[CH3:12].Br[CH:32]([CH3:47])[CH2:33][CH2:34][CH2:35][N:36]1[C:40](=[O:41])[C:39]2=[CH:42][CH:43]=[CH:44][CH:45]=[C:38]2[C:37]1=[O:46]>CCN(CC)CC>[CH3:30][O:29][C:4]1[C:5]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:6]2[C:11](=[C:2]([NH:1][CH:32]([CH3:47])[CH2:33][CH2:34][CH2:35][N:36]3[C:40](=[O:41])[C:39]4=[CH:42][CH:43]=[CH:44][CH:45]=[C:38]4[C:37]3=[O:46])[CH:3]=1)[N:10]=[CH:9][CH:8]=[C:7]2[CH3:12]
Reactant: CC(Br)CCCN1C(=O)c2ccccc2C1=O
Reactant: COc1cc(N)c2nccc(C)c2c1OCCCCCCCCCc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc(NC(C)CCCN2C(=O)c3ccccc3C2=O)c2nccc(C)c2c1OCCCCCCCCCc1ccccc1
Reaction time: 2 h
Yield: 72.4 %

Procedure:
A stirred mixture of 8-amino-6-methoxy-4-methyl-5-(9-phenylnonoxy) quinoline (0.85 g, 0.002 mol) and 4-bromo-1-phthalimidopentane (BPP) (2.4 g, 0.008 mol) was heated at 125°-135° C. while Et3N (1 ml) was added in small portions during 0.5 hr. After 2 h, second portions of BPP (0.6 g) and Et3N (2 drops) were introduced. Identical additions of BPP (0.6 g) and Et3N (2 drops were made three more times at 1 h intervals. The mixture was allowed to cool, extracted with Et2O and the extract was treated with Darco and evaporated to dryness. The residue was redissolved in Et2O (100 ml) and treated with an excess of ethereal hydrogen chloride. The resulting dark red precipitate was separated by decantation, basified with ethereal Et3N and the solvent was evaporated. The residual brown oil was dissolved in CHCl3, placed on a silica gel column (100 g) and eluted with CHCl3. Concentration of the eluate provided 0.9 g (72%) of 6-methoxy-4-methyl-8-(1-methyl-4-phthalimidobutylamino)-5-(9-phenylnonoxy) quinoline as a pale brown oil which was used without further purification.