Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:20]([CH:21]=[O:22])=[C:19]([CH:23]([CH3:25])[CH3:24])[CH:18]=[C:17]3[C:9]=2[C:10](=[O:26])[CH2:11][C:12]2([O:16]3)[CH2:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[F:27][C:28]([F:39])([F:38])[O:29][C:30]1[CH:35]=[CH:34][C:33]([Mg]Br)=[CH:32][CH:31]=1.C(=O)(O)[O-].[Na+]>O1CCCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:20]([CH:21]([OH:22])[C:33]3[CH:32]=[CH:31][C:30]([O:29][C:28]([F:27])([F:38])[F:39])=[CH:35][CH:34]=3)=[C:19]([CH:23]([CH3:24])[CH3:25])[CH:18]=[C:17]3[C:9]=2[C:10](=[O:26])[CH2:11][C:12]2([O:16]3)[CH2:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C=O)C(=O)CC1(CCC1)O2
Reactant: FC(F)(F)Oc1ccc([Mg]Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(O)c1ccc(OC(F)(F)F)cc1)C(=O)CC1(CCC1)O2
Temperature: -70 °C
Reaction time: 1 h

Procedure:
Under argon, 0.60 g (1.70 mmol) of 5-(4-fluorophenyl)-7-isopropyl-4-oxo-3,4-dihydrospiro-[chromen-2,1′-cyclobutane]-6-carbaldehyde (Example 51A) is suspended in 15 ml of tetrahydrofuran and cooled to −70° C. 4.3 ml (2.13 mmol) of a freshly prepared 0.5 M solution of [4-(trifluoromethoxy)phenyl]magnesium bromide in tetrahydrofuran are added slowly. The mixture is stirred briefly at −78° C. and then warmed to 0° C. After 1 h, the mixture is hydrolyzed with sodium bicarbonate solution, diluted with water and extracted repeatedly with ethyl acetate. The combined organic phases are washed twice with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The crude product is purified on a silica gel column (mobile phase: cyclohexane/ethyl acetate 25:1→10:1). This gives 710 mg (81% of theory) of the title compound in a purity of 70%.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].C([C:7]1[N:8]=[C:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[S:10][CH:11]=1)C.[OH-].[K+].Cl>C(O)C.C(OCC)(=O)C>[CH2:12]([C:9]1[S:10][CH:11]=[C:7]([CH2:2][C:1]([OH:4])=[O:3])[N:8]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CC(=O)O
Reactant: CCCCCCCCCCCCCc1nc(CC)cs1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCc1nc(CC(=O)O)cs1

Procedure:
Ethyl-2-tridecyl-thiazole acetate (2.13 g, 6.35 mmol) and potassium hydroxide (0.39 g, 6.98 mmol) were refluxed overnight in ethanol (200 mL). The mixture was then acidified with 1M HCl and the precipitate filtered to give a solid which was dissolved in ethyl acetate and washed with brine, dried (MgSO4), filtered concentrated, and triturated with hexanes. The solid was filtered and air dried to yield 0.75 g, 37%. %C,H,N(found): C, 66.16; H, 9.50; N 3.99.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C(N(CC)CC)C.[C:12]([NH:16][C:17]1[O:18][C:19]([C:26](Cl)=[O:27])=[C:20]([C:22]([F:25])([F:24])[F:23])[N:21]=1)([CH3:15])([CH3:14])[CH3:13]>C(Cl)Cl>[CH3:13][C:12]([NH:16][C:17]1[O:18][C:19]([C:26]([NH:4][CH2:3][CH2:1][OH:2])=[O:27])=[C:20]([C:22]([F:25])([F:24])[F:23])[N:21]=1)([CH3:15])[CH3:14]
Reactant: NCCO
Reactant: CC(C)(C)Nc1nc(C(F)(F)F)c(C(=O)Cl)o1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)Nc1nc(C(F)(F)F)c(C(=O)NCCO)o1
Yield: 34.3 %

Procedure:
By the procedure of Example 38, a stirred mixture of 50 ml methylene chloride, 0.70 g (11.46 mmol) of ethanolamine, 1.27 g (12.61 mmol) of triethylamine, and 3.1 g (11.46 mmol) of 2-(tert-butylamino)-4-trifluoromethyl-5-oxazolecarbonyl chloride, was reacted for 64 hours at ambient temperature. The product was separated and then recrystallized to yield 1.16 g of a yellow solid product (m.p.=154°-156° C.) identified in Table 1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C:5](Cl)=[N:6][CH:7]=1.C[O-].[Na+].[C:23](=O)(O)[O-:24].[Na+].Cl>>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C:5]([O:24][CH3:23])=[N:6][CH:7]=1
Reactant: O=S(=O)(Nc1cc(Br)cnc1Cl)c1ccc(O)cc1
Reactant: O=C([O-])O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: COc1ncc(Br)cc1NS(=O)(=O)c1ccc(O)cc1
Yield: 82 %

Procedure:
N-(5-Bromo-2-chloropyridin-3-yl)-4-hydroxybenzenesulfonamide (587 mg, 1.61 mmol) and sodium methoxide (25% in methanol, 10 ml, 43.73 mmol) were stirred at 120° C. for 20 min under microwave conditions. The reaction mixture was poured into sodium bicarbonate saturated solution, neutralized with concentrated chlorohydric acid and extracted with ethyl acetate (×3). The organic phase was dried over magnesium sulphate, filtered and the solvent evaporated under reduced pressure to obtain 475 mg (82% yield, 100% purity) of the title compound, which was used in the next synthetic step without further purification.
Reaction SMILES: Br[CH2:2][C:3]#[N:4].C(N(C(C)C)C(C)C)C.[CH:14]([S:17][C:18](=[O:31])[CH2:19][C@H:20]([NH:24][C:25](=[O:30])[CH2:26][CH2:27][CH:28]=[CH2:29])[C:21]([OH:23])=[O:22])([CH3:16])[CH3:15].[Cl-].[NH4+]>CN(C=O)C>[CH:14]([S:17][C:18](=[O:31])[CH2:19][C@H:20]([NH:24][C:25](=[O:30])[CH2:26][CH2:27][CH:28]=[CH2:29])[C:21]([O:23][CH2:2][C:3]#[N:4])=[O:22])([CH3:16])[CH3:15]
Reactant: C=CCCC(=O)N[C@@H](CC(=O)SC(C)C)C(=O)O
Reactant: N#CCBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CCCC(=O)N[C@@H](CC(=O)SC(C)C)C(=O)OCC#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
2-Bromoacetonitrile (0.510 ml, 7.32 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.153 ml, 0.878 mmol) were added to a solution of (S)-4-(isopropylthio)-4-oxo-2-(pent-4-enamido)butanoic acid (Compound 1f-IB) (200 mg, 0.732 mmol) in DMF (1 ml), and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous ammonium chloride solution (1 ml) was added to the reaction mixture, after which the mixture was extracted with ethyl acetate and the organic layer was washed with water. The organic extract was then dried over magnesium sulfate. Following concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→60/40) to afford (S)-cyanomethyl 4-(isopropylthio)-4-oxo-2-(pent-4-enamido)butanoate (Compound 1g-IB) (161 mg, 70%).
Reaction SMILES: FC1C=CN=C(NC(=O)C2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)C=1.[F:26][C:27]1[CH:35]=[C:34]([B:36]2[O:40][C:39]([CH3:42])([CH3:41])[C:38]([CH3:44])([CH3:43])[O:37]2)[CH:33]=[CH:32][C:28]=1[C:29]([OH:31])=O.[CH2:45]([C:48]1[CH:53]=[CH:52][N:51]=[C:50]([NH2:54])[CH:49]=1)[CH2:46][CH3:47]>>[F:26][C:27]1[CH:35]=[C:34]([B:36]2[O:40][C:39]([CH3:42])([CH3:41])[C:38]([CH3:44])([CH3:43])[O:37]2)[CH:33]=[CH:32][C:28]=1[C:29]([NH:54][C:50]1[CH:49]=[C:48]([CH2:45][CH2:46][CH3:47])[CH:53]=[CH:52][N:51]=1)=[O:31]
Reactant: CC1(C)OB(c2ccc(C(=O)O)c(F)c2)OC1(C)C
Reactant: CCCc1ccnc(N)c1
Agent: CC1(C)OB(c2ccc(C(=O)Nc3cc(F)ccn3)cc2)OC1(C)C
Product: CCCc1ccnc(NC(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2F)c1
Yield: 63.3 %

Procedure:
This compound was prepared, in an analogous manner as described in Intermediate 4, starting from commercially available 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid and 4-propyl-pyridin-2-ylamine, to afford the title compound (830 mg, 63.3%).
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][N:21]3[CH:24]=[CH:25][CH:26]=[C:20]3[CH:19]=2)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:34][CH2:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C)C=O.O>[C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:34][CH2:35][O:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][N:21]3[CH:24]=[CH:25][CH:26]=[C:20]3[CH:19]=2)=[CH:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(O)cc12
Reactant: ICCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCOc3ccccc3)cc12
Yield: 38.1 %

Procedure:
A mixture of 6-hydroxy-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl-oxime (example 81A) (150 mg, 0.43 mmol), cesium carbonate (280 mg, 0.85 mmol) and (2-Iodo-ethoxy)-benzene (413 mg, 3.87 mmol), in dimethylformamide (6 rill) was stirring at room temperature for 24 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were washed with a saturated solution of ammonium chloride, water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography over silica gel (gradient cyclohexane/ethyl acetate: 0-10%) to yield the title compound (77 mg, 38%) as a yellow solid.
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([OH:21])[C@@H:5]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[BH4-].[Na+].Cl>C(O)C.O>[C:17]([O:16][C:14]([NH:13][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[C@@H:4]([OH:21])[CH2:3][OH:2])=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: COC(=O)[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CO
Temperature: 20 °C
Reaction time: 2.5 h
Yield: 72.6 %

Procedure:
A solution of N-tert-butoxycarbonyl-3(S)-amino-2(R)-hydroxy-4-phenylbutyric acid methyl ester 99 g dissolved in ethanol 130 ml was kept at 15-25° C. and mixed with sodium borohydride 15.7 g and stirred at 15-25° C. for 2.5 hrs. The reaction solution was diluted with water, adjusted with 6N-HCl to pH 2.5-3.5 and thereafter the solvent was distilled away to half the volume of the resultant solution, and then ethyl acetate was added to the solution. The solution thus obtained was washed with water and aqueous 10% sodium chloride solution successively to separate an organic phase. The solvent in the organic phase was distilled away and then ethyl acetate was added to the resultant concentrated solution to cool it and n-heptane was added to the solution halfway. Further n-heptane was added to the cloudy solution obtained. Thereafter, the solution was stirred at 10° C. to deposit crystals, which were filtered and dried in vacuum to obtain the N-tert-butoxycarbonyl-3(S)-amino-2(R)-hydroxy-4-phenyl-1-butanol(65.4 g).
Reaction SMILES: [S:1]([O-])([O-])(=O)=[S:2].[Na+].[Na+].Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20].II.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>O1CCOCC1.O>[C:19]([OH:21])(=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][S:1][S:2][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20]
Reactant: O=C(O)CCCCCCCCCCBr
Reactant: O=S([O-])([O-])=S
Agent: II
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CCCCCCCCCCSSCCCCCCCCCCC(=O)O
Temperature: 90 °C

Procedure:
Sodium thiosulfate (55.3 g; 350 mmol) is added to a suspension of 11-bromo-undecanoic acid (92.8 g, 350 mmol) in 50% aqueous 1,4-dioxane (1000 ml). The mixture is heated at reflux (90° C.) for 2 h until the reaction to the intermediate Bunte salt was complete (clear solution). The oxidation to the corresponding disulfide is carried out in situ by adding iodine in portions until the solution retained with a yellow to brown color. The surplus of iodine is retitrated with 15% sodium pyrosulfite in water. After removal of 1,4-dioxane by rotary evaporation the creamy suspension is filtered to yield product 11,11′-dithiobis(undecanoic acid). Recrystallization from ethyl acetate/THF provides a white solid (73.4 g, 96.5%): mp 94° C.; 1H NMR (400 MHz, CDCl3 /CD3OD 95:5): δ 2.69 (t, 2H, J=7.3 Hz), 2.29 (t, 2H, J=7.5 Hz), 1.76-1.57 (m, 4H), and 1.40-1.29 (m, 12H); FAB-MS (Cs+, 20 keV): m/z (relative intensity) 434 (100, M+). Anal: Calcd. for C22H42O4S2: C, 60.79; H, 9.74; S, 14.75. Found: C, 60.95; H, 9.82; S, 14.74. To a solution of 11,11′-dithiobis(undecanoic acid). (1.0 g, 2.3 mmol) in THF (50 ml) is added N-hydroxysuccinimide (0.575 g, 5 mmol) followed by DCC (1.03 g, 5 mmol) at 0° C. After the reaction mixture is allowed to warm to 23° C. and is stirred for 36 h at room temperature, the dicyclohexylurea (DCU) is filtered. Removal of the solvent under reduced pressure and recrystallization from acetone/hexane provides 11,11′-dithiobis(succinimidylundecanoate)as a white solid. Final purification is achieved by medium pressure liquid chromatography (9 bar) using silica gel and a 2:1 mixture of ethyl acetate and hexane. The organic phase is concentrated and dried in vacuum to afford 11,11′-dithiobis(succinimidylundecanoate) (1.12 g, 78%): mp 95° C.; 1H NMR (400 MHz, CDCl3): δ 2.83 (s, 4H), 2.68(t, 2H, J=7.3 Hz), 2.60 (t, 2H, J=7.5 Hz), 1.78-1.63 (m, 4H), and 1.43-1.29 (m, 12H); FAB-MS (Cs+, 20 keV): m/z (relative intensity) 514 (100), 628 (86, M+). Anal. Calcd. for C30H48N2O8S2: C, 57.30; H, 7.69; N, 4.45; S, 10.20. Found: C, 57.32; H 7.60; N, 4.39; S, 10.25.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Cl)=[CH:6][C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1OCCOCCOCCOCCOCCOC1.[OH:37][C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1.[K]>C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:37][C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)=[CH:6][C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Oc1cccnc1
Reactant: COC(=O)c1ccc(CCl)cc1-c1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(COc2cccnc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 50.2 %

Procedure:
To a solution of 11.1 g (42.3 mmol) of 4-chloromethyl-2-phenylbenzoic acid methyl ester, prepared as in Example 187A, in 150 mL of toluene was added 1.7 g (6.4 mmol) of 18-Crown-6, and 8.40 g (63.1 mmol) of 3-hydroxypyridine, potassium salt. The reaction was stirred at ambient temperature for 20 minutes, then heated to reflux under N2. After 3 hours, the mixture was poured into 100 mL of water. The layers were separated, then the aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic layers were back extracted with 2M aqueous NaOH (2×30 mL), brine (1×100 mL), dried over magnesium sulfate, filtered, and concentrated to an oil which slowly crystallized. The product was recrystallized from 50 mL of 2-propanol to give 6.78 g of a tan solid. The supernatant was concentrated and purified via silica gel chromatography (50:50 hexanes:ethyl acetate) to give another 2.18 g of product, for a total yield of 8.96 g (66%). 1H NMR (300 MHz, d6-DMSO) δ 3.60 (s, 3H), 5.33 (s, 2H), 7.28-7.54 (m, 8H), 7.57 (dd, J=1.5, 9.0 Hz, 1H), 7.78 (d, J=9 Hz, 1H), 8.18 (dd, J=1.0, 5.5 Hz, 1H), 8.38 (d, J=3.0 Hz, 1H).
Reaction SMILES: F[C:2](F)(F)C(O)=O.ICI.[F:11][C:12]([F:21])([CH2:18][CH:19]=[CH2:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14].Cl>ClCCl.[Cu].[Zn]>[CH:19]1([CH2:18][C:12]([F:21])([F:11])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:2][CH2:20]1
Reactant: O=C(O)C(F)(F)F
Reactant: C=CCC(F)(F)C(=O)OCC
Agent: [Cu]
Agent: Cl
Agent: [Zn]
Solvent: ClCCl
Solvent: ICI
Product: CCOC(=O)C(F)(F)CC1CC1
Temperature: 2.5 °C

Procedure:
Zinc-copper (Zn—Cu) couple (1.6 Kg, 800 mol %) and dichloromethane (7.5 L) was charged into a dry 20.0 L, 4-neck round bottomed flask, fitted with an over head stirrer, a thermo socket and a condenser under a nitrogen atmosphere. Trifluoroacetic acid (235 mL, 100 mol %) was added to the above Zn—Cu couple at ambient temperature via addition funnel over 30 minutes. Diiodomethane (860 mL; 2.86 Kg; 10.7 mol; 352 mol %) was added to above the Zn—Cu couple at ambient temperature via addition funnel over 1.5 hours. The reaction temperature was raised to reflux and then ethyl 2,2-difluoropent-4-enoate (500 g; 3.05 mol) in dichloromethane (500 mL) was added slowly via addition funnel over 30 minutes at reflux. The reaction temperature was maintained for 40-60 hours at reflux. Progress of the reaction was monitored by GC analysis which showed about 93% conversion to product based on relative area % of the peaks corresponding to product and starting material. The reaction mass was cooled to 0-5° C. and 5% dilute hydrochloric acid (500 mL) was added then the solution was filtered and washed with dichloromethane (1500 mL). The filtrate was washed with a solution of 5% aqueous hydrochloric acid (500 mL), water (1000 mL) followed by a solution of brine (1000 mL). The organic layer was concentrated under vacuum at 35° C./260-360 mm Hg to provide crude ethyl 3-cyclopropyl-2,2-difluoropropanoate (740 g), which was 79% pure by GC analysis. The crude product was then subjected to an oxidative work-up as described below to remove residual starting material (5% by area as determined by GC analysis).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N(C(C)C)CC)(C)C.[CH:32]1([C:35]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)=[O:36])[CH2:34][CH2:33]1.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[CH:32]1([C:35]([N:37]2[CH2:42][CH2:41][N:40]([C:4]([C:3]3[CH:7]=[C:8]([CH:9]=[CH:10][C:2]=3[F:1])[CH2:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15](=[O:22])[NH:14][N:13]=3)=[O:6])[CH2:39][CH2:38]2)=[O:36])[CH2:33][CH2:34]1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: O=C(C1CC1)N1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCN(C(=O)C2CC2)CC1
Temperature: 18 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
2-Fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoic acid (D)(15.23 g, 51.07 mmol) was suspended with stirring under nitrogen in acetonitrile (96 ml). Diisopropylethylamine (19.6 ml, 112.3 mmol) was added followed by 1-cyclopropylcarbonylpiperazine (I)(9.45 g, 61.28 mmol) and acetonitrile (1 ml). The reaction mixture was cooled to 18° C. 0-Benzotriazol-1-yl-tetramethyluronium hexafluorophosphate (25.18 g, 66.39 mmol) was added over 30 minutes and the reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was cooled to 3° C. and maintained at this temperature for 1 hour, before being filtered. The filter cake was washed with cold (3° C.) acetonitrile (20 ml) before being dried in vacuo at up to 40° C. to give the title compound as a pale yellow solid (20.21 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[C:12]([C:16]4([CH3:23])[NH:21][C:20](=O)[CH2:19][O:18][CH2:17]4)[CH:13]=[CH:14][CH:15]=3)=[N:7][C:6]=2[CH:24]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[C:12]([C:16]4([CH3:23])[NH:21][C:20](=[S:34])[CH2:19][O:18][CH2:17]4)[CH:13]=[CH:14][CH:15]=3)=[N:7][C:6]=2[CH:24]=1
Reactant: CC1(c2cccc(-c3nc4cc(Cl)ccc4o3)c2)COCC(=O)N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: CC1(c2cccc(-c3nc4cc(Cl)ccc4o3)c2)COCC(=S)N1
Yield: 57 %

Procedure:
In close analogy to the procedure described for the preparation of Intermediate XVIII-1, the reaction of (RS)-5-[3-(5-chloro-benzooxazol-2-yl)-phenyl]-5-methyl-morpholin-3-one with Lawesson's reagent yielded the title compound (57% of theory). MS (ISP): m/z=359.1 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][OH:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C>CS(C)=O>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH:13]=[O:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC1CCN(Cc2ccccc2)C1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=CC1CCN(Cc2ccccc2)C1

Procedure:
(1-Benzylpyrolidin-3-yl)methanol was reacted in the presence of triethylamine and sulfur trioxide-pyridine complex in dimethylsulfoxide to produce 1-benzylpyrrolidine-3-carbaldehyde.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([NH:13][CH:14]([CH:18]1[CH2:20][CH2:19]1)[CH:15]1[CH2:17][CH2:16]1)[CH2:9][CH2:8]2.[Br:21]Br>CCO.C(Cl)Cl>[Br:21][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:12]2[C:7]=1[CH2:8][CH2:9][CH:10]([NH:13][CH:14]([CH:18]1[CH2:20][CH2:19]1)[CH:15]1[CH2:17][CH2:16]1)[CH2:11]2
Reactant: COc1cccc2c1CC(NC(C1CC1)C1CC1)CC2
Reactant: BrBr
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc(Br)c2c1CC(NC(C1CC1)C1CC1)CC2

Procedure:
8-Methoxy-2-(di-cyclopropylmethylamino)tetralin (OSU427) (311 mg, 1.09 mmol) was brominated in EtOH with 1.5 ml of a solution containing 0.6 ml Br2 in 10 ml CH2Cl2). After night in room temperature, the solvent was evaporated and the raw product (HBr salt) was recrystallized from acetone/ether to give 311 mg of white crystals melting at 153°-154° C. αD20 =-51.2°. GC/MS shows M+/M+2 at m/e=363.10 (43.1%) and 365.00 (41.9%) and the base peak at m/e=160.05.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:18][CH2:19][C:20]34[CH2:29][CH:24]5[CH2:25][CH:26]([CH2:28][CH:22]([C:23]5([F:31])[F:30])[CH2:21]3)[CH2:27]4)=[CH:6][C:7]([F:17])=[C:8]([CH:16]=2)[C:9]([O:11]C(C)(C)C)=[O:10])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([C:4]2[C:5]([O:18][CH2:19][C:20]34[CH2:29][CH:24]5[CH2:25][CH:26]([CH2:28][CH:22]([C:23]5([F:31])[F:30])[CH2:21]3)[CH2:27]4)=[CH:6][C:7]([F:17])=[C:8]([CH:16]=2)[C:9]([OH:11])=[O:10])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC23CC4CC(C2)C(F)(F)C(C4)C3)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1cc(C2CC2)c(OCC23CC4CC(C2)C(F)(F)C(C4)C3)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.1 %

Procedure:
To a solution of tert-butyl 5-cyclopropyl-4-((4,4-difluoroadamantan-1-yl)-methoxy)-2-fluorobenzoate (1.0 g, 2.29 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (15 ml). The reaction mixture was stirred at ambient temperature for 2 hours and then concentrated in vacuo. The residue was triturated in mixture of dichloromethane and hexanes afforded the title compound as colorless solid (0.82 g, 94%): 1H NMR (300 MHz, DMSO-d6) δ 12.83 (s, 1H), 7.34 (d, J=8.5 Hz, 1H), 6.88 (d, J=13.1 Hz, 1H), 3.57 (s, 2H), 2.24 (br s, 2H), 2.04-1.95 (m, 2H), 1.87-1.68 (m, 10H), 0.93-0.87 (m, 2H), 0.65-0.56 (m, 2H); MS (ES+) m/z 381.1 (M+1); MS (ES−) m/z 379.2 (M−1).