Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1([CH2:26][O:27][CH3:28])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1.CCN(S(F)(F)[F:35])CC>ClCCl>[F:35][C:2]1([CH2:26][O:27][CH3:28])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1
Reactant: COCC1(O)CCN(c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)CC1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: COCC1(F)CCN(c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)CC1
Yield: 68 %

Procedure:
The title compound was prepared by reacting ((S)—N-{3-[4-(4-hydroxy-4-methoxymethyl piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.37 mmol) with DAST (4.10 mmol) in dichloromethane (10 ml) at a temperature 0° C. for one hour and by purifying the compound by silica gel column chromatography in 68% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:21][O:22][CH2:23][C:24]3[C:32]4[N:31]=[N:30][N:29]([CH3:33])[C:28]=4[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=3)[CH2:13][CH2:12][N:11]([C:14](OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].C=O>FC(F)(F)C(O)=O.C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:21][O:22][CH2:23][C:24]3[C:32]4[N:31]=[N:30][N:29]([CH3:33])[C:28]=4[CH:27]=[C:26]([C:34]([F:37])([F:35])[F:36])[CH:25]=3)[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Cn1nnc2c(COCC3(c4ccc(F)cc4)CCN(C(=O)OC(C)(C)C)CC3)cc(C(F)(F)F)cc21
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: CN1CCC(COCc2cc(C(F)(F)F)cc3c2nnn3C)(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl 4-(4-fluorophenyl)-4-(((1-methyl-6-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-4-yl)methoxy)methyl)piperidine-1-carboxylate (14 mg, 0.027 mmol) was dissolved in trifluoroacetic acid (25% in dichloromethane, 1 mL) and stirred at room temperature for 30 min. The reaction was concentrated, loaded onto a strong cation exchange cartridge in methanol, and flushed with several volumes of methanol which were discarded. The crude secondary amine was eluted in 2M ammonia and concentrated. The resulting residue was dissolved in acetonitrile (1 mL), cooled to 0° C., and treated with sodium cyanoborohydride (3.4 mg, 0.054 mmol) and formalin (75 μl). After 5 min, the reaction was treated with 1 drop of acetic acid. The ice bath was removed and stirring continued for 1 h. The reaction was diluted with ether and washed with 1M sodium hydroxide. The ethereal was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which was discarded. The product was eluted with 2 M ammonia and concentrated to give 8 mg (68%) as a colorless film. 1H-NMR (CDCl3, 500 MHz) δ 7.70 (s, 1H), 7.36 (s, 1H), 7.33 (m, 2H), 6.99 (m, 2H), 5.01 (s, 2H), 4.34 (s, 3H), 3.57 (s, 2H), 2.59 (m, 2H), 2.22 (m, 7H), 2.02 (m, 2H). Mass spec.: 437.16 (MH)+.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([F:7])=[C:4]([F:6])[F:5].[CH2:10]=[CH:11][C:12]([NH:14][C:15]([CH2:18][OH:19])([CH3:17])[CH3:16])=[O:13].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[CH2:10]=[CH:11][C:12]([NH:14][C:15]([CH2:18][O:19][C:4]([CH:3]([C:2]([F:9])([F:8])[F:1])[F:7])([F:6])[F:5])([CH3:17])[CH3:16])=[O:13]
Reactant: C=CC(=O)NC(C)(C)CO
Reactant: FC(F)=C(F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: C=CC(=O)NC(C)(C)COC(F)(F)C(F)C(F)(F)F
Reaction time: 1 h
Yield: 73.1 %

Procedure:
Hexafluoropropene (13 g, 0.086 mol) was added over 30 minutes to a stirred mixture of CH2═CH(CO)NHC(CH3)2CH2OH (5.0 g, 0.035 mol), acetonitrile (190 mL) and Cs2CO3 (1.0 g, 0.003 mol) at 15-20° C. The resultant light yellow solution was stirred for an additional 1 h, after which TLC analysis (eluting with CH2Cl2 and CH3OH; 17:1 v/v) indicated the reaction was complete. The solution was filtered, and the filtrate concentrated under reduced pressure to give CH2═CHC(O)NHC(CH3)2CH2OCF2CFHCF3 as a light brown liquid (7.5 g ). 19F NMR (CDCl3): δ−75.8 (m, 3F), −79.9 (dm, 1F), −82.8 (dm, 1F), and −212.3 (dm, 1F) ppm; 1H NMR (CDCl3): δ 6.2 (dd, 1H), 6.1 (dd, 1H), 5.6 (dd, 1H), 5.6 (brs, 1H, overlaps), 4.8 (dm, 2H, JHF=44 Hz), 4.2 (dm, 2H), 1.4 (s, 6H) ppm.
Reaction SMILES: S(O)(O)(=O)=O.[C:6]([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)(=[NH:8])[NH2:7].[OH-].[Na+].[CH2:24]([N:26]1[CH2:31][CH2:30][C:29](=O)[C:28](=[CH:33]OC)[C:27]1=[O:36])[CH3:25]>C(O)C>[CH2:15]([N:12]1[CH2:13][CH2:14][N:9]([C:6]2[N:7]=[CH:33][C:28]3[C:27](=[O:36])[N:26]([CH2:24][CH3:25])[CH2:31][CH2:30][C:29]=3[N:8]=2)[CH2:10][CH2:11]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N=C(N)N1CCN(Cc2ccccc2)CC1
Reactant: CCN1CCC(=O)C(=COC)C1=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCN1CCc2nc(N3CCN(Cc4ccccc4)CC3)ncc2C1=O
Yield: 80.8 %

Procedure:
To a suspension which had been obtained by adding 1.56 g of 1-amidino-4-benzylpiperazine sulfate to an ethanol solution of 0.23 g of sodium hydroxide, 1.07 g of 1-ethyl-3-methoxymethylenepiperidine-2,4-dione (Referential Example 37) was added. The resultant mixture was refluxed for 2 hours. After distilling off ethanol, water was added to the residue, followed by extraction with chloroform. After drying the chloroform layer, it was concentrated to obtain 1.4 g of 2-(4-benzylpiperazino)-6-ethyl-5-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (yield: 69%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=3)[NH:23][C:22]2=[O:35])[CH2:17][CH2:16]1.Br[CH2:37][C:38]#[N:39]>>[C:38]([CH2:37][N:23]1[C:24]2[C:29](=[CH:28][C:27]([N+:32]([O-:34])=[O:33])=[CH:26][CH:25]=2)[C:30](=[O:31])[N:21]([CH:18]2[CH2:19][CH2:20][N:15]([C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH2:16][CH2:17]2)[C:22]1=[O:35])#[N:39]
Reactant: N#CCBr
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)[nH]c5ccc([N+](=O)[O-])cc5c4=O)CC3)c2cc1OC
Product: COc1cc2ncnc(N3CCC(n4c(=O)c5cc([N+](=O)[O-])ccc5n(CC#N)c4=O)CC3)c2cc1OC
Yield: 27 %

Procedure:
The procedure similar to that described in Example 1 was repeated, except that 300 mg (0.63 mmol) of Compound 24 was used and bromoacetonitrile was used in place of methyl iodide. As a result, 87.3 mg (yield: 27%) of Compound 7 was obtained as pale yellow crystals.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:28])=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH:20]4[CH2:25][CH2:24][N:23](C=O)[CH2:22][CH2:21]4)[CH2:15][CH2:14]3)[CH:11]=2)[C:6](=[O:29])[C:5]([C:30]([OH:32])=[O:31])=[CH:4]1)[CH3:2].[ClH:33]>O1CCOCC1>[ClH:33].[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:28])=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH:20]4[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]4)[CH2:15][CH2:14]3)[CH:11]=2)[C:6](=[O:29])[C:5]([C:30]([OH:32])=[O:31])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(CC4CCN(C=O)CC4)CC3)cc21
Agent: Cl
Solvent: C1COCCO1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(CC4CCNCC4)CC3)cc21
Yield: 85 %

Procedure:
A solution of the N-formylquinolone from Example 18, (1.0 g, 2.25 mmol) in dioxane (20 mL) and aqueous hydrochloric acid (1N, 20 mL) was heated at 100° C. for 31/2 hours. The solvent was removed and the residue was recrystallized from methanal to give the product as a white crystalline solid (0.85 g, 85% yield).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[O:18][C@@:17]3([C:26]4[C:21](=[CH:22][C:23]([Cl:36])=[C:24]([CH2:27][C:28]5[CH:33]=[CH:32][C:31]([CH2:34][CH3:35])=[CH:30][CH:29]=5)[CH:25]=4)[CH2:20][O:19]3)[C@H:16]([OH:37])[C@@H:15]([OH:38])[C@@H:14]2[OH:39])(=O)=O)=CC=1.[F:40][C:41]([F:45])([F:44])[CH2:42][O-:43].[Na+]>>[Cl:36][C:23]1[CH:22]=[C:21]2[C:26](=[CH:25][C:24]=1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH3:35])=[CH:30][CH:29]=1)[C@:17]1([C@H:16]([OH:37])[C@@H:15]([OH:38])[C@H:14]([OH:39])[C@@H:13]([CH2:12][O:43][CH2:42][C:41]([F:45])([F:44])[F:40])[O:18]1)[O:19][CH2:20]2
Reactant: CCc1ccc(Cc2cc3c(cc2Cl)CO[C@]32O[C@H](COS(=O)(=O)c3ccc(C)cc3)[C@@H](O)[C@H](O)[C@H]2O)cc1
Reactant: [O-]CC(F)(F)F
Agent: [Na+]
Product: CCc1ccc(Cc2cc3c(cc2Cl)CO[C@]32O[C@H](COCC(F)(F)F)[C@@H](O)[C@H](O)[C@H]2O)cc1

Procedure:
To ((1S,3′R,4′S,5′S,6′R)-5-chloro-6-(4-ethylbenzyl)-3′,4′,5′-trihydroxy-3′,4′,5′,6′-tetrahydro-3H-spiro[isobenzofuran-1,2′-pyran]-6′-yl)methyl 4-methylbenzenesulfonate (14 mg, 0.024 mmol) was added 1 mL of freshly prepared sodium trifluoroethoxide solution (1.5 M). After refluxing for 5 h at temperature, the reaction was quenched with 2 mL of water. The organic solvent was distilled off and the water layer was extracted with ethyl acetate. The combined organic layers were washed with brine prior to drying over Na2SO4. Concentration under reduced pressure provided the crude product, which was purified by preparative TLC to give 6 mg of title compound. 1H NMR (CD3OD, 300 MHz) δ 7.36 (s, 1H), 7.19 (s, 1H), 7.09 (s, 4H), 5.12 (d, J=13.2 Hz, 1H), 5.07 (d, J=13.2 Hz, 1H), 4.11 (d, J=15.5 Hz, 1H), 4.05 (d, J=15.5 Hz, 1H), 3.89-3.66 (m, 7H), 3.48 (t, J=9.2 Hz, 1H), 2.59 (q, J=7.8 Hz, 2H), 1.19 (t, J=7.8 Hz, 3H); MS ESI (m/z) 503 (M+1)+, calc. 502.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=O)[O:9][CH:8]2OCC)([CH3:4])([CH3:3])[CH3:2].O.[NH2:19][NH2:20].C(O)(=O)C>O>[C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:9])[NH:20][N:19]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CCOC1OC(=O)c2ccc(C(C)(C)C)cc21
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc2c(=O)[nH]ncc2c1
Reaction time: 8 h
Yield: 92.3 %

Procedure:
2.9 g (12 mmol) of 5-tert-butyl-3-ethoxy-3H-isobenzofuran-1-one was weighed into a 50 mL round bottom flask fitted with a stir bar and cap. Added 10 mL (130 mmol) of hydrazine monohydrate. Added 15 mL of glacial acetic acid. Stirred at 100° overnight. Poured the reaction mixture into 200 mL of stirred water. Collected the solids by filtration and washed with water. Dried under high vacuum to obtain 2.24 g of the title compound as an off-white solid. MS (ESI) 203 (M+H)+.
Reaction SMILES: C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([CH2:38][CH2:39][CH2:40][O:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]([OH:50])=O)=[CH:44][C:43]=2[CH3:51])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].[CH3:52][N:53]1[C:62]2[NH:61][C:60]3[CH:63]=[CH:64][CH:65]=[CH:66][C:59]=3[NH:58][CH2:57][C:56]=2[CH:55]=[N:54]1.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.ClCCl>[C:25]([O:29][C:30]([N:32]1[CH2:33][CH2:34][CH:35]([CH2:38][CH2:39][CH2:40][O:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]([N:58]3[CH2:57][C:56]4[CH:55]=[N:54][N:53]([CH3:52])[C:62]=4[NH:61][C:60]4[CH:63]=[CH:64][CH:65]=[CH:66][C:59]3=4)=[O:50])=[CH:44][C:43]=2[CH3:51])[CH2:36][CH2:37]1)=[O:31])([CH3:27])([CH3:26])[CH3:28]
Reactant: Cn1ncc2c1Nc1ccccc1NC2
Reactant: Cc1cc(C(=O)O)ccc1OCCCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1OCCCC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 40 %

Procedure:
PyBroP (224 mg, 0.48 mmol) and DMAP (39 mg, 0.32 mmol) were added to a solution of 4-[3-(4-carboxy-2-methyl-phenoxy)-propyl]-piperidine-1-carboxylic acid tert-butyl ester from Example E68.3 (120 mg, 0.32 mmol) and 3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E11 (70 mg, 0.35 mmol) in dichloromethane (5 ml) and DIEA (0.111 ml, 0.64 mmol). The mixture was heated at reflux for 2 days, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloro-methane) to yield the title compound (71 mg, 40%).
Reaction SMILES: O[CH:2]=[C:3]1[C:8](=[O:9])[O:7][C:6]([CH3:11])([CH3:10])[O:5][C:4]1=[O:12].[CH3:13][O:14][C:15](=[O:18])[CH2:16][SH:17]>CO>[CH3:10][C:6]1([CH3:11])[O:7][C:8](=[O:9])[C:3](=[CH:2][S:17][CH2:16][C:15]([O:14][CH3:13])=[O:18])[C:4](=[O:12])[O:5]1
Reactant: COC(=O)CS
Reactant: CC1(C)OC(=O)C(=CO)C(=O)O1
Solvent: CO
Product: COC(=O)CSC=C1C(=O)OC(C)(C)OC1=O
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A mixture of 5-(hydroxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (8.6 g, 50 mmole), described by Bihlmayer et al., supra, and mercaptoacetic acid methyl ester (13 g, 0.125 mole) in dry methanol (50 mL) was heated at reflux for 2 hr. Thereafter, the mixture was stirred for 18 hr at 20°-22° C., and then poured into ice-water. The resultant mixture was extracted with diethyl ether. The extract was dried (MgSO4) and concentrated to dryness under reduced pressure. The residue (8.0 g) was purified by chromatography on silica gel, using 30% ethyl acetate in hexane (v/v) as the eluant. The pure fractions were combined and the solvent removed under reduced pressure. Crystallization of the residue from ethyl acetate-hexane gave the title compound; mp 117°-118° C.; NMR (CDCl3) δ 1.7 (s, 6H), 3.65 (s, 2H), 3.75 (s, 3H), 8.95 (s, 1H); IR (CHCl3) 1735, 1700, 1535 cm-1 ; UVλmax (MeOH) 315 um (ε 8900), 260 (7950).
Reaction SMILES: [CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:25]1[N:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][N:26]=1.CC#N>CN1C(=O)CCC1>[CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:23][CH2:22][N:21]([C:25]3[N:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][N:26]=3)[CH2:20][CH2:19]2)=[N:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1cnc(Cl)nc1
Reactant: c1ccc(Cc2nnc(N3CCNCC3)c3ccccc23)cc1
Solvent: CN1CCCC1=O
Solvent: CC#N
Product: N#Cc1cnc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)nc1

Procedure:
Using the general protocol, 1-benzyl-4-piperazin-1-yl-phthalazine (56 mg, 0.184 mmol) and 2-chloro-5-cyanopyrimidine (44.5 mg, 0.239 mmol) are added into a microwave vial, equipped with a stir bar, and MeCN (0.5 ml) and NMP (0.5 ml) are dispensed. The vial is sealed and the reaction was irradiated at high level absorption in the microwave at 180° C. for 15 min. The product is observed as the main peak (m/z; M+1=408). The compound is purified by preparative HPLC using a C8-254 nm method.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=1)[CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[C@@H:43]([CH2:54][CH3:55])[C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])(=O)=O.C(OCC)(=O)C>C(#N)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:23][C:24]1[CH:25]=[C:26]([CH:27]=[CH:28][CH:29]=1)[O:30][C@H:43]([CH2:54][CH3:55])[C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1
Reactant: CC[C@H](OS(=O)(=O)C(F)(F)F)C(=O)OCc1ccccc1
Reactant: COc1ccc(OCCCN(Cc2cccc(O)c2)c2nc3ccccc3o2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC[C@@H](Oc1cccc(CN(CCCOc2ccc(OC)cc2)c2nc3ccccc3o2)c1)C(=O)OCc1ccccc1
Reaction time: 0.17 h
Yield: 97.8 %

Procedure:
To a solution of N-(benzoxazol-2-yl)-N-(3-(4-methoxyphenoxy)propyl)-3-hydrox ybenzylamine (52 mg) in acetonitrile (5 mL), potassium carbonate (18 mg) in a powder form was added at room temperature, and the resulting mixture was stirred for 10 minutes. A solution of benzyl (S)-2-trifluoromethanesulfonyloxybutyrate (50 mg) in acetonitrile (2 mL) was added dropwise to the reaction liquor, and the mixture was stirred at the same temperature for 18 hours. Ethyl acetate (50 mL) was added to the reaction liquor, and the mixture was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to obtain a colorless oil (73 mg, 98.3%).
Reaction SMILES: C(C1C=C([C:16]2[C:21]3[CH:22]=[C:23]4[CH2:28][CH2:27][CH2:26][C:24]4=[CH:25][C:20]=3[O:19][C:18](=[O:29])[C:17]=2[C:30]([O:32]CC)=[O:31])C=C(C(C)(C)C)C=1O)(C)(C)C.[OH-].[K+].C(O)C.Cl>O>[O:29]=[C:18]1[C:17]([C:30]([OH:32])=[O:31])=[CH:16][C:21]2[CH:22]=[C:23]3[CH2:28][CH2:27][CH2:26][C:24]3=[CH:25][C:20]=2[O:19]1
Reactant: CCOC(=O)c1c(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c2cc3c(cc2oc1=O)CCC3
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc2cc3c(cc2oc1=O)CCC3
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of ethyl 4-(3,5-di-tert-butyl-4-hydroxy -phenyl)-2-oxo-2,6,7,8-tetrahydrocyclopenta [g] [1]benzopyran-3-carboxylate (1.85 g), potassium hydroxide (1.12 g) and 80% ethanol (12 ml) was stirred at room temperature for 3 hours. The reaction mixture was then diluted with water, adjusted to pH4 with 6N HCl and extracted with ethyl acetate. The extract was washed with water and dried (MgSO4) and the solvent was distilled off to give crystals of 4-3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-2,6,7,8-tetrahydrocyclopenta[g] [1]benzopyran-3-carboxylic acid. The crystals were collected by filtration and washed with isopropyl ether (1.13 g, 64.9%). mp. 256°-260° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:10][CH3:11])[CH2:5][CH2:6][CH2:7][CH2:8]O)[CH3:2].N1C=CC=CC=1.S(Cl)([Cl:20])=O>O>[Cl:20][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]([O:3][CH2:1][CH3:2])[CH2:10][CH3:11]
Reactant: CCOC(CC)CCCCO
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCOC(CC)CCCCCl
Temperature: 25 °C

Procedure:
5-Ethoxyheptanol (238 g, 1.49 moles) is diluted in pyridine (128 g, 1.62 moles). The solution is stirred at room temperature and thionyl chloride (388 g, 3.22 moles) is added dropwise over 2 hours, after which time the reaction is heated in a 70° C. water bath for 2 additional hours. Water (700 ml) is added to the reaction and the organic layer separated. The aqueous layer is extracted with hexane (3×400 ml) and the extracts combined with the organic phase. The organic phase is then washed with a 10% sodium hydroxide solution (1000 ml). The solvent volume is reduced under vacuum and the residue dried over anhydrous magnesium sulfate. The remaining solvent is removed leaving 1-chloro-5-ethoxyheptane as a clear light yellow oil. The crude product is fractionally distilled under reduced pressure leaving 1-chloro-5-ethoxyheptane as a clear, colorless oil (162 g, 1.13 moles), BP 96° C./9.5 cm Hg.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].CC(C)([O-])C.[K+].C(O)(=O)C>C1COCC1>[CH:6]1([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]2[C:4](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:3][CH2:2][O:1]1
Reactant: CCOC(=O)C=Cc1ccccc1CCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)CC1OCCc2ccccc21
Reaction time: 0.08 h

Procedure:
Ethyl 2-(2-hydroxyethyl)cinnamate (CXXX, EXAMPLE 112, theoretically 2.40 moles) is dissolved in THF (2.4 liters) and cooled to 0°. Potassium t-butoxide (5 mol %, 120 ml of a 1 molar THF solution) is added via syringe. After 5 min HPLC shows the cyclization is completed. Acetic acid (6 mol %, 8.2 ml, 144 mmol) is added. The slurry is filtered through approximately 300 g of 200 mesh silica gel. The solvent is Diatomaceous earth (100 g) is added followed by hexane (4.5 liters). This slurry is filtered through 200 mesh silica gel (400 g), washing with THF/hexane (1/9) until TLC shows no remaining product. Solvent removal gives the title compound. This material is filtered through silica gel more carefully, giving an analytical sample of the title compound, NMR (300 MHz, CDCl3) 7.1-7.2, 7.05, 5.26, 4.23, 4.12, 3.83, 3.0-2.7, 1.28; high resolution MS calculated for 220.1099, found 220.1105.
Reaction SMILES: C(OC(C[CH:12]([O:17][C:18](=[O:58])[C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([C@H:28]2[C@H:32]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=3[F:40])[C@:31]([C:43]3[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][C:44]=3[F:50])([C:41]#[N:42])[C@H:30]([CH2:51][C:52]([CH3:55])([CH3:54])[CH3:53])[NH:29]2)=[O:27])=[C:21]([O:56][CH3:57])[CH:20]=1)[O:13][C:14](=[O:16])[NH2:15])=O)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[Pd]>[Cl:39][C:35]1[C:34]([F:40])=[C:33]([C@@H:32]2[C@:31]([C:43]3[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][C:44]=3[F:50])([C:41]#[N:42])[C@H:30]([CH2:51][C:52]([CH3:55])([CH3:53])[CH3:54])[NH:29][C@H:28]2[C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([C:18]([O:17][CH2:12][O:13][C:14]([NH:15][CH2:19][C:18]([OH:58])=[O:17])=[O:16])=[O:58])=[CH:20][C:21]=2[O:56][CH3:57])=[O:27])[CH:38]=[CH:37][CH:36]=1
Reactant: [H][H]
Reactant: COc1cc(C(=O)OC(CC(=O)OCc2ccccc2)OC(N)=O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)OCOC(=O)NCC(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 24, a solution of 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid benzyloxycarbonylmethyl-carbamoyloxymethyl ester (Example 29) in ethyl acetate was treated with 10% palladium on carbon under 1 atm of hydrogen to give 2-(((4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoyloxy)methoxy)-carbonylamino)acetic acid as a white solid. MS (ES+) m/z calcd. for C35H36Cl2F2N4O8 [(M+H)+]: 747, found: 747.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.[H-].[Na+].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCOC(C)=O>CN(C=O)C>[CH2:11]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[N:3][CH:4]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Oc1ccc(Br)nc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Brc1ccc(OCc2ccccc2)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 71.9 %

Procedure:
2-Bromo-5-hydroxypyridine (347 mg, 2 mmol) in DMF (3 mL) was added dropwise over a period of 10 min to a suspension of NaH (88 mg, 2.3 mmol) in DMF (2 mL) at 0° C. under Ar(g). The reaction mixture was then stirred at it for 10 min, after which it was again cooled down at 0° C., and benzyl bromide (0.25 mL, 2.1 mmol) was added. The reaction mixture was stirred at it for 2.5 h, after which it was poured onto brine (20 mL) and EtOAc (20 mL) was added. The phases were separated and the aqueous phase was extracted with EtOAc (20 mL). The organic phases were combined, dried over MgSO4, filtered and subsequently evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography eluting with hexane/EtOAc (95:5 to 90:10) to furnish I as a colourless oil (380 mg, 72%).
Reaction SMILES: [CH:1]1([C:6]([O:8][CH3:9])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].CC([N-]C(C)C)C.[Cl:18][C:19]([CH2:21]Cl)=[CH2:20]>C1COCC1>[Cl:18][C:19](=[CH2:20])[CH2:21][C:1]1([C:6]([O:8][CH3:9])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C1CCCC1
Reactant: C=C(Cl)CCl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(Cl)CC1(C(=O)OC)CCCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 57.6 %

Procedure:
To a solution of methyl cyclopentanecarboxylate (2.0 g, 15.60 mmol) in THF (70 mL) cooled to −78° C. was added 2 M solution of LDA in THF (10.1 mL, 20.3 mmol). The mixture was stirred at −78° C. for 1 hour. To this mixture was added 2,3-dichloroprop-1-ene (3.46 g, 31.2 mmol) and allowed to warm to room temperature. The reaction mixture was quenched with aq. NH4Cl and extracted with EtOAc. The organic layer was washed with water, brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by chromatography using EtOAc/heptane gradient to give methyl 1-(2 chloroallyl)cyclopentanecarboxylate (1.82 g). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.46-1.75 (m, 6H), 1.98-2.18 (m, 2H), 2.66 (s, 2H), 3.61 (s, 3H), 5.02 (d, J=1.3 Hz, 1H), 5.14 (d, J=1.3 Hz, 1H).