Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:9]1[CH2:12][C:11]2([CH2:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[C:17](/[CH:23]=[CH:24]/[C:25](O)=[O:26])[CH:18]=3)[O:13]2)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:42][O:43][CH:44]1[CH2:49][CH2:48][CH2:47][CH2:46][O:45]1>C(Cl)Cl>[C:1]([N:9]1[CH2:12][C:11]2([CH2:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[C:17](/[CH:23]=[CH:24]/[C:25]([NH:42][O:43][CH:44]4[CH2:49][CH2:48][CH2:47][CH2:46][O:45]4)=[O:26])[CH:18]=3)[O:13]2)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NOC1CCCCO1
Reactant: O=C(O)/C=C/c1ccc2c(c1)C(=O)CC1(CN(C(=O)c3ccccc3)C1)O2
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CN(C(=O)c3ccccc3)C1)O2)NOC1CCCCO1
Yield: 51.9 %

Procedure:
A suspension of (E)-3-[1′-benzoyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-acrylic acid (200 mg, 0.50 mmol) in DCM (5 ml) was treated with TEA (0.11 ml, 0.82 mmol) and then with EDC (158 mg, 0.827 mmol), HOBt (107 mg, 0.793 mmol) and NH2OTHP (74 mg, 0.63 mmol) following the procedure described in Example 30, Step B, giving (E)-3-[1′-benzoyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (120 mg) as a light yellow solid.
Reaction SMILES: C(=O)(O)[O-].[Na+].CC(O[CH2:10][C:11]1[CH2:20][S:19][C@@H:14]2[C@H:15]([NH2:18])[C:16](=[O:17])[N:13]2[C:12]=1[C:21]([OH:23])=[O:22])=O.C1(C=CC(O)=CC=1)O.[C:32]([O-:35])(=[S:34])[CH3:33].[K+]>O.C(O)(=O)C>[NH2:18][CH:15]1[C:16](=[O:17])[N:13]2[C:12]([C:21]([OH:23])=[O:22])=[C:11]([CH2:10][S:34][C:32](=[O:35])[CH3:33])[CH2:20][S:19][C@H:14]12
Reactant: CC([O-])=S
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: O=C([O-])O
Agent: Oc1ccc(O)cc1
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 85.1 %

Procedure:
1.7 g of sodium bicarbonate were added under an inert gas to a stirred mixture of 5.44 g of 7-amino-cephalosporanic acid in 50 ml of water containing 1% of hydroquinone and after dissolution occured, 3 g of potassium thioacetate were added thereto. The mixture was stirred for 3 hours at 60° C. and was then cooled and acidified with acetic acid. The mixture was stirred at room temperature and was vacuum filtered and the product was washed and dried to obtain 4.9 g of 7-amino-3-acetylthiomethyl-ceph-3-eme-4-carboxylic acid.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([O:8][C@@H:9]2[CH2:14][C@H:13]3[CH2:15][CH2:16][C@H:17]4[C@@:22]5([OH:32])[CH2:23][CH2:24][C@H:25]([C:26]6[CH2:31][O:30][C:28](=[O:29])[CH:27]=6)[C@@:21]5([CH3:33])[C@H:20]([OH:34])[CH2:19][C@@H:18]4[C@@:12]3([CH3:35])[CH2:11][CH2:10]2)[CH2:5][C@H:4]([OH:36])[C@@H:3]1[O:37][C@@H:38]1[O:43][C@H:42]([CH3:44])[C@@H:41]([O:45][CH:46]([O:50][CH:51]([CH:53]=[O:54])[CH3:52])[CH2:47][CH:48]=[O:49])[C@@H:40]([OH:55])[CH2:39]1.CN(C)C=O.C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl.CO>[CH3:52][C@H:51]1[O:50][C@@H:46]([O:45][C@H:41]2[C@@H:40]([OH:55])[CH2:39][C@H:38]([O:37][C@H:3]3[C@@H:4]([OH:36])[CH2:5][C@H:6]([O:8][C@@H:9]4[CH2:14][C@H:13]5[CH2:15][CH2:16][C@H:17]6[C@@:22]7([OH:32])[CH2:23][CH2:24][C@H:25]([C:26]8[CH2:31][O:30][C:28](=[O:29])[CH:27]=8)[C@@:21]7([CH3:33])[C@H:20]([OH:34])[CH2:19][C@@H:18]6[C@@:12]5([CH3:35])[CH2:11][CH2:10]4)[O:7][C@@H:2]3[CH3:1])[O:43][C@@H:42]2[CH3:44])[CH2:47][C@H:48]([OH:49])[C@@H:53]1[OH:54]
Reactant: CC(C=O)OC(CC=O)O[C@H]1[C@@H](O)C[C@H](O[C@H]2[C@@H](O)C[C@H](O[C@H]3CC[C@@]4(C)[C@H](CC[C@@H]5[C@@H]4C[C@@H](O)[C@]4(C)[C@@H](C6=CC(=O)OC6)CC[C@]54O)C3)O[C@@H]2C)O[C@@H]1C
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H]1O[C@@H](O[C@H]2[C@@H](O)C[C@H](O[C@H]3[C@@H](O)C[C@H](O[C@H]4CC[C@@]5(C)[C@H](CC[C@@H]6[C@@H]5C[C@@H](O)[C@]5(C)[C@@H](C7=CC(=O)OC7)CC[C@]65O)C4)O[C@@H]3C)O[C@@H]2C)C[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 25 mg (0.05 mmol) of DCAS bis-hydrazide prepared as described in Example 6 and 78 mg (0.10 mmol) of digoxin dialdehyde prepared as above was added 2 ml of dry dimethylformamide and 17 μl (0.10 mmol) of N,N-diisopropylethylamine. The reaction was stirred at room temperature under nitrogen for 48 hours, during which time a new product formed. By thin layer chromatography, using chloroform-methanol (9:1, v/v) as developing solvent; this product had Rf 0.45 and was blue-green in color. The reaction mixture was evaporated to dryness by rotary evaporation and purified by preparative thin layer chromatography on two 20×20 cm silica gel type GF preparative plates, using chloroform-methanol (9:1, v/v) as developing solvent. The band corresponding to the produce at Rf 0.45 was scraped off the plate and eluted from the silica gel with methanol. Evaporation of methanol yielded a dark greenish-blue solid product.
Reaction SMILES: I[C:2]1[N:3]=[C:4]2[S:11][C:10]([S:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[N:9][N:5]2[C:6](=[O:8])[CH:7]=1.C(N(CC)CC)C.O1C[CH2:29][CH2:28][CH2:27]1.C#CC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1.O>[C:27]([C:2]1[N:3]=[C:4]2[S:11][C:10]([S:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[N:9][N:5]2[C:6](=[O:8])[CH:7]=1)#[C:28][CH3:29]
Reactant: C1CCOC1
Reactant: CCCCCCSc1nn2c(=O)cc(I)nc2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C#CC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CC#Cc1cc(=O)n2nc(SCCCCCC)sc2n1
Reaction time: 1 h
Yield: 72 %

Procedure:
Into a solution of 8.6 g of the thus obtained 7-iodo-2-hexylthio-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5one, 11 g of triethylamine, 0.15 g of bis(triphenylphosphine)palladium(II) chloride, 0.04 g of cuprous iodide and 33 ml of tetrahydrofurane, 2.6 g of 1-propyne was introduced through a bubbling glass tube under ice-cold-water chilling and constant stirring over a 1 hour period. Thereafter, the solution was further stirred at room temperature for 30 minutes, and 0.23 g of bis(triphenylphosphine)palladium(II) chloride and 0.06 g of cuprous iodide were added. The solution was stirred further for 4 hours. Then toluene was added, and the solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in toluene, the solution was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was recrystallized from an ethanol/hexane mixture and thus 3.9 g of 7-(1-propynyl)-2-hexylthio-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]1[CH:22]=[C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:20]=[CH:19][C:16]=1[CH:17]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:14][C:15]1[CH:22]=[C:21]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[CH:20]=[CH:19][C:16]=1[CH2:17][N:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1
Reactant: O=Cc1ccc(N2CCOCC2)cc1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(N3CCOCC3)cc2F)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 91.8 %

Procedure:
A 50 mL round-bottom flask, equipped with a magnetic stir bar, was charged with tert-butyl-1-piperazine carboxylate (445 mg, 2.39 mmol) under nitrogen. The solid was dissolved in 10 mL dichloromethane (anhydrous) and stirred at room temperature. 2-Fluoro-4-morpholinobenzaldehyde (500 mg, 2.39 mmol) was added followed by molecular sieves (440 mg, 8-12 mesh beads). The reaction was allowed to continue to stir at room temperature for 1 h. At that point, sodium triacetoxyborohydride (557 mg, 2.63 mmol, 1.10 equiv) was added. The reaction was monitored for disappearance of aldehyde by thin layer chromatography. After 15 h, the reaction was quenched with saturated sodium bicarbonate (15 mL). After the addition of dichloromethane (15 mL), the mixture was partitioned into two phases. The aqueous phase was extracted twice with dichloromethane (15 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The crude mixture was applied to a chromatography column containing 24 g silica and dichloromethane. A gradient solvent was used from 100% dichloromethane to 10% methanol in dichloromethane to provide 833 mg (92%) of tert-butyl 4-(2-fluoro-4-morpholinobenzyl)piperazine-1-carboxylate as a pale yellow solid. 1H NMR 400 MHz (CDCl3) δ 7.22 (t, J=8.4 Hz, 1H), 6.66 (d, J=8.4 Hz, 1H), 6.57 (d, J=13.0 Hz, 1H), 3.90-3.85 (m, 4H), 3.53 (s, 2H), 3.43 (bs, 4H), 3.20-3.15 (m, 4H), 2.41 (bs, 4H), 1.46 (s, 9H).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[O:3].[OH-].[Na+].[Br:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[C:12]([F:18])[CH:11]=1>C(O)C>[Br:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[CH:4][C:2](=[O:3])[C:1]([OH:6])=[O:5])=[C:12]([F:18])[CH:11]=1
Reactant: CC(=O)C(=O)O
Reactant: O=Cc1ccc(Br)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C(=O)C=Cc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81.9 %

Procedure:
A solution of pyruvic acid (1.9 mL, 27.1 mmol) in ethanol (2.5 mL) was added to a 0.5 M sodium hydroxide solution (74.0 mL). The reaction mixture was stirred at room temperature for 10 minutes and then a solution of 4-bromo-2-fluorobenzaldehyde (5.0 g, 24.6 mmol) in ethanol (22.5 mL) was slowly added thereto at room temperature for 1 hour. The reaction mixture was stirred at room temperature for 18 hours and then filtered. The resulting solid was washed with ethyl acetate, diluted with a 1N hydrochloric acid solution and then extracted with ethyl acetate. The extract was washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 5.5 g of the titled compound as a yellow solid.
Reaction SMILES: Cl[C:2]([O:4][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][CH2:20][CH2:21][CH3:22])=[O:3].[P:23]([O:28]C)([O:26][CH3:27])[O:24][CH3:25]>>[CH2:5]([O:4][C:2]([P:23](=[O:28])([O:26][CH3:27])[O:24][CH3:25])=[O:3])[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][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCCCCCCCOC(=O)Cl
Reactant: COP(OC)OC
Product: CCCCCCCCCCCCCCCCCCOC(=O)P(=O)(OC)OC
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of octadecyl chloroformate (7.0 g, 21 mmol) and P(OMe)3 (37.2 mL) was stirred at 80° C. for 2 hours and allowed to cool overnight. The white solid of the title compound which formed was collected, washed with hexane, and dried overnight in a vacuum oven; yield 6.0 g. A second crop was obtained from the filtrate upon cooling (2.1 g); total yield 8.1 g (95%); mp 41-42° C. (hexane); IR (KBr): υ 2950-2880, 2830, 1710, 1470, 1375, 1350, 1280, 1220 cm−1; 1H NMR (CDCl3) δ 0.8-1.8 (m, 35H, CH3 (CH2)16), 3.9 (d, 6H, P(OCH3)2), 4.3 (t, 2H, CH2O). Anal. Calcd. for C21H43O5P: C, 62.03; H, 10.68; P, 7.62. Found: C, 62.16; H, 10/71; P, 7.69.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[N:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[H][H]>[Pd].CO>[O:4]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[N:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=3)[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: Nc1cnc(C2=CCC3(CC2)OCCO3)cn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1cnc(C2CCC3(CC2)OCCO3)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.4 %

Procedure:
To 5-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyrazin-2-amine (645 mg, 2.77 mmol) in a round bottom flask that was flushed with argon was added Pd—C 10% degaussa (294 mg, 0.277 mmol). Then under argon with syringe was added MeOH (10 mL) and then last a hydrogen balloon was added. The flask was evacuated and refilled with hydrogen (6 X). The reaction was stirred at room temperature for total of 16 h, under the hydrogen balloon, followed by LCMS. The reaction was flushed with argon and 25 mL of DCM was added. The crude mixture was filtered through a Celite plug, and concentrated to constant mass to give 635 mg of the desired product as free base, used as is (98% yield). LCMS (m/z): 236.2 (MH+), 0.41 min; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.78 (d, J=1.2 Hz, 1H), 7.74 (d, J=1.2 Hz, 1H), 6.09 (s, 2H), 3.85 (s, 4H), 2.52-2.60 (m, 1H), 1.65-1.78 (m, 6H), 1.49-1.61 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24]Br)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[Cl:28][C:29]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:30]=1[CH:31]=[CH:32][C:33]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)=[N:34]2>>[F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24][N:42]2[CH2:43][CH2:44][N:39]([C:33]3[CH:32]=[CH:31][C:30]4[C:35](=[CH:36][CH:37]=[CH:38][C:29]=4[Cl:28])[N:34]=3)[CH2:40][CH2:41]2)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: Clc1cccc2nc(N3CCNCC3)ccc12
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2Oc2ccccc21
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3ccc4c(Cl)cccc4n3)CC2)c2ccccc2Oc2ccccc21

Procedure:
Prepared analogously to Example 2 from 9-(4-bromo-butyl)-9H-xanthene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 5-chloro-2-piperazin-1-yl-quinoline.
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][C@H:4]([N:8]1[CH2:12][C:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])=[CH:10][C:9]1=[O:21])[C:5]([OH:7])=O.[CH3:23][N:24]1[CH:28]=[CH:27][C:26]([NH2:29])=[N:25]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[CH3:23][N:24]1[CH:28]=[CH:27][C:26]([NH:29][C:5](=[O:7])[C@@H:4]([N:8]2[CH2:12][C:11]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH3:20])=[CH:10][C:9]2=[O:21])[CH2:3][CH:2]([CH3:1])[CH3:22])=[N:25]1
Reactant: Cc1ccccc1OC1=CC(=O)N([C@@H](CC(C)C)C(=O)O)C1
Reactant: Cn1ccc(N)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccccc1OC1=CC(=O)N([C@@H](CC(C)C)C(=O)Nc2ccn(C)n2)C1
Temperature: 0 °C
Yield: 18.9 %

Procedure:
To a solution of (S)-4-methyl-2-(2-oxo-4-o-tolyloxy-2,5-dihydro-pyrrol-1-yl)-pentanoic acid (0.208 g, 0.69 mmol) in N,N-dimethylformamide (4 mL) was added 1-methyl-1H-pyrazol-3-ylamine (0.080 g, 0.82 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.620 g, 1.40 mmol). The mixture was stirred at 0° C. and triethylamine (0.150 g, 1.48 mmol) was added. The mixture was stirred at room temperature for 3 h and the solvents were evaporated. The residue was treated with ethyl acetate and ammonium chloride solution, and the organic layer separated. The organic layer was washed with brine and dried over sodium sulfate. The solvents were evaporated and the residue was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 25 g, 20% to 100% ethyl acetate/hexanes) which afforded (S)-4-methyl-2-(2-oxo-4-o-tolyloxy-2,5-dihydro-pyrrol-1-yl)-pentanoic acid (1-methyl-1H-pyrazol-3-yl)-amide (0.050 g, 19%) as a tan solid: HR-ES-MS m/z calculated for C21H26N4O3 [M+H]+ 383.2078, observed 383.2077, 1H NMR (300 MHz, DMSO-d6) δ ppm 1.00-0.90 (d, J=6.3 Hz, 3H), 0.94 (d, J=6.3 Hz, 3H), 1.20-1.92 (m, 3H), 2.19 (s, 3H), 3.73 (s, 3H), 4.20 (d, J=18.1 Hz, 1H), 4.57 (d, J=18.1 Hz, 1H), 4.63 (s, 1H), 4.87 (dd, J=10.3, 4.8 Hz, 1H), 6.40 (d, J=1.8 Hz, 1H), 7.17-7.33 (m, 3H), 7.36 (d, J=7.2 Hz, 1H), 7.55 (d, J=1.8 Hz, 1H), 10.72 (s, 1H).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2].[CH3:57][Li]>C1COCC1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1([OH:56])[CH3:57])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reactant: [Li]C
Solvent: C1CCOC1
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1(C)O)C(C)CC2OC
Temperature: -78 °C
Reaction time: 24 h
Yield: 68 %

Procedure:
A solution of 0.101 g (0.1 mmole) of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetrone in 5 mL of dry THF was cooled to 0° C. under nitrogen. Then 1 mL of a 0.5M solution of methyllithium was added dropwise and the solution was stirred at -78° C. for 24 h. The solution was quenched at -78° C. by addition of 0.2 mL of glacial acetic acid and then diluted with 20 mL of ether and partitioned between ether and 1M KHCO3 solution. The ether layer was washed with 1M KHCO3 and brine, dried over MgSO4, and concentrated. The residue was dissolved in 2 mL of 1:9 48% aqueous HF-acetonitrile was stirred at room temperature for 8 h. The reaction was quenched by addition of 2 mL of ethoxytrimethylsilane and the solution was concentrated to dryness under vacuum. The residue was purified by flash chromatography (2×20 cm silica gel) using 25% acetone-hexane to afford 0.053 g (68%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:31][CH3:32])=[C:4](/[C:17](/[CH3:30])=[C:18](/[F:29])\[CH:19]=[CH:20]\[C:21](\[CH3:28])=[CH:22]\[C:23]([O:25]CC)=[O:24])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH3:13])([CH3:12])[CH:8]=[C:7]2[CH:14]([CH3:16])[CH3:15].[OH-].[Na+]>C(O)C.C1COCC1>[Cl:1][C:2]1[C:3]([O:31][CH3:32])=[C:4](/[C:17](/[CH3:30])=[C:18](/[F:29])\[CH:19]=[CH:20]\[C:21](\[CH3:28])=[CH:22]\[C:23]([OH:25])=[O:24])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH3:12])([CH3:13])[CH:8]=[C:7]2[CH:14]([CH3:15])[CH3:16]
Reactant: CCOC(=O)/C=C(C)/C=C/C(F)=C(/C)c1cc2c(c(Cl)c1OC)OC(C)(C)C=C2C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1c(/C(C)=C(F)\C=C\C(C)=C\C(=O)O)cc2c(c1Cl)OC(C)(C)C=C2C(C)C

Procedure:
Following General Procedure G, a solution of ethyl 7-(8-chloro-4-isopropyl-7-methoxy-2,2-dimethyl-2H-chromen-6-yl)-6-fluoro-3-methyl-octa-2E,4E,6E-trienoate (Compound 164, 38 mg, 0.082 mmol) in ethanol and THF was hydrolyzed with 1M NaOH to give rise to the title compound as a white solid.
Reaction SMILES: [OH-].[Na+].Cl.C([O:6][C:7]([C@H:9]1[CH2:14][C:13]([CH3:15])=[CH:12][CH2:11][N:10]1[C:16](=[O:43])[C@H:17]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40](=[NH:42])[NH2:41])[CH:35]=1)[NH:18][S:19]([C:22]1[CH:31]=[C:30]2[C:25]([CH2:26][CH2:27][N:28]([CH3:32])[CH2:29]2)=[CH:24][CH:23]=1)(=[O:21])=[O:20])=[O:8])C.Cl>O1CCOCC1>[CH3:15][C:13]1[CH2:14][C@H:9]([C:7]([OH:8])=[O:6])[N:10]([C:16](=[O:43])[C@H:17]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40](=[NH:41])[NH2:42])[CH:35]=2)[NH:18][S:19]([C:22]2[CH:31]=[C:30]3[C:25]([CH2:26][CH2:27][N:28]([CH3:32])[CH2:29]3)=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:11][CH:12]=1
Reactant: CCOC(=O)[C@H]1CC(C)=CCN1C(=O)[C@H](Cc1cccc(C(=N)N)c1)NS(=O)(=O)c1ccc2c(c1)CN(C)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC1=CCN(C(=O)[C@H](Cc2cccc(C(=N)N)c2)NS(=O)(=O)c2ccc3c(c2)CN(C)CC3)[C@@H](C(=O)O)C1
Reaction time: 3.5 h
Yield: 101.4 %

Procedure:
1M Aqueous sodium hydroxide solution (16.4 ml, 16.4 mmol) was added to a stirred solution of 4-methyl-1-[N-(2-methyl-1,2,3,4-tetrahydroisoquinoline-7-sulphonyl)-3-amidino-(S)-phenylalanyl]-1,2,3,6-tetrahydropyridine-2(R)-carboxylic acid ethyl ester hydrochloride (Preparation 67; 1.99 g, 3.29 mmol) in 1,4-dioxan (15 ml). After 3.5 hours at room temperature, the excess sodium hydroxide was carefully neutralised by the dropwise addition of 1M hydrochloric acid and the resulting clear solution evaporated to dryness under reduced pressure. The residue was extracted with a hot mixture of dichloromethane and 2-propanol (1:1), then the extract filtered and the filtrate evaporated under reduced pressure to afford the title compound (1.80 g) as a white solid. Rf 0.12 (SS 13). [α]D25 +44° (c=0.1, C3OH). Found: C,55.75; H,6.34; N,11.01. C27H33N5O5S; 2.50 H2O; 0.50 (CH3)2CHOH requires C,55.62; H,6.49; N,10.99%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][C:9](=O)[CH2:8][CH2:7]2.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>C1(C)C=CC=CC=1>[N:13]1([C:9]2[CH2:8][CH2:7][C:6]3[C:11]([CH:10]=2)=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=3)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C1CCc2cccc(Cl)c2C1
Reactant: C1CCNC1
Solvent: Cc1ccccc1
Product: Clc1cccc2c1C=C(N1CCCC1)CC2
Yield: 92.3 %

Procedure:
To 100 ml of toluene were added 5.0 g (27.8 mmol) of 8-chloro-2-tetralone. To the resulting solution then were added 3.5 g of pyrrolidine, and the mixture was heated to reflux for three hours after which the solvent was removed in vacuo to give 3-pyrrolidino-5-chloro-1,2-dihydronaphthalene as a dark oil (about 6 g).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][S:13](=[O:17])(=[O:16])[CH2:12][CH2:11]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:10]2[CH2:15][CH2:14][S:13](=[O:17])(=[O:16])[CH2:12][CH2:11]2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=S1(=O)CCNCC1
Reactant: O=Cc1cccc(Br)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: O=S1(=O)CCN(Cc2cccc(Br)n2)CC1

Procedure:
The title compound was prepared as described in Example 2, Step 1 using 6-bromopyridine-2-carbaldehyde (3.0 g, 16.13 mmol), thiomorpholine 1,1-dioxide (2.18 g, 16.13 mmol), and sodium triacetoxyborohydride (4.79 g, 22.58 mmol) as starting materials. 1H NMR (600 MHz, d6-DMSO) δ 7.72 (t, 1H), 7.51 (d, 1H), 7.50 (d, 1H), 3.74 (s, 2H), 3.10 (m, 4H), 2.90 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:13])[NH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.C[Si](C)(C)N[Si](C)(C)C.[C:23]([O:26][CH2:27][CH3:28])(=[O:25])[CH3:24].CO>C1(C)C=CC=CC=1.S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:13])[NH:7][C:8](=[O:12])[N:9]2[CH2:24][C:23]([O:26][CH2:27][CH3:28])=[O:25])=[CH:4][CH:3]=1
Reactant: O=c1[nH]c(=O)c2ccc(Cl)cc2[nH]1
Reactant: CCOC(C)=O
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: CO
Product: CCOC(=O)Cn1c(=O)[nH]c(=O)c2ccc(Cl)cc21
Reaction time: 6 h

Procedure:
To a mixed suspension of 7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazoline (20 g) and hexamethyldisilazane (16.42 g) in toluene (60 ml) was added sulfuric acid (0.80 g) dropwise and the silylation reaction was carried out at an internal temperature of 110˜120° C. for 6 hours. After completion of silylation, the toluene was distilled off to recover a concentrate containing 7-chloro-2,4-bis(trimethylsilyloxy)quinazoline. To this concentrate were added propylene carbonate (40 ml), ethyl chloroacetate (13.72 g) and ethyl bromoacetate (3.40 g), and the reaction was carried out at an internal temperature of 125˜140° C. for 6 hours. After completion of reaction, the reaction mixture was cooled to an internal temperature of ≦70° C. and ethyl acetate (80 ml) was added. Then, methanol (60 ml) was added dropwise over 30 minuets. After completion of dropwise addition, the mixture was cooled to ≦20° C. and stirred for 1 hour. The resulting crystal crop was harvested by filtration, washed serially with methanol (40 ml) and water (100 ml) and dried to provide ethyl 2-(7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-1-yl)acetate (28.16 g) as white crystals.