Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[C@H:15]([OH:24])[CH2:16][C@H:17]([OH:23])[CH2:18][C:19]([O:21]C)=[O:20])=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:3].O.[OH-].[Na+:34]>C1COCC1>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:24])[CH2:16][CH:17]([OH:23])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:34]
Reactant: COC(=O)C[C@@H](O)C[C@@H](O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Reaction time: 1.5 h
Yield: 82 %

Procedure:
A 100 ml round bottom flask was loaded with fluvastatin methyl ester (5 g, 11.7 mmole), water (45 ml), THF (12.5 ml) and NaOH (0.48 g). The solution was stirred for 1.5 h then extracted with ethyl acetate (20 ml) and filtered. The aqueous phase was distilled and acetonitrile (100 ml) was added and the mixture was stirred at room temperature over night. The product was isolated by filtration under nitrogen flow, washed with acetonitrile (15 ml) and dried at 50° C. in a vacuum oven for 24 h to obtain 4.16 g (82%) of fluvastatin sodium crystal Form LXXIII.
Reaction SMILES: FC(F)(F)C(O)=O.[I:8][C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([NH2:18])[CH:16]=2)[N:11]([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:10]=1.C(N(CC)CC)C.[CH2:35]([N:37]=[C:38]=[O:39])[CH3:36]>ClCCl>[CH2:35]([NH:37][C:38]([NH:18][C:15]1[CH:16]=[C:17]2[C:9]([I:8])=[CH:10][N:11]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C:12]2=[N:13][CH:14]=1)=[O:39])[CH3:36]
Reactant: CCN=C=O
Reactant: Nc1cnc2c(c1)c(I)cn2S(=O)(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1cnc2c(c1)c(I)cn2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of Example 226a (120 mg, 0.234 mmol) in 5 mL dichloromethane was added triethylamine (0.326 mL, 2.34 mmol) followed by addition of ethyl isocyanate (0.074 mL, 0.935 mmol). The reaction mixture was stirred 16 hours at room temperature and then concentrated to dryness. The residue was partitioned with sodium bicarbonate solution and ethyl acetate. The organics were concentrated to dryness and the residue purified by silica gel flash chromatography eluting with 15% ethyl acetate, 85% dichloromethane to give the title compound as a pink-brown powder in quantitative yield. MS (ESI+) m/z 471.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:11]([OH:13])=[O:12])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:14]1(C)C=CC(S(O)(=O)=O)=C[CH:15]=1>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)C1(c2cccc(Br)c2)CC1
Solvent: CCO
Product: CCOC(=O)C1(c2cccc(Br)c2)CC1
Reaction time: 2 h
Yield: 435.8 %

Procedure:
1-(3-Bromophenyl)cyclopropanecarboxylic acid (976 mg, 4.05 mmol) was dissolved in ethanol (20 mL) and p-toluenesulfonic acid (139 mg, 0.810 mmol) was added. The reaction mixture was heated at reflux for 15 h. The temperature of the oil bath was increased from 80° C. to 110° C. and the reaction mixture was stirred for 2 h at that temperature, after which the mixture was cooled and the solvent was removed under reduced pressure. The crude material was purified via flash chromatography (pentane:ethyl acetate 9:1) to afford ethyl 1-(3-bromophenyl)cyclopropanecarboxylate as a colorless oil (950 mg, 87.2%). 1H NMR (400 MHz, CDCl3) δ 1.13-1.20 (m, 5H), 1.57-1.62 (m, 2H), 4.10 (q, 2H), 7.17 (s, 1H), 7.27 (s, 1H), 7.38 (s, 1H), 7.47-7.50 (m, 1H).
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].[CH2:12]([C:18]([NH:20][NH2:21])=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16]C>>[CH2:2]([N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)/[C:4](=[N:21]/[NH:20][C:18](=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])/[C:2]1=[O:3])[CH2:4][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCC(=O)NN
Reactant: O=C1Nc2ccccc2C1=O
Product: CCCCCCN1C(=O)/C(=N\NC(=O)CCCCC)c2ccccc21
Yield: 32 %

Procedure:
The title compound was prepared as a yellow solid, using isatin 3 and hexanecarbohydrazide according to the synthetic method E. The resulting solid was washed with ethanol. Yield: 32%. 1H NMR (DMSO-d6): δ 0.82-0.91 (m, 6H), 1.27-1.33 (m, 10H), 1.62 (m, 4H), 2.71 (br s, 1H), 3.74 (t, J=7.2 Hz, 2H), 7.15 (t, J=7.5 Hz, 1H), 7.19 (d, J=7.8 Hz, 1H), 7.45 (t, J=7.8 Hz, 1H), 7.58 (d, J=7.5 Hz, 1H), 12.44 (br s, 1 H). 13C NMR (DMSO-d6): δ 14.25 (CH3), 14.29 (CH3), 22.30 (CH2), 22.42 (CH2), 26.33 (CH2), 27.36 (CH2), 31.26 (CH2), 31.28 (CH2), 39.59 (CH2), 110.46 (CH), 119.72 (C), 120.62 (CH), 123.41 (CH), 131.73 (CH), 143.22 (C═N), 161.01 (C═O). HRMS (ES+) calcd for C20H30N3O2 (M+H+), m/e, 344.2335; found, 344.2333.
Reaction SMILES: C([O:8][C:9]([CH2:11][CH2:12][CH2:13][C@H:14]([NH:37][C:38](=[O:56])[CH2:39][C@@H:40]([OH:55])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH:52]([CH3:54])[CH3:53])[C:15]([O:17][C@@H:18]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH2:19][C:20]([NH2:22])=[O:21])=[O:16])=[O:10])C1C=CC=CC=1.O>O1CCOCC1.CO.[Pd]>[C:9]([CH2:11][CH2:12][CH2:13][C@H:14]([NH:37][C:38](=[O:56])[CH2:39][C@@H:40]([OH:55])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH:52]([CH3:54])[CH3:53])[C:15]([O:17][C@@H:18]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH:34]([CH3:35])[CH3:36])[CH2:19][C:20]([NH2:22])=[O:21])=[O:16])([OH:10])=[O:8]
Reactant: CC(C)CCCCCCCCCCC[C@H](O)CC(=O)N[C@@H](CCCC(=O)OCc1ccccc1)C(=O)O[C@@H](CCCCCCCCCCCC(C)C)CC(N)=O
Agent: [Pd]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)CCCCCCCCCCC[C@H](O)CC(=O)N[C@@H](CCCC(=O)O)C(=O)O[C@@H](CCCCCCCCCCCC(C)C)CC(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
To a solution of (3S)-3-[(2S)-5-benzyloxycarbonyl-2-{(3S)-3-hydroxy-15-methylhexadecanoylamino}pentanoyl]oxy-15-methylhexadecanamide (80 mg) in a mixture of 1,4-dioxane (10 ml) and methanol (10 ml) were added 10% palladium on active carbon (50 mg) and water (1 ml). The mixture was stirred at room temperature under hydrogen atmosphere for 1 hour. The catalyst was filtered off and the solvent was removed under reduced pressure to give (3S)-3-[(2S)-5-carboxy-2-{(3S)-3-hydroxy-15-methylhexadecanoylamino}-pentanoyl]oxy-15-methylhexadecanamide as white powder (56 mg).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[S:15][CH:14]=[C:13]([CH2:16][O:17][C:18]3[CH:23]=[C:22]([C:24]4[O:25][C:26]([CH2:29][C:30]5[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=5)=[N:27][N:28]=4)[CH:21]=[CH:20][C:19]=3[CH3:37])[C:8]=2[C:9]([NH2:12])=[N:10][CH:11]=1)=[O:5])C.[CH2:38]([CH2:40][NH2:41])[OH:39]>CS(C)=O>[OH:39][CH2:38][CH2:40][NH:41][C:4]([C:6]1[C:7]2[S:15][CH:14]=[C:13]([CH2:16][O:17][C:18]3[CH:23]=[C:22]([C:24]4[O:25][C:26]([CH2:29][C:30]5[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=5)=[N:27][N:28]=4)[CH:21]=[CH:20][C:19]=3[CH3:37])[C:8]=2[C:9]([NH2:12])=[N:10][CH:11]=1)=[O:5]
Reactant: CCOC(=O)c1cnc(N)c2c(COc3cc(-c4nnc(Cc5ccc(Cl)cc5)o4)ccc3C)csc12
Reactant: NCCO
Solvent: CS(C)=O
Product: Cc1ccc(-c2nnc(Cc3ccc(Cl)cc3)o2)cc1OCc1csc2c(C(=O)NCCO)cnc(N)c12
Temperature: 160 °C

Procedure:
A solution of 4-amino-3-{5-[5-(4-chloro-benzyl)-[1,3,4]oxadiazol-2-yl]-2-methyl-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.07 g, 0.13 mmol) (from Example 42 supra) in dimethylsulfoxide (0.5 mL) was treated with ethanolamine (1.5 mL) and heated at 160° C. for 2.8 hours in a microwave reactor. The reaction mixture was purified by C18 column chromatography and SFC column chromatography to give 4-amino-3-{5-[5-(4-chloro-benzyl)-[1,3,4]oxadiazol-2-yl]-2-methyl-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide as a white powder. (Yield 8 mg, 11%).
Reaction SMILES: [C:1]([NH:5][NH:6]C(OC(C)(C)C)=O)([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[CH:25]=[CH:24][C:23]([CH2:26][NH:27][C:28](=[O:33])[C:29]([F:32])([F:31])[F:30])=[CH:22][C:16]=1[C:17]([N:19]=[C:20]=[O:21])=O.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]([N:5]1[C:20](=[O:21])[NH:19][C:17]([C:16]2[CH:22]=[C:23]([CH:24]=[CH:25][C:15]=2[Cl:14])[CH2:26][NH:27][C:28](=[O:33])[C:29]([F:32])([F:31])[F:30])=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C=NC(=O)c1cc(CNC(=O)C(F)(F)F)ccc1Cl
Reactant: CC(C)(C)NNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)n1nc(-c2cc(CNC(=O)C(F)(F)F)ccc2Cl)[nH]c1=O
Yield: 22.1 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using tert-butyl 2-tert-butylhydrazinecarboxylate (Intermediate-74, 0.233 g, 1.2 mmol), 2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzoyl isocyanate (step-3 of Intermediate-26, 0.400 g, 1.2 mmol), DCM (10 mL), trifluoro acetic acid (5.0 mL) to afford 0.100 g of the desired product. 1H NMR (400 MHz; DMSO d6): δ 1.52 (s, 9H), 4.42 (s, 2H), 7.39 (d, 1H), 7.41 (s, 1H), 7.58 (d, J=2.1 Hz, 2H), 10.0 (br s, 1H), 12.0 (br s, 1H); MS (in/z): 377.20 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([C:6]#[CH:7])[CH2:3][CH2:4][OH:5].[CH3:9][O:10][C:11]([C:13]1[S:14][C:15](I)=[CH:16][C:17]=1[N:18]([CH:28]1[CH2:33][CH2:32][CH:31]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH2:30][CH2:29]1)[C:19]([CH:21]1[CH2:26][CH2:25][CH:24]([CH3:27])[CH2:23][CH2:22]1)=[O:20])=[O:12].C(N(CC)CC)C>CN(C=O)C.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.[Cu]I>[CH3:9][O:10][C:11]([C:13]1[S:14][C:15]([C:7]#[C:6][C:2]([CH3:8])([CH3:1])[CH2:3][CH2:4][OH:5])=[CH:16][C:17]=1[N:18]([CH:28]1[CH2:29][CH2:30][CH:31]([O:34][Si:35]([C:38]([CH3:39])([CH3:41])[CH3:40])([CH3:36])[CH3:37])[CH2:32][CH2:33]1)[C:19]([CH:21]1[CH2:22][CH2:23][CH:24]([CH3:27])[CH2:25][CH2:26]1)=[O:20])=[O:12]
Reactant: C#CC(C)(C)CCO
Reactant: COC(=O)c1sc(I)cc1N(C(=O)C1CCC(C)CC1)C1CCC(O[Si](C)(C)C(C)(C)C)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1sc(C#CC(C)(C)CCO)cc1N(C(=O)C1CCC(C)CC1)C1CCC(O[Si](C)(C)C(C)(C)C)CC1
Yield: 90.2 %

Procedure:
A solution of 3,3-dimethyl-pent-4-yn-1-ol (600 mg, 5.36 mmol), 3-[[4-(tert-Butyl-dimethyl-silanyloxy)-cyclohexyl]-(4-methyl-cyclohexanecarbonyl)-amino]-5-iodo-thiophene-2-carboxylic acid methyl ester (2767 mg, 4.46 mmol) and triethylamine (10.8 mL, 77.48 mmol) in DMF (25 mL) was degassed for 10 minutes with nitrogen. PdCl2(PPh3)2 (314 mg, 0.45 mmol) and CuI (170 mg, 0.90 mmol) was added and the resulting mixture was degassed with nitrogen for an additional 5 minutes after which the reaction was placed in a 80° C. oil bath and heated for 3.5 h. The reaction was cooled and partitioned between ethyl acetate and sat. NaHCO3. The organic layer was separated, washed with 5% LiCl, brine, dried over Na2SO4 and concentrated to give a dark brown foam. Purification by flash column chromatography on silica gel using 30% ethyl acetate in hexanes then 5% methanol in ethyl acetate provided 3-[[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-(4-methyl-cyclohexanecarbonyl)-amino]-5-(5-hydroxy-3,3-dimethyl-pent-1-ynyl)-thiophene-2-carboxylic acid methyl ester (2.43 g, 90%) as a pale yellow foam.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[O:7]([CH2:14][CH:15]([OH:17])[CH3:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:4]([O:17][CH:15]([CH3:16])[CH2:14][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:5])[CH2:3][C:2]([CH3:1])=[O:6]
Reactant: C=C1CC(=O)O1
Reactant: CC(O)COc1ccccc1
Product: CC(=O)CC(=O)OC(C)COc1ccccc1

Procedure:
In a similar manner, diketene was reacted with 1-phenoxy-2-propanol to obtain 1-methyl-2-(phenoxy)ethyl acetoacetate, BP 115°-122° C./0.05-0.1 mm.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:6](=[S:8])[NH2:7])#[N:2].[CH2:17]([O:19][C:20](=[O:26])[CH:21](Cl)[C:22]([CH3:24])=O)[CH3:18]>O>[C:1]([C:3]1[CH:4]=[C:5]([C:6]2[S:8][C:21]([C:20]([O:19][CH2:17][CH3:18])=[O:26])=[C:22]([CH3:24])[N:7]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH:14]([CH3:16])[CH3:15])#[N:2]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: CC(C)COc1ccc(C(N)=S)cc1C#N
Solvent: O
Product: CCOC(=O)c1sc(-c2ccc(OCC(C)C)c(C#N)c2)nc1C
Temperature: 25 °C
Yield: 90.7 %

Procedure:
Water (30 mL) was placed into a round bottom flask and 3-cyano-4-isobutoxybenzothioamide (3.0 g) was added, followed by addition of ethyl-2-chloroacetoacetate (2.52 g). The mixture was heated to reflux and maintained until reaction completion. After the reaction was completed, the mass was cooled to about 25° C. and maintained for about 20 minutes. The mass was then filtered. The wet solid was dried at about 60° C. to a constant weight to yield 4.0 g of the title compound. Purity by HPLC: 95.74%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([OH:17])=[C:14]([C:18]#[N:19])[C:13](=[O:20])[NH:12][C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1.[S:21]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22]1.OC1C=CC(B(O)O)=CC=1>>[OH:17][C:15]1[C:16]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:23]4[CH:24]=[CH:25][S:21][CH:22]=4)=[CH:3][CH:4]=3)=[CH:9][S:10][C:11]=2[NH:12][C:13](=[O:20])[C:14]=1[C:18]#[N:19]
Reactant: OB(O)c1ccsc1
Reactant: N#Cc1c(O)c2c(-c3ccc(Br)cc3)csc2[nH]c1=O
Agent: OB(O)c1ccc(O)cc1
Product: N#Cc1c(O)c2c(-c3ccc(-c4ccsc4)cc3)csc2[nH]c1=O

Procedure:
Example 109 was prepared from 3-(4-Bromo-phenyl)-4-hydroxy-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carbonitrile (Example 9) using the same procedure as described for Example 189 substituting 3-thiopheneboronic acid for 4-hydroxyphenyl boronic acid. MS (ESI) m/z 350.9 (M+H+); 1H NMR (300 MHz, DMSO-d6) δ ppm 7.91 (dd, 1H), 7.71 (d, 2H), 7.65 (dd, 1H), 7.60 (dd, 1H), 7.45 (d, 1H).
Reaction SMILES: CO[CH:3]([CH3:7])[CH2:4][CH:5]=[O:6].[CH2:8]([C:10]([CH2:12]C)=O)[CH3:9].[CH3:14][O-].[Na+]>CO>[CH3:14][C:4]1[C:5](=[O:6])[CH:8]([CH3:9])[CH:10]([CH3:12])[CH2:7][CH:3]=1
Reactant: COC(C)CC=O
Reactant: C[O-]
Reactant: CCC(=O)CC
Agent: [Na+]
Solvent: CO
Product: CC1=CCC(C)C(C)C1=O
Yield: 56 %

Procedure:
102 g of β-methoxybutyraldehyde is dripped in the course of one hour into a mixture of 500 g of diethyl ketone and 10 g of a 30% solution of sodium methylate in methanol which is boiling under reflux. The whole is then heated for another hour under reflux. The reaction mixture is processed as described in Example 2. 77 g of 2,5,6-trimethyl-2-cyclohexen-1-one is obtained, i.e. a 56% yield with reference to β-methoxybutyraldehyde.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([F:38])=[C:13]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:17][CH:16]2[C:35]([OH:37])=O)[CH:14]=1.[NH2:39][C:40]1[CH:49]=[CH:48][C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][CH:41]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:47][O:46][C:44](=[O:45])[C:43]1[CH:48]=[CH:49][C:40]([NH:39][C:35]([C@H:16]2[C@H:15]([C:13]3[CH:14]=[C:9]([Cl:8])[CH:10]=[CH:11][C:12]=3[F:38])[C@:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[C@H:18]([CH2:30][C:31]([CH3:33])([CH3:34])[CH3:32])[NH:17]2)=[O:37])=[CH:41][CH:42]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cc(Cl)ccc2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: COC(=O)c1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cc(Cl)ccc2F)cc1
Yield: 26.2 %

Procedure:
In a manner similar to the method described in Examples 1e, rac-(2R,3S,4R,5S)-3-(5-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 98c (0.5 g, 0.89 mmol) was reacted with methyl 4-aminobenzoate (0.24 g, 1.6 mmol), HATU (0.61 g, 1.6 mmol) and iPr2NEt (0.39 mL, 2.2 mmol) in CH2Cl2 at room temperature to give rac-4-{[(2R,3S,4R,5S)-3-(5-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid methyl ester as a white solid (0.14 g, 27%).
Reaction SMILES: C[O:2][C:3]1[N:4]=[C:5]2[CH2:13][CH2:12][CH2:11][O:10][C:6]2=[N:7][C:8]=1[CH3:9].I[Si](C)(C)C>S1(CCCC1)(=O)=O.C(OCC)(=O)C>[CH3:9][C:8]1[N:7]=[C:6]2[O:10][CH2:11][CH2:12][CH2:13][C:5]2=[N:4][C:3]=1[OH:2]
Reactant: COc1nc2c(nc1C)OCCC2
Agent: C[Si](C)(C)I
Solvent: O=S1(=O)CCCC1
Solvent: CCOC(C)=O
Product: Cc1nc2c(nc1O)CCCO2
Temperature: 42.5 °C
Reaction time: 48 h

Procedure:
To a suspension of 2-methoxy-3-methyl-7,8-dihydro-6H-pyrano[2,3-b]pyrazine (1.95 g, 10.8 mmol) in sulfolane (25 mL) was added iodotrimethylsilane (15.0 g, 75.0 mmol) at 30° C. The reaction mixture was heated at 40-45° C. for 8 h, and then cooled to ambient temperature and stirred for 2 days. And the reaction mixture was diluted with ethyl acetate and washed with 2% aqueous sodium sulfite. The aqueous layer was extracted with ethyl acetate and chloroform. The organic layer was combined, dried over sodium sulfate, filtrated and concentrated in vacuo. The crude was purified by silica gel column chromatography (ethyl acetate to ethyl acetate:methanol=93:7) to give 3-methyl-7,8-dihydro-6H-pyrano[2,3-b]pyrazin-2-ol and recovered starting material. MS (APCI): m/z 177 (M+H).
Reaction SMILES: [C:1]([OH:4])(=O)C.C(O)=O.[NH2:8][CH2:9][C:10]1[S:14][C:13]2=[CH:15][N:16]=[CH:17][N:12]2[CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>O.ClCCl>[CH:1]([NH:8][CH2:9][C:10]1[S:14][C:13]2=[CH:15][N:16]=[CH:17][N:12]2[CH:11]=1)=[O:4]
Reactant: NCc1cn2cncc2s1
Reactant: CC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=CO
Solvent: O
Solvent: ClCCl
Product: O=CNCc1cn2cncc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixed solution of 0.14 ml of acetic acid and 0.28 ml of formic acid which had been beforehand reacted with each other at 50° C. for 15 minutes was added to 3 ml of dry dichloromethane containing 154.6 mg of 2-aminomethylimidazo[5,1-b]thiazole at room temperature, and the mixture was then stirred at room temperature for 1 hour. Then, 2 ml of water was added to the reaction solution, and the solution was alkalified with anhydrous potassium carbonate under stirring. The solution was extracted with dichloromethane (15 ml×3). The combined organic layer was dried over anhydrous magnesium sulfate and then filtered, and the solvent was then evaporated under reduced pressure. The resulting crude product was purified by a silica gel column chromatograph to obtain 118.4 mg of the title compound as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]([OH:17])([CH3:16])[CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH:3]=1.[Cl:18][C:19]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:20]=1[CH2:21]Cl>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:21][C:20]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:19]=2[Cl:18])=[C:4]([C:9]([OH:17])([CH3:16])[CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH:3]=1
Reactant: CC(O)(Cn1ccnc1)c1cc(Cl)ccc1O
Reactant: ClCc1ccc(Cl)cc1Cl
Product: CC(O)(Cn1ccnc1)c1cc(Cl)ccc1OCc1ccc(Cl)cc1Cl
Yield: 51.9 %

Procedure:
The general procedure of Example 6 was repeated using 4-chloro-2-(1-hydroxy-2-(1H-1-imidazolyl)-1-methylethyl)phenol [compound (2-1)] and 2,4-dichlorobenzyl chloride, to thereby yield 2-(5-chloro-2-((2,4-dichlorobenzyl)oxy)phenyl)-1-(1H-1-imidazolyl)-2-propanol as colorless crystals (yield: 51.9%).
Reaction SMILES: [F-].[K+:2].C1COS(=O)(=O)CC1.[C:11]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][S:29]([OH:32])(=[O:31])=[O:30])([C:14]([C:17]([C:20]([F:23])([F:22])[F:21])([F:19])[F:18])([F:16])[F:15])([F:13])[F:12].[NH4+]>>[C:11]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][S:29]([O:32][K:2])(=[O:31])=[O:30])([C:14]([C:17]([C:20]([F:23])([F:21])[F:22])([F:19])[F:18])([F:16])[F:15])([F:13])[F:12]
Reactant: [K+]
Reactant: O=S(=O)(O)CCCCOC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: O=S1(=O)CCCCO1
Agent: [F-]
Agent: [NH4+]
Product: O=S(=O)(CCCCOC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)O[K]

Procedure:
n-C4F9OC4H8SO3K was prepared from normal-perfluorobutyl acid fluoride, KF and 1,4-butane sultone and isolated in 92% purity as described in U.S. Pat. No. 6,890,452, as FC-11. The sulfonic acid salt was converted to the corresponding acid through an ion-exchange column packaged with acidified Amberlite IR-120 ion-exchange resin. The corresponding ammonium salt was prepared by adjusting the pH of C4F9O(CH2)4SO3H aqueous solution to ˜10 with 10% aqueous ammonium solution.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH:8]1OC2C(Cl)=C(Cl)C(Cl)=C(Cl)C=2O1)=O.[C:21]1([NH:27][NH2:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[C:6](=[N:28]/[NH:27][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)/[CH:8]=[N:28][NH:27][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NNc1ccccc1
Reactant: O=C(c1ccco1)C1Oc2c(Cl)c(Cl)c(Cl)c(Cl)c2O1
Solvent: CCO
Product: C(=NNc1ccccc1)/C(=N\Nc1ccccc1)c1ccco1
Yield: 86.8 %

Procedure:
A mixture of furan-2-yl(4,5,6,7-tetrachlorobenzo[d][1,3]dioxol-2-yl)methanone (200 mg, 0.568 mmol) and phenylhydrazine (185 mg, 1.704 mmol) in ethanol (3 ml) was heated under reflux for 30 minutes. During the course of the reflux, a yellow solid initially precipitated, but then dissolved upon further heating. The solvent was evaporated to dryness, and the resulting crude material was subjected to flash column chromatography using 7% ethyl acetate/hexane as an eluent to yield (2E)-2,2′-(1-(furan-2-yl)ethane-1,2-diylidene)bis(1-phenylhydrazine) as a yellow solid (150 mg, 87%).
Reaction SMILES: C([O:4][C:5](=[O:52])[C@H:6]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][P:33]([CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:34])=[C:28]([N+:49]([O-:51])=[O:50])[CH:27]=1)[NH:7][C:8]([O:10][CH2:11][CH:12]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9])C=C.CNC1C=CC=CC=1.CCOC(C)=O.OS([O-])(=O)=O.[K+]>C1COCC1>[C:8]([NH:7][C@H:6]([C:5]([OH:52])=[O:4])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][P:33]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([CH2:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[O:34])=[C:28]([N+:49]([O-:51])=[O:50])[CH:27]=1)([O:10][CH2:11][CH:12]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9]
Reactant: C=CCOC(=O)[C@H](Cc1ccc(OP(=O)(Cc2ccccc2)Cc2ccccc2)c([N+](=O)[O-])c1)NC(=O)OCC1c2ccccc2-c2ccccc21
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CNc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(N[C@@H](Cc1ccc(OP(=O)(Cc2ccccc2)Cc2ccccc2)c([N+](=O)[O-])c1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Yield: 95.7 %

Procedure:
Synthesis Fmoc-3-nitro-O-(dibenzylphosphoryl)tyrosine allyl ester 3 (3.15 g, 4.2 mmol) was dissolved in dry THF (20 mL), after which N-methylaniline (1.40 mL, 12.9 mmol) and tetrakis triphenylphosphine palladium (254 mg, 0.22 mmol) were added. After stirring for 2 h at room temperature under a N2-atmosphere in the dark, EtOAc (50 mL) and 1M KHSO4 (50 mL) were added. After drying on Na2SO4 and column chromatography (5% MeOH in DCM), the product (2.72 g, 91%) was obtained as a light yellow foam.