Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][N:3]=1.[C-:9]#[N:10].[Na+]>CS(C)=O.C(OCC)(=O)C>[C:9]([C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][N:3]=1)#[N:10]
Reactant: Fc1cc(I)ccn1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#Cc1cc(I)ccn1
Temperature: 100 °C
Yield: 5 %

Procedure:
2-Fluoro-4-iodopyridine (4.99 g, 22.4 mmol) prepared according to a known method (WO2005/041663) was dissolved in dimethyl sulfoxide (75 mL), and the mixture was stirred at 100° C. after adding sodium cyanide (1.21 g, 24.7 mmol). The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with an aqueous sodium bicarbonate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate. The residue obtained upon concentration under reduced pressure was purified by silica gel column chromatography to give 2-cyano-4-iodopyridine (258 mg, 5%).
Reaction SMILES: CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].Br[CH2:16][C:17]1[N:21]([C:22]2[C:27]([Cl:28])=[CH:26][C:25]([C:29]([F:32])([F:31])[F:30])=[CH:24][C:23]=2[Cl:33])[N:20]=[C:19]([C:34]#[N:35])[C:18]=1[S:36][C:37]([F:40])([F:39])[F:38].OO.O>C1COCC1.C(OCC)(=O)C>[C:34]([C:19]1[C:18]([S:36][C:37]([F:38])([F:40])[F:39])=[C:17]([CH3:16])[N:21]([C:22]2[C:27]([Cl:28])=[CH:26][C:25]([C:29]([F:31])([F:32])[F:30])=[CH:24][C:23]=2[Cl:33])[N:20]=1)#[N:35]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(CBr)c1SC(F)(F)F
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: OO
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1c(SC(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.6 %

Procedure:
A solution of L-selectride (14.2 mL, 1M in THF) was added to a solution of 5-bromomethyl-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylthiopyrazole (6.75 g) in THF at −78° C. The reaction mixture was allowed to warm to room temperature with stirring over one hour, and then hydrogen peroxide (2.6 mL, 30% w/v) was added followed by water and ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by chromatography (SiO2, heptane/EA) to afford the title compound as a white solid (3.67 g, 65%). MS (ES): M/Z [M+NH4]=437. 1H NMR: (400 MHz, DMSO-d6): 2.30 (s, 3H) and 8.39 (s, 2H). 19F NMR (376 MHz, DMSO-d6): −44.03 (s, 3F) and −61.98 (s, 3F).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([NH:16][CH2:17][CH2:18][NH:19][C:20](=[O:22])[CH3:21])[C:10]([CH2:23]O)=[CH:9]3)[CH2:3][CH2:2]1.O=S(Cl)[Cl:27]>C(Cl)Cl>[ClH:27].[Cl:27][CH2:23][C:10]1[C:11]([NH:16][CH2:17][CH2:18][NH:19][C:20](=[O:22])[CH3:21])=[N:12][C:13]2[C:8]([CH:9]=1)=[CH:7][C:6]([O:5][CH2:4][CH:1]1[CH2:3][CH2:2]1)=[CH:15][CH:14]=2
Reactant: O=S(Cl)Cl
Reactant: CC(=O)NCCNc1nc2ccc(OCC3CC3)cc2cc1CO
Solvent: ClCCl
Product: CC(=O)NCCNc1nc2ccc(OCC3CC3)cc2cc1CCl
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a stirred solution of N-(2-(6-(cyclopropylmethoxy)-3-(hydroxymethyl)quinolin-2-ylamino)ethyl)acetamide SLA 47096A (0.374 g, 1.1 mmol) in dry CH2Cl2 (11 mL) in a 25 mL round-bottomed flask equipped with a magnetic stirrer was added dropwise SOCl2 (1.65 mL, 22.7 mmol). The mixture was stirred for 2 h at RT then concentrated to dryness at 40° C. under vacuum. The residue was then taken up in CH2Cl2 (20 mL) before concentration back to dryness at 40° C. under vacuum (done 3 times) to give N-(2-(3-(chloromethyl)-6-(cyclopropylmethoxy)quinolin-2-ylamino)ethyl)acetamide hydrochloride SLA 47096B as a yellow solid (0.475 g, 100% yield).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH:3]=1.[NH2:22][CH2:23][CH:24]([OH:27])[CH2:25][NH2:26]>>[ClH:1].[NH2:22][CH2:23][CH:24]([OH:27])[CH2:25][NH:26][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH:3]=1
Reactant: COc1ccc2c(Cl)cc(-c3ccc(Cl)c(Cl)c3)nc2c1
Reactant: NCC(O)CN
Product: COc1ccc2c(NCC(O)CN)cc(-c3ccc(Cl)c(Cl)c3)nc2c1
Product: Cl

Procedure:
The title compound, m.p. 230-233° C., and MS: m/e=391 (M+), was prepared from 4-chloro-2-(3,4-dichloro-phenyl)-7-methoxy-quinoline and 1,3-diamino-2-propanol.
Reaction SMILES: FC1C=CC(C[N:7]2C(=O)N(C3SC(C(O)=O)=C(C)N=3)C=N2)=CC=1.[F:24][C:25]1[CH:47]=[CH:46][C:28]([CH2:29][N:30]2[C@H:34]([CH3:35])[CH2:33][N:32]([C:36]3[S:37][C:38]([C:42]([OH:44])=O)=[C:39]([CH3:41])[N:40]=3)[C:31]2=[O:45])=[CH:27][CH:26]=1>>[F:24][C:25]1[CH:47]=[CH:46][C:28]([CH2:29][N:30]2[C@H:34]([CH3:35])[CH2:33][N:32]([C:36]3[S:37][C:38]([C:42]([NH2:7])=[O:44])=[C:39]([CH3:41])[N:40]=3)[C:31]2=[O:45])=[CH:27][CH:26]=1
Reactant: Cc1nc(N2C[C@@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Product: Cc1nc(N2C[C@@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(N)=O

Procedure:
Following the procedure as described in Example 1, making variations as required to replace 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methyl-thiazole-5-carboxylic acid with (R)-2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid: mp 185-186° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.40-7.32 (m, 4H), 7.21-7.15 (m, 2H), 4.59 (d, J=15.6 Hz, 1H), 4.30 (d, J=15.6 Hz, 1H), 4.18 (dd, J=10.0, 9.1 Hz 1H), 3.77-3.70 (m, 1H), 3.54 (dd, J=10.1, 6.8 Hz, 1H), 2.45 (s, 3H), 1.22 (d, J=6.2 Hz, 3H); MS (ES+) m/z 348.9 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:26])=[CH:3][CH2:4][N:5]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=1)[CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[CH3:27][C:28]([CH3:33])([CH3:32])[CH2:29][CH:30]=O>>[CH3:27][C:28]([CH3:33])([CH3:32])[CH2:29][CH2:30][N:9]1[CH2:8][CH2:7][CH:6]([N:5]([CH2:4][CH:3]=[C:2]([CH3:26])[CH3:1])[C:12]2[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10]1
Reactant: CC(C)=CCN(c1ccc(CCc2ccccc2)cc1)C1CCNCC1
Reactant: CC(C)(C)CC=O
Product: CC(C)=CCN(c1ccc(CCc2ccccc2)cc1)C1CCN(CCC(C)(C)C)CC1

Procedure:
The preparation of Example 48: [1-(3,3-Dimethyl-butyl)-piperidin4-yl]-(3-methyl-but-2-enyl)-(4-phenethyl-phenyl)-amine was prepared in accordance with the methods of Step 8 in Example 37 except that (3-Methyl-but-2-enyl)-(4-phenethyl-phenyl)-piperidin-4-yl-amine (48g) was used instead of [4-(3,3-Dimethyl-butyl)-phenyl]-(3-methyl-but-2-enyl)-pipendin-4-yl-amine (37g) and 3,3-dimethylbutyraldehyde was used instead of isovaleraldehyde.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6](Cl)=[CH:7][CH:8]=2)[N:3]=1.[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20].[OH-].[K+]>>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6]([O:20][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[Br:13])=[CH:7][CH:8]=2)[N:3]=1
Reactant: Oc1ccccc1Br
Reactant: Nc1ccc2ccc(Cl)nc2n1
Agent: [K+]
Agent: [OH-]
Product: Nc1ccc2ccc(Oc3ccccc3Br)nc2n1
Temperature: 120 °C
Yield: 36.9 %

Procedure:
The procedure is similar to that described in Example 4, but starting with 2-amino-7-chloro-1,8-naphthyridine (19.7 g), 2-bromophenol (81.5 g) and potassium hydroxide pellets (15.15 g; 85% purity). After 10 hours' heating at 120° C. and treatment under the conditions described above in Example 4, the product produced (21.5 g; m.p. 160° C.) is purified by chromatography on a column 45 mm in diameter containing silica (300 g; 0.040-0.063 mm), eluting with a mixture (95:5 by volume) of methylene chloride and methanol and collecting 100-cc fractions. After concentration to dryness of the fractions 2 to 10 at 40° C. under reduced pressure (4 kPa), 2-amino-7-(2-bromophenoxy)-1,8-naphthyridine (12.8 g) is produced, m.p. 206° C.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]2([CH2:21][CH2:20][CH2:19]2)[CH2:16][C:15]2[N:14]=[C:13]([CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:12]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:11](I)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:34]1[CH2:39][CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH2:36][CH2:35]1.C(=O)([O-])[O-].[Cs+].[Cs+].[F-].[Cs+]>O.O1CCCC1.C1(C)C=CC=CC=1>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]2([CH2:21][CH2:20][CH2:19]2)[CH2:16][C:15]2[N:14]=[C:13]([CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:12]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:11]([C:37]3[CH2:38][CH2:39][O:34][CH2:35][CH:36]=3)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1c(C2CCOCC2)nc2c(c1I)[C@@H](O[Si](C)(C)C(C)(C)C)CC1(CCC1)C2
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1c(C2CCOCC2)nc2c(c1C1=CCOCC1)[C@@H](O[Si](C)(C)C(C)(C)C)CC1(CCC1)C2

Procedure:
Obtained by starting from (S)-ethyl 5′-(tert-butyldimethylsilyloxy)-4′-iodo-2′-(tetrahydro-2H-pyran-4-yl)-6′,8′-dihydro-5′H-spiro[cyclobutane-1,7′-quinoline]-3′-carboxylate and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. A 2 M solution of caesium carbonate in water is used instead caesium fluoride. The reaction is run in tetrahydrofurane/toluene 4:1.
Reaction SMILES: C(CC(O)=S)=CC1C=CC=CC=1.[CH:13]([S:21]([CH2:24][C:25]([OH:27])=[O:26])(=[O:23])=[O:22])=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)(=O)C.OO>[CH:13](/[S:21]([CH2:24][C:25]([OH:27])=[O:26])(=[O:22])=[O:23])=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)CS(=O)(=O)C=Cc1ccccc1
Agent: OC(=S)CC=Cc1ccccc1
Agent: OO
Solvent: CC(=O)O
Product: O=C(O)CS(=O)(=O)/C=C\c1ccccc1
Temperature: 0 °C

Procedure:
The styrylthioacetic acid is then oxidized to styrylsulfonylacetic acid as follows. A mixture of styrylthioacetic acid (5 g, 25 mmol) in glacial acetic acid (35 ml) and 30% hydrogen peroxide (15 ml) is heated under reflux for 60 minutes and the mixture is poured onto crushed ice (200 ml) after cooling. The compound separated is filtered and recrystallized from hot water to give white crystalline flakes of (Z)-styrylsulfonylacetic acid; yield 2.4 g (41%); m.p. 150-51° C.
Reaction SMILES: [BH4-].[Na+].O.C([O:6][C:7]([C:9]1([NH:13][C:14]([C:16]2[C:17]3[CH2:18][C@H:19]4[CH2:30][C@H:20]4[C:21]=3[N:22]([C:24]3[CH:29]=[N:28][CH:27]=[CH:26][N:25]=3)[N:23]=2)=[O:15])[CH2:12][CH2:11][CH2:10]1)=O)C>O1CCOCC1>[OH:6][CH2:7][C:9]1([NH:13][C:14]([C:16]2[C:17]3[CH2:18][C@H:19]4[CH2:30][C@H:20]4[C:21]=3[N:22]([C:24]3[CH:29]=[N:28][CH:27]=[CH:26][N:25]=3)[N:23]=2)=[O:15])[CH2:12][CH2:11][CH2:10]1
Reactant: CCOC(=O)C1(NC(=O)c2nn(-c3cnccn3)c3c2C[C@H]2C[C@@H]32)CCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(NC1(CO)CCC1)c1nn(-c2cnccn2)c2c1C[C@H]1C[C@@H]21
Temperature: 25 °C
Yield: 56.5 %

Procedure:
To a solution of sodium borohydride (0.206 g, 5.44 mmol) in dioxane (2.0 mL) with water (1.0 mL) was added 1-[((1aR,5aR)-2-pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonyl)-amino]-cyclobutanecarboxylic acid ethyl ester (1.0 g, 2.72 mmol) at 0° C. The mixture was stirred at room temperature until the starting materials were consumed. The mixture was concentrated and added 2 M HCl was added to adjust pH to 3. The isolated precipitate was dissolved in DCM and purified by silica gel column chromatography to give the title compound (0.5 g) as a solid. LCMS m/z=326.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.47 (dd, J=8.0 and 4.7 Hz, 1H), 1.26 (td, J=7.8 and 4.9 Hz, 1H), 1.85-2.26 (m, 2H), 2.21-2.40 (m, 5H), 2.73-2.78 (m, 1H), 2.91 (d, J=16.8 Hz, 1H), 3.00 (dd, J=16.6 and 6.3 Hz, 1H), 3.90 (s, 2H), 7.21 (bs, NH, 1H), 8.42 (dd, J=2.3 and 1.5 Hz, 1H), 8.51 (d, J=2.5 Hz, 1H), 9.26 (d, J=1.4 Hz, 1H).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11](=[O:33])[CH:12]([C:16]1[CH:17]=[C:18]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[CH:19]=[C:20]([OH:22])[CH:21]=1)[CH2:13][CH2:14][CH3:15])[CH3:9].[F:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1>CC([O-])=O.CC([O-])=O.[Cu+2].C(Cl)Cl>[CH2:8]([O:10][C:11](=[O:33])[CH:12]([C:16]1[CH:17]=[C:18]([C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:32])[F:31])=[CH:27][CH:28]=2)[CH:19]=[C:20]([O:22][C:38]2[CH:39]=[CH:40][C:35]([F:34])=[CH:36][CH:37]=2)[CH:21]=1)[CH2:13][CH2:14][CH3:15])[CH3:9]
Reactant: CCCC(C(=O)OCC)c1cc(O)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: OB(O)c1ccc(F)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(C(=O)OCC)c1cc(Oc2ccc(F)cc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Reaction time: 24 h
Yield: 58.2 %

Procedure:
Triethylamine (100 μL, 0.72 mmol) was added to a stirred mixture of 2-(5-hydroxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (90 mg, 0.25 mmol), Cu(OAc)2 (68 mg, 0.38 mmol), 4-fluorophenylboronic acid (70 mg, 0.57 mmol), 4 {acute over (Å)} molecular sieves (25 mg, powdered) and DCM (2 mL) at room temperature open to the air. After 24 h, the reaction mixture was loaded onto silica and purified (0-10% ethyl acetate in petrol) to give 2-(5-(4-fluorophenoxy)-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (67 mg) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:26][C@H:25]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:10]2[O:11][C:12](=[O:14])[CH3:13])[OH:9])=[CH:4][C:3]=1[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][C:40]2([C:45](O)=[O:46])[CH2:44][CH2:43][CH2:42][CH2:41]2)=[CH:35][CH:34]=1.C(Cl)(=O)C(Cl)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:26][C@H:25]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:10]2[O:11][C:12](=[O:14])[CH3:13])[OH:9])=[CH:4][C:3]=1[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][C:40]2([CH2:45][OH:46])[CH2:44][CH2:43][CH2:42][CH2:41]2)=[CH:35][CH:34]=1
Reactant: CC(=O)OC[C@H]1O[C@](O)(c2ccc(Cl)c(Cc3ccc(OC4(C(=O)O)CCCC4)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@](O)(c2ccc(Cl)c(Cc3ccc(OC4(CO)CCCC4)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1-chloro-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-2-[4-(1-hydroxycarbonyl-cyclopent-1-yloxy)-benzyl]-benzene (1.50 g) in dichloromethane (7 mL) cooled in an ice-bath is added oxalyl chloride (1 mL). The solution is stirred at ambient temperature for 4 h and then concentrated under reduced pressure. The residue is dissolved in dry tetrahydrofuran (4 mL), cooled in an ice-bath and treated with sodium borohydride (86 mg). The resultant mixture is stirred at room temperature for 16 h. Water is added and the resulting mixture is extracted with ethyl acetate. The combined extracts are dried (Na2SO4), the solvent is removed in vacuo and the residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 1:0→2:1).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:12])[O:8][CH2:9][CH2:10][F:11])[C@H:3]1[C:13]([OH:15])=[O:14].FCCO.[CH2:21]([N:24]1[CH2:28][C:27](=[O:29])[N:26]([CH2:30]O)[C:25]1=[O:32])[C:22]#[CH:23]>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:16])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:12])[O:8][CH2:9][CH2:10][F:11])[C@H:3]1[C:13]([O:15][CH2:30][N:26]1[C:27](=[O:29])[CH2:28][N:24]([CH2:21][C:22]#[CH:23])[C:25]1=[O:32])=[O:14]
Reactant: C#CCN1CC(=O)N(CO)C1=O
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1/C=C\C(=O)OCCF
Agent: OCCF
Solvent: ClC(Cl)Cl
Product: C#CCN1CC(=O)N(COC(=O)[C@@H]2[C@H](/C=C\C(=O)OCCF)C2(C)C)C1=O

Procedure:
Using the procedure of Step F of Example 9, (1R,cis) 2,2-dimethyl-3-[(Z) 3-oxo-3-(2-fluoroethoxy)-1-propenyl]-cyclopropane-carboxylic acid prepared as in Example 21 except 2-fluoroethanol was used and (3-propargyl-2,5-dioxo-imidazolidinyl)-methanol were reacted to obtain (3-propargyl-2,5-dioxo-1-imidazolidinyl)-methyl (1R,cis) 2,2-dimethyl-3-[(Z) 3-oxo-3-(2-fluoroethoxy)-1-propenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+18°±2° (c=1% in CHCl3)
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][C:7]([CH2:8]CN)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:13][NH:14]CC1C=CC2C(=CC=CC=2)C=1CCC.Cl.[O:30]=[C:31]1[NH:40][C:39]2[N:38]=[CH:37][C:36](/[CH:41]=[CH:42]/[C:43]([OH:45])=O)=[CH:35][C:34]=2[CH2:33][CH2:32]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:14]([CH3:13])[C:43](=[O:45])/[CH:42]=[CH:41]/[C:36]2[CH:37]=[N:38][C:39]3[NH:40][C:31](=[O:30])[CH2:32][CH2:33][C:34]=3[CH:35]=2)=[CH:11][CH:12]=1)([CH3:2])[CH3:3]
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: CCCc1c(CNC)ccc2ccccc12
Reactant: CC(C)c1ccc(CCN)cc1
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: CC(C)c1ccc(CN(C)C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)cc1
Yield: 61 %

Procedure:
According to the procedure of Example 1 (a), except substituting (4-isopropyl-benzyl)methylamine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3yl)acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (0.223 g, 61%) was prepared as a light orange solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 10.66-10.64 (m, 1H), 8.36-8.33 (m, 1H), 8.07 (s, 1H), 7.55-7.48 (m, 1H), 7.33-7.11 (m, 5H), 4.77-4.56 (m, 2H), 3.09-2.81 (m, 6H), 2.56-2.49 (m 2H), 1.19-1.16 (m, 6H); MS (APCI) m/e 364 (M+H)+.
Reaction SMILES: Br[CH2:2][CH:3]1[CH:7]([CH2:8]Br)[O:6][C:5](=[O:10])[O:4]1.N12CCCNC1C=CCCC2.[CH3:22][OH:23].C([O:26][CH2:27]C)C.CCCCCC>C(Cl)Cl>[CH3:22][O:23][C:7]1([CH3:8])[C:3]([O:26][CH3:27])([CH3:2])[O:4][C:5](=[O:10])[O:6]1
Reactant: CO
Reactant: CCOCC
Reactant: O=C1OC(CBr)C(CBr)O1
Agent: C1=CC2NCCCN2CCC1
Solvent: ClCCl
Solvent: CCCCCC
Product: COC1(C)OC(=O)OC1(C)OC
Temperature: 20 °C
Reaction time: 4 h
Yield: 42 %

Procedure:
A mixture of 4,5-dibromomethyl-1,3-dioxolan-2-one (1.21 g, 4.4 mmole) and 1,8-diazabicyclo[5.4.0]undec-5-ene (1.31 ml, 8.8 mmole) in CH2Cl2 (25.0 ml) was stirred at 20° C. for 4 h. Methanol (2.0 ml, 49 mmole) was then added and the mixture was stirred for 1 h at 20° C. Flash chromato graphy (ethyl ether-hexane eluent) of the mixture yielded 4,5-dimethyoxy-4,5-dimethyl-1,3-dioxolan-2-one as a colorless crystalline solid (0.208 g, 42%): mp 76°-77° C.; IR (KBr) 2980, 2945, 1803, 1790, 1358, 1279, 1167, 1023, 990 cm-1 ; 'H NMR (CDCl3) 1.55(s, 1 H), 3.48 (s, 1H); Anal. C7H12O5 calcd. C 47.73, H 6.87, obsd. C47.69, H 6.49.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].[CH3:16][O:17][C:18]1[CH:36]=[CH:35][C:21]2[CH2:22][CH2:23][C:24]([CH3:34])([CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[O:25][C:20]=2[CH:19]=1.N1C=CC=CC=1.ClCCCl>O>[CH3:16][O:17][C:18]1[CH:36]=[CH:35][C:21]2[CH2:22][CH2:23][C:24]([CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][N:31]([C:6](=[O:7])[C:5]4[CH:4]=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=4)[CH2:30][CH2:29]3)([CH3:34])[O:25][C:20]=2[CH:19]=1
Reactant: COc1ccc2c(c1)OC(C)(CCN1CCNCC1)CC2
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCCl
Product: COc1ccc2c(c1)OC(C)(CCN1CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)CC1)CC2
Yield: 42.8 %

Procedure:
3,4,5-Trimethoxybenzoyl chloride (6.7 g, 0.029 mol) was added dropwise to a solution composed of 7.0 g (0.0241 mol) of 3,4-dihydro-7-methoxy-2-methyl-2-[2-(piperazin-1-yl)ethyl]-2H-benzopyran, 2.28 g of pyridine and 100 ml of 1,2-dichloroethane. The resultant mixture was stirred at room temperature for 2 hours. The reaction mixture obtained was poured into water and extracted with diethyl ether, the extract was dried over anhydrous sodium sulfate, and low-boiling substances were distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give 5.0 g of 1-[2-(3,4-dihydro-7-methoxy-2-methyl-2H-benzopyran-2-yl)ethyl]-4-(3,4,5-trimethoxybenzoyl)piperazine [Compound (25)] having the following physical characteristics.
Reaction SMILES: C([O:5][C:6](=[O:33])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:26]2[N:31]=[CH:30][C:29](Br)=[CH:28][N:27]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[CH:34]1([NH2:39])[CH2:38][CH2:37][CH2:36][CH2:35]1.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>ClCCl>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[CH:34]1([NH:39][C:29]2[CH:28]=[N:27][C:26]([N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:17][CH2:16][C:14]3[N:15]=[C:11]([S:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:5])=[O:33])[S:12][CH:13]=3)=[N:31][CH:30]=2)[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: NC1CCCC1
Reactant: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)c1ncc(Br)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1ncc(NC2CCCC2)cn1

Procedure:
A compound obtained using 2-[(4-{2-[(5-bromopyrimidin-2-yl)(heptyl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester synthesized in Example 442-1 and cyclopentylamine as starting materials and by an operation similar to that of Example 442-2 was treated with dichloromethane and trifluoroacetic acid. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; chloroform:methanol=10:1) to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][N:6]=1)=[O:4].[F:12][C:13]([F:21])([F:20])[CH2:14]OS(C)(=O)=O.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:14][C:13]([F:21])([F:20])[F:12])=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(O)cn1
Reactant: CS(=O)(=O)OCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(OCC(F)(F)F)cn1
Reaction time: 8 h

Procedure:
A mixture of 5-Hydroxy-pyridine-2-carboxylic acid methyl ester 2 (0.5 g, 3.26 mmol), methanesulfonic acid 2,2,2-trifluoro-ethyl ester (1.0 g, 5.34 mmol) and K2CO3 (1.4 g, 9.8 mmol) in acetonitrile (50 mL) was stirred overnight. The solid was filtered off and the filtrate was concentrated. The residue was purified by column chromatography (eluting with hexane and ethyl acetate 1:1) to afford 5-(2,2,2-Trifluoro-ethoxy)-pyridine-2-carboxylic acid methyl ester 3 as a white solid. Yield: 0.437 g, 57.1%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([S:22](=[O:40])(=[O:39])[NH:23][C:24]2[CH:25]=[CH:26][C:27]3[C@H:28]4[CH2:38][C@H:29]4[CH2:30][O:31][C:32]=3[C:33]=2[C:34]([O:36][CH3:37])=[O:35])=[C:6]([CH:21]=1)[CH2:7][O:8][C@H:9]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]1.F[C:42](F)(F)[C:43](O)=O>C(Cl)Cl>[CH2:42]([C@H:7]([O:8][CH:9]1[CH2:13][CH2:12][NH:11][CH2:10]1)[C:6]1[CH:21]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[S:22]([NH:23][C:24]1[C:33]([C:34]([O:36][CH3:37])=[O:35])=[C:32]2[C:27]([C@H:28]3[CH2:38][C@H:29]3[CH2:30][O:31]2)=[CH:26][CH:25]=1)(=[O:40])=[O:39])[CH3:43]
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2CO[C@H]2CCN(C(=O)OC(C)(C)C)C2)ccc2c1OC[C@@H]1C[C@H]21
Solvent: ClCCl
Product: CC[C@H](OC1CCNC1)c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OC[C@@H]1C[C@H]21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of tert-butyl (S)-3-[(1aR,7bS)-5-fluoro-2-(4-methoxycarbonyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-5-ylsulfamoyl)benzyloxy]pyrrolidine-1-carboxylate (Intermediate 214, 0.284 g) in trifluoroacetic acid (4 mL) and DCM (4 mL) was left at room temperature for 30 minutes. The mixture was evaporated in vacuo and the residue was azeotroped with toluene. The residue was dissolved in DCM (4 mL) and acetaldehyde (0.044 g) was added followed by sodium triacetoxyborohydride (0.212 g). The mixture was stirred at room temperature for 1 hour. The resulting solution was diluted with DCM and 1M sodium hydroxide solution and the organic layer was dried (Na2SO4) and filtered. The filtrate was evaporated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-20% to give methyl (1aR,7bS)-5-[2-((S)-1-ethylpyrrolidin-3-yloxymethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.221 g) as a white foam.