Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]2[CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[N:14]([C:23](=[O:40])[CH2:24][NH:25][C:26]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][C:36]([O:38]C)=[O:37])[CH:30]=3)=[O:27])[CH:13]([C:41](=[O:47])[NH:42]CC(C)C)[CH2:12]2)(=[O:10])=O)=[CH:4][CH:3]=1.[OH-:48].[K+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]2[CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[N:14]([C:23](=[O:40])[CH2:24][NH:25][C:26](=[O:27])[NH:28][C:29]3[CH:30]=[C:31]([CH2:35][C:36]([OH:38])=[O:37])[CH:32]=[CH:33][CH:34]=3)[C:13]([C:41](=[O:47])[NH2:42])([CH2:15][CH:16]([CH3:21])[CH3:17])[CH2:12]2)(=[O:10])=[O:48])=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: COC(=O)Cc1cccc(NC(=O)NCC(=O)N2C(C(=O)NCC(C)C)CC(S(=O)(=O)c3ccc(Cl)cc3)C2c2ccccc2F)c1
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)CC1(C(N)=O)CC(S(=O)(=O)c2ccc(Cl)cc2)C(c2ccccc2F)N1C(=O)CNC(=O)Nc1cccc(CC(=O)O)c1
Yield: 100.6 %

Procedure:
A The process is performed as in Example 1A, but starting with 3.35 g of (2 RS,4 SR,5RS)-4-(4-chlorophenyl)sulphonyl-5-(2-fluorophenyl)-2-isobutylcarbamoyl-1-{2-[3-(3-methoxycarbonylmethylphenyl)ureido]acetyl}-pyrrolidine and 0.36 g of potassium hydroxide in a mixture of 60 cm3 of methanol and 20 cm3 of distilled water. After treatment, 1.65 g of 3-(3-{2-[4-(4-chlorophenyl)sulphonyl-5-(2-fluorophenyl)-2-isobutyl carbamoyl-1-pyrrolidinyl]-2-oxoethyl}ureido)phenylacetic acid are obtained [Rf=0.45; eluent: methylene chloride/methanol (90/10); 1H NMR spectrum (200 MHz, (CD3)2SO with addition of a few drops of CD3COOD, at a temperature of 373 K, δ in ppm): 0.94 (d, J=6.5 Hz, 6H: C(CH3)2); 1.85 (mt, 1H: CH); from 2.30 to 2.55 and 2.84 (2 mts, 1H each: CH2 at 3); 3.06 (mt, 2H: NCH2); 3.50 (s, 2H: ArCH2COO); 3.67 and 3.88 (broad d and d respectively, J=17 Hz, 1H each:COCH2N); 4.08 (mt, 1H: H4); 4.78 (t, J=8 Hz, 1H: H2); 5.68 (d, J=3 Hz, 1H: H5); 6.12 (residual t:NHCO); 6.85 (broad d, J=7.5 Hz, 1H: aromatic H (H4 : ortho to the CH2)); from 6.95 to 7.30 (mt, 6H: aromatic H); 7.69 (broad d, J=8.5 Hz, 2H: H of the aromatic at 4 (H ortho to the Cl)); 7.96 (broad d, J=8.5 Hz, 2H: H aromatic at 4 (H meta to the Cl)); 8.20 (broad t, J=8 Hz, 1H: H of the aromatic at 5 (H6)); 8.40 (residual s: CONHAr)].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[Cl:18][C:19]1[C:20]([C:24](O)=[O:25])=[N:21][NH:22][CH:23]=1>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:24]([C:20]3[C:19]([Cl:18])=[CH:23][NH:22][N:21]=3)=[O:25])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: O=C(O)c1n[nH]cc1Cl
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Product: C[C@]1(c2cc(NC(=O)c3n[nH]cc3Cl)ccc2F)N=C(N)OC[C@@H]1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and 4-chloro-1H-pyrazole-3-carboxylic acid (CAS 84547-87-5) following procedure I yielded the title compound as a white solid. MS (ISP): m/z=370.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([C:21]([OH:23])=O)[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[C:25]([NH:28][CH2:29][CH2:30][NH2:31])(=[O:27])[CH3:26]>>[C:25]([NH:28][CH2:29][CH2:30][NH:31][C:21]([C:17]1[N:18]([CH3:20])[N:19]=[C:15]([O:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][O:10][C:11]=2[CH3:24])[CH:16]=1)=[O:23])(=[O:27])[CH3:26]
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)O)n(C)n1
Reactant: CC(=O)NCCN
Product: CC(=O)NCCNC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2C)nn1C
Yield: 56 %

Procedure:
As described for example 55, 5-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid (100 mg, 0.3 mmol) was converted, using N-acetylethylendiamine instead of 2-amino-2-methyl-1-propanol, to the title compound (70 mg, 56%) which was obtained as a white solid. MS: m/e=414.1 [M−H]−.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.O[CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[O:17]1[CH2:18][CH2:19][CH:14]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)[CH2:15][CH2:16]1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: OC1CCOCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(OC2CCOCC2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
An ice-cold solution of ethyl 4-hydroxybenzoate (0.82 g), 4-hydroxy-tetrahydro-2H-pyran (0.5 g) and triphenylphosphine in THF (50 ml) was treated dropwise with diisopropyl azodicarboxylate (1.69 ml). After 15 min the cooling bath was removed and the reaction stood overnight at rt. The mixture was evaporated, redissolved in toluene and successively washed with 2N sodium hydroxide (2×20 ml), water (2×20 ml) and brine (20 ml). After drying (magnesium sulfate) the solution was loaded directly on to a silica flash column (step gradient 10-30% EtOAc in light petroleum 40-60) to give the title compound (D5) (0.75 g). 1H NMR δ (CDCl3): 7.98 (2H, d, J=8.5Hz), 6.91 (2H, d, J=8.5 Hz), 4.60 (1H, m), 4.35 (2H, q, J=9.8 Hz), 3.98 (2H, m), 3.57 (2H, m), 2.05 (2H, m), 1.80 (2H, m), 1.38 (3H, t, J=9.8 Hz).
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]2[C:13]([S:14](Cl)(=[O:16])=[O:15])=[C:12]([Cl:18])[CH:11]=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>C1COCC1>[C:1]([C:5]1[O:6][C:7]2[C:13]([S:14]([N:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)(=[O:16])=[O:15])=[C:12]([Cl:18])[CH:11]=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCNCC1
Reactant: CC(C)(C)c1nc2ccc(Cl)c(S(=O)(=O)Cl)c2o1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1CCN(S(=O)(=O)c2c(Cl)ccc3nc(C(C)(C)C)oc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.5 %

Procedure:
To a solution of 2-tert-butyl-6-chloro-benzooxazole-7-sulfonyl chloride (2.69 g, 8.73 mmol) and triethylamine (2.44 mL, 17.5 mmol) in THF (60 mL) at 0° C. was added 1-methylpiperazine (0.98 mL, 8.83 mmol). The reaction was warmed to room temperature and allowed to stir overnight. The solution was concentrated and then diluted with water and extacted with ethyl acetate (3 times). The combined organic layers were dried with MgSO4, filtered, and concentrated. Flash chromatography (80% ethyl acetate/20% Ethanol) on silica gel gave the title compound (2.45 g, 76%). EI-MS m/z 372(M+H)+.
Reaction SMILES: [CH2:1]1[C:5]2=[C:6]3[C:7]([CH2:10][CH2:11]/[C:12]/3=[CH:13]\[CH2:14][NH2:15])=[N:8][CH:9]=[C:4]2[O:3][CH2:2]1.[C:16](Cl)(=[O:18])[CH3:17]>N1C=CC=CC=1.C(=O)([O-])O.[Na+]>[CH2:1]1[C:5]2=[C:6]3[CH:12]([CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])[CH2:11][CH2:10][C:7]3=[N:8][CH:9]=[C:4]2[O:3][CH2:2]1
Reactant: NC/C=C1\CCc2ncc3c(c21)CCO3
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)NCCC1CCc2ncc3c(c21)CCO3
Reaction time: 0.17 h
Yield: 21.7 %

Procedure:
To a solution of (2E)-2-(1,2,6,7-tetrahydro-8H-cyclopenta[b]furo[3,2-d]pyridin-8-ylidene)ethanamine (186 mg, 0.920 mmol) in pyridine (3.7 mL) was added acetyl chloride (78.5 μL, 1.10 mmol) under ice-cooling, and the mixture was stirred for 10 min. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=50/50→100/0). The residue was dissolved in methanol (1.1 mL), palladium-carbon powder (11 mg) was added, and the mixture was stirred at 50° C. for 3 hr under a hydrogen atmosphere. The catalyst was filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=90/10→100/0) to give the title compound (49.1 mg, yield 22%).
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1)#[N:2].[CH:18]([NH2:21])([CH3:20])[CH3:19]>C(#N)C>[C:1]([N:3]=[C:4]([NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1)[NH:21][CH:18]([CH3:20])[CH3:19])#[N:2]
Reactant: CC(C)N
Reactant: CSC(=NC#N)NC1CCCc2ccccc21
Solvent: CC#N
Product: CC(C)NC(=NC#N)NC1CCCc2ccccc21
Reaction time: 154 h

Procedure:
A solution of 30.0 g of N'-cyano-N-(1,2,3,4-tetrahydro-1-napthyl)-S-methylisothiourea and 40 ml of isopropylamine in 300 ml of acetonitrile was heated at reflux with stirring for 154 hours. The solvent and excess isopropylamine were removed by evaporation in vacuo, leaving the crude product as a tacky, white solid. Crystallization from isopropyl acetate followed by a recrystallization from a mixture of isopropyl acetate and 2-propanol gave 5.13 g of N"-cyano-N-isopropyl-N'-(1,2,3,4-tetrahydro-1-naphthyl)guanidine as a white, crystalline solid, mp 170.5°-172.5° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].Br[CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C([O-])(O)=O.[Na+]>C(N(CC)CC)C>[C:18]([CH2:17][CH2:16][NH:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13])([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)CCBr
Reactant: COc1ccc(C(C)=O)c(N)c1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNc1c(C(C)=O)ccc(OC)c1OC
Temperature: 135 °C
Reaction time: 5 h

Procedure:
Triethylamine (19.4 g, 192 mM) was added to a mixture of 2'-amino-3',4'-dimethoxyacetophenone (25 g, 128 mM) and ethyl 3-bromopropionate (139 g, 770 mM), in a 250 mL flask (equipped with a large stirring bar, reflux condenser and nitrogen inlet). The pale solid which formed was stirred at 135° C. for 5 hours. The brown homogeneous oil which formed was then cooled to 10° C. and 200 mL of 2% NaHCO3 was added. The solution was then extracted with CHCl3 (3×100 mL), the organic layer washed with H2O (100 mL) and dried over MgSO4. Following filtration, the CHCl3 and most of the bromopropionate were removed under reduced pressure. The oily residue was charged onto a 10×75 cm, SilicAR CC-7 column (800 g, hexane packed) and eluted with 5 to 20% ethylacetate/hexane, collecting 1 L fractions. Evaporation of fractions 7-9 gave purified 2'-(N-2-carbethoxyethylamino)-3',4'-dimethoxyacetophenone as a yellow oil (5.86 g, 15%); UV (EtOH) nm: 244 (ε29110), 284 (ε11480); MS (Probe) 295 (M+).
Reaction SMILES: [NH2:1][C:2]([C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=1)([CH3:6])[C:3]([NH2:5])=[O:4].[C:15](=O)(OC)[O:16]C>>[C:13]([C:10]1[CH:9]=[CH:8][C:7]([C:2]2([CH3:6])[C:3](=[O:4])[NH:5][C:15](=[O:16])[NH:1]2)=[CH:12][CH:11]=1)#[N:14]
Reactant: CC(N)(C(N)=O)c1ccc(C#N)cc1
Reactant: COC(=O)OC
Product: CC1(c2ccc(C#N)cc2)NC(=O)NC1=O

Procedure:
(R or S)-4-(4-Cyanophenyl)-4-methyl-2,5-dioxoimidazolidine was prepared from (R or S)-2-amino-2-(4-cyanophenyl)propionamide using dimethyl carbonate analogously to the procedure indicated in EP-A-173522.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)([OH:8])[CH2:6][CH3:7])[CH3:3].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH2:26][CH2:27][C:28](Cl)=[O:29])[CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23]>>[CH3:25][O:24][C:20]1[CH:19]=[C:18]([CH2:26][CH2:27][C:28]([O:8][C:5]([CH2:4][N:2]([CH3:3])[CH3:1])([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH2:6][CH3:7])=[O:29])[CH:17]=[C:16]([O:15][CH3:14])[C:21]=1[O:22][CH3:23]
Reactant: COc1cc(CCC(=O)Cl)cc(OC)c1OC
Reactant: CCC(O)(CN(C)C)c1cccs1
Product: CCC(CN(C)C)(OC(=O)CCc1cc(OC)c(OC)c(OC)c1)c1cccs1
Yield: 51.9 %

Procedure:
1-Dimethylaminomethyl-1-(2-thienyl)-1-propanol (1.12 g) and 3-(3,4,5-trimethoxyphenyl)propionyl chloride (1.61 g) are treated in the same manner as described in Example 1-(2), whereby 1-dimethylaminomethyl-1-(2-thienyl)propyl 3-(3,4,5-trimethoxyphenyl)propionate (1.23 g) is obtained as colorless oil.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[Cl:9][C:10]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([N+:21]([O-:23])=[O:22])=[C:17]([CH:20]=1)[CH:18]=O>O.C(O)C>[Cl:9][C:10]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([N+:21]([O-:23])=[O:22])=[C:17]([CH:20]=1)[CH:18]=[N:2][OH:3]
Reactant: NO
Reactant: O=Cc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1C=NO

Procedure:
To a solution of hydroxylamine hydrochloride (0.33 g., 0.0048 mole) and sodium acetate (0.394 g., 0.0048 mole) in 2-3 ml of water was added a hot solution of 5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-nitrobenzaldehyde (1.5 g., 0.00434 mole) in ethanol (10-12 ml). The clear yellow solution was heated for 1.5 hours and then the solvent was stripped on a rotary evaporator to give a yellow waxy solid which solidified giving 1.5 g., mp. 111°-115° C. Recrystallization from ethanol/water gave a solid mp. 114°-118° C.
Reaction SMILES: Br[C:2]12[CH2:9][CH2:8][C:5]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.[C:15]1([CH:21]2[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>[N+](C1C=CC=CC=1)([O-])=O.ClCCl.[Fe](Cl)(Cl)Cl>[CH2:10]([C:5]12[CH2:8][CH2:9][C:2]([C:18]3[CH:19]=[CH:20][C:15]([CH:21]4[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]4)=[CH:16][CH:17]=3)([CH2:3][CH2:4]1)[CH2:7][CH2:6]2)[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: O=C1CCC(c2ccccc2)CC1
Reactant: CCCCCC12CCC(Br)(CC1)CC2
Agent: Cl[Fe](Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: O=[N+]([O-])c1ccccc1
Product: CCCCCC12CCC(c3ccc(C4CCC(=O)CC4)cc3)(CC1)CC2
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 66.6 %

Procedure:
A solution of 1-bromo-4-pentylbicyclo[2.2.2]octane (6 g, 23 mmol) in sieve-dried nitrobenzene (100 cm3) is added dropwise to a stirred solution of 4-phenylcyclohexanone (3.9 g, 23 mmol) and anhydrous iron(III)chloride (1.2 g, 9 mmol) in sieve-dried nitrobenzene (100 cm3) maintained at 80° C. through the addition and overnight. The cooled solution is added to a small volume of hydrochloric acid and stirred for 20 min. The organic layer is separated off and steam-distilled to yield a solid residue. This is taken up in dichloromethane and dried (MgSO4). The raw product is crystallised from ethanol to yield the desired 4-[4-(4-pentylbicyclo[2.2.2]octyl)phenyl]cyclohexanone (5.4 g, 69%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[NH:10]N.[CH2:12]1[CH2:19][C:17](=O)[C:15](=[O:16])[CH2:14][CH2:13]1>CO.CC(O)=O.Cl>[Cl:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]2[C:4]=1[NH:10][C:14]1[C:15](=[O:16])[CH2:17][CH2:19][CH2:12][C:13]2=1
Reactant: O=C1CCCCC1=O
Reactant: NNc1ccc(F)cc1Cl
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Product: O=C1CCCc2c1[nH]c1c(Cl)cc(F)cc21
Temperature: 60 °C
Reaction time: 12 h
Yield: 56.1 %

Procedure:
To 2-chloro-4-fluoro phenyl hydrazine hydrochloride (0.3 g, 1.5 mmol) in MeOH (2.5 mL), a solution of 1,2-cyclohexadione (0.17 g, 1.5 mmol) in AcOH (2.5 mL) and conc. HCl (1 mL) were added. The resulting mixture was stirred at 60° C. for 12 h, then cooled to room temperature and MeOH was removed in vacuo. Water (25 mL) was added and the reaction mixture was basified with NaHCO3 (pH 8). The crude residue was extracted with EtOAc (2×30 mL). The combined organic extracts were washed with water (50 mL), dried over Na2SO4 and concentrated in vacuo to give the crude material which was purified by silica gel chromatography [EtOAc-hexane (1:19) as eluant] to afford the title compound (0.2 g, 55%). 1H NMR (200 MHz, CDCl3, δ in ppm) 8.84 (bs, 1H), 7.26-7.17 (m, 2H), 2.99-2.93 (t, J=6.0 Hz, 2H), 2.70-2.64 (q, J=7.4, 5.8 Hz, 2H), 2.34-2.21 (m, 2H).
Reaction SMILES: [CH3:1][CH:2]1[C:7]([CH3:19])([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[N:15]=[N:16][NH:17][CH:18]=3)[CH:9]=2)[CH2:6][CH2:5][NH:4][CH2:3]1.Cl[CH2:21][CH2:22][CH:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[OH:24].[I-].[Na+].C(=O)([O-])O.[Na+]>CN(C)C=O>[OH:24][CH:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:22][CH2:21][N:4]1[CH2:5][CH2:6][C:7]([CH3:19])([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[N:15]=[N:16][NH:17][CH:18]=3)[CH:9]=2)[CH:2]([CH3:1])[CH2:3]1
Reactant: OC(CCCl)c1ccccc1
Reactant: CC1CNCCC1(C)c1cccc(-c2c[nH]nn2)c1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1CN(CCC(O)c2ccccc2)CCC1(C)c1cccc(-c2c[nH]nn2)c1
Reaction time: 8 h
Yield: 24.3 %

Procedure:
To a solution of 3,4-dimethyl-4-(3-(1H-1,2,3-triazol-4-yl)phenyl)piperidine (Preparation 44, 50 mg, 0.20 mmol) in N,N-dimethylformamide (6 mL) was added commercially available 3-chloro-1-phenyl-1-propanol (33 mg, 0.21 mmol), sodium iodide (15 mg) and aqueous sodium hydrogencarbonate (25 mg, 0.29 mmol). The resultant mixture was heated to 80° C. and stirred overnight. The reaction mixture was cooled, poured onto saturated aqueous sodium hydrogencarbonate solution (100 mL) and extracted with ethyl acetate (3×20 mL). The combined extracts were dried over MgSO4, filtered and concentrated in vacuo to give an off-white gum. The crude product was purified by column chromatography on a 5 g silica Waters Sep-Pak3 eluting with dichloromethane and then dichloromethane:methanol (5:95) to give the title compound as a clear oil (19 mg, 25%).
Reaction SMILES: [CH2:1]([O:9][C:10]1[C:11](=[O:22])[O:12][C:13]2[C:20]([OH:21])=[CH:19][CH:18]=[CH:17][C:14]=2[C:15]=1[OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Br[CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[CH2:1]([O:9][C:10]1[C:11](=[O:22])[O:12][C:13]2[C:20]([O:21][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:19][CH:18]=[CH:17][C:14]=2[C:15]=1[OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1c(O)c2cccc(O)c2oc1=O
Reactant: CCOC(=O)CCBr
Product: CCCCCCCCOc1c(O)c2cccc(OCCC(=O)OCC)c2oc1=O

Procedure:
In the same manner as in Reference Example 3, except that an equimolar amount of 3-octyloxy-4,8-dihydroxy-2H-1-benzopyran-2-one was used in place of 3-hexyloxy-4,5-dihydroxy-2H-1-benzopyran-2-one, and ethyl 3-bromopropionate was used in place of ethyl bromoacetate in Reference Example 3, 3-octyloxy-4-hydroxy-8-(2-ethoxycarbonylethoxy)-2H-1-benzopyran-2-one was obtained.
Reaction SMILES: [OH-].[Na+].Cl[CH2:4][C@H:5]([OH:17])[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][CH2:8]1>C1COCC1.O>[O:17]1[CH2:4][C@H:5]1[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][CH2:8]1
Reactant: CS(=O)(=O)N1CCN(C[C@@H](O)CCl)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)N1CCN(C[C@@H]2CO2)CC1
Reaction time: 0.58 h

Procedure:
Sodium hydroxide (1.07 g, 26.7 mmol) was added to a vigorously stirred solution of 1-chloro-(R)-2-hydroxy-3-(4-methanesulfonylpiperazin-1-yl)propane, the product of the previous step (5.69 g, 22.2 mmol) in THF/water (150 mL/35 mL). The reaction mixture was stirred for 35 min, concentrated in vacuo to approximately 50 mL volume, diluted with chloroform (200 mL), and washed with 1M NaOH (2×70 mL) and brine (70 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo to yield a white crystalline solid which was then recrystallised from hot EtOAc/hexane 1:1 (800 mL) to yield the title intermediate (2.62 g) as a white crystalline solid. (The filtrate could be further recrystallised to obtain additional product material.) ESMS (C8H16N2O3S): calcd. 221.10; found 221.3 (m/z): [M+H]+; 1H NMR (DMSO-d6): δ (ppm) 2.22 (dd, 1H), 2.45-2.60 (m, 5H), 2.69-2.75 (m, 2H), 2.87 (s, 3H), 3.02 (m, 1H), 3.11 (m, 4H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]1[O:4][CH2:3]1.[NH2:12][CH2:13][CH2:14][NH:15][C:16]1[N:17]([CH3:26])[C:18](=[O:25])[N:19]([CH3:24])[C:20](=[O:23])[C:21]=1[CH3:22]>CO>[O:5]([CH2:1][CH:2]([OH:4])[CH2:3][NH:12][CH2:13][CH2:14][NH:15][C:16]1[N:17]([CH3:26])[C:18](=[O:25])[N:19]([CH3:24])[C:20](=[O:23])[C:21]=1[CH3:22])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cc1c(NCCN)n(C)c(=O)n(C)c1=O
Reactant: c1ccc(OCC2CO2)cc1
Solvent: CO
Product: Cc1c(NCCNCC(O)COc2ccccc2)n(C)c(=O)n(C)c1=O

Procedure:
3.4 g. Phenyl glycidyl ether and 9.6 g. 4-(2-aminoethylamino)-1,3,5-trimethylpyrimidine-2,6(1H,3H)-dione are stirred for about 24 hours at 70° C. The reaction mixture is dissolved in methanol and then separated by column chromatography, using a weakly acidic cation exchanger ("Amberlite" CG 50 II pract. (Serva)). The column is pre-treated with about 1.5 liters 0.1M methanolic triethylammonium acetate solution. The elution agent used is 0.1M methanolic triethylammonium acetate solution. The fractions containing the pure substance are evaporated, then rendered alkaline with 2N aqueous sodium hydroxide solution, extracted with methylene chloride and the extracts dried and evaporated. The light colored oil obtained becomes crystalline upon triturating with diethyl ether. After recrystallized from ethyl acetate, there are obtained 3.6 g. (44% of theory) of the desired product in the form of colorless crystals; m.p. 104°-106° C.
Reaction SMILES: [CH2:1]([C:5]1[C:9](/[CH:10]=[CH:11]/[C:12]2[S:13][C:14]([C:18]([OH:20])=O)=[C:15]([CH3:17])[N:16]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].Cl.[CH3:23][O:24][CH:25]1[CH2:28][NH:27][CH2:26]1>>[CH2:1]([C:5]1[C:9](/[CH:10]=[CH:11]/[C:12]2[S:13][C:14]([C:18]([N:27]3[CH2:28][CH:25]([O:24][CH3:23])[CH2:26]3)=[O:20])=[C:15]([CH3:17])[N:16]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)O)s1
Reactant: COC1CNC1
Agent: Cl
Product: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)N2CC(OC)C2)s1
Yield: 24 %

Procedure:
As described for example 108, 2-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-4-methyl-thiazole-5-carboxylic acid (200 mg, 0.65 mmol) was converted, using 3-methoxy-azetidine hydrochloride instead of 3,3-difluoroazetidine hydrochloride, to the title compound (58 mg, 24%) which was obtained as a light yellow oil. MS: m/e=376.3 [M+H]+.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH:13]([CH3:14])[CH2:12][N:11]([C:15]2[CH:24]=[C:23]3[C:18]([C:19](=[O:31])[C:20]([C:28]([OH:30])=[O:29])=[CH:21][N:22]3[CH:25]3[CH2:27][CH2:26]3)=[C:17]([CH3:32])[C:16]=2[F:33])[CH2:10]1)=O)(C)(C)C.[ClH:34]>C(O)C>[ClH:34].[NH2:8][CH:9]1[CH:13]([CH3:14])[CH2:12][N:11]([C:15]2[CH:24]=[C:23]3[C:18]([C:19](=[O:31])[C:20]([C:28]([OH:30])=[O:29])=[CH:21][N:22]3[CH:25]3[CH2:27][CH2:26]3)=[C:17]([CH3:32])[C:16]=2[F:33])[CH2:10]1
Reactant: Cc1c(F)c(N2CC(C)C(NC(=O)OC(C)(C)C)C2)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Agent: Cl
Solvent: CCO
Product: Cc1c(F)c(N2CC(C)C(N)C2)cc2c1c(=O)c(C(=O)O)cn2C1CC1

Procedure:
A mixture comprising 7-(3-t-butoxycarbonylamino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (trans form) (120 mg), ethanol (4 ml) and 10% hydrochloric acid (4 ml) is refluxed for 30 minutes After concentrating, the obtained residue is recrystallized from methanol - ethyl acetate to give 7-(3-amino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride (trans form) (60 mg), as white powder, m.p. 272°-275° C.