Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C=O)C.[F:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[NH:18][C:17](/[CH:19]=[CH:20]/[C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]4)=[C:23]([O:33][CH3:34])[CH:22]=3)=[N:16][N:15]=2)=[CH:9][CH:8]=1.[C:35](Cl)(=[O:38])[CH:36]=[CH2:37]>C(OCC)(=O)C>[F:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[C:35](=[O:38])[CH2:36][CH2:37][N:15]3[N:16]=[C:17](/[CH:19]=[CH:20]/[C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]5)=[C:23]([O:33][CH3:34])[CH:22]=4)[N:18]=[C:14]23)=[CH:11][CH:12]=1
Reactant: C=CC(=O)Cl
Reactant: COc1cc(/C=C/c2nnc(Nc3ccc(F)cc3)[nH]2)ccc1-n1cnc(C)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(/C=C/c2nc3n(n2)CCC(=O)N3c2ccc(F)cc2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
DMF (3 mL) and TEA (0.06 mL) were added to (4-fluorophenyl)-{5-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-4H-[1,2,4]triazol-3-yl}amine synthesized in Example 162 (44 mg), and the reaction solution was stirred at room temperature for 10 minutes. Acrylic acid chloride (0.01 mL) was added to the reaction solution at room temperature, and the reaction solution was stirred at room temperature for one hour and at 60° C. for two hours. TEA (0.03 mL) and acrylic acid chloride (0.01 mL) were added to the reaction solution at 60° C., and the reaction solution was stirred at 60° C. for four hours. The reaction solution was left to cool to room temperature and then diluted with ethyl acetate and washed with a saturated sodium bicarbonate solution and a saturated sodium chloride solution. The resulting organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system, then ethyl acetate-methanol system) and further purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system, then ethyl acetate-methanol system) to obtain 6 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:24][C:25]1[CH:26]=[C:27]([N:31]2[CH2:36][CH2:35][N:34]([C:37](=[O:49])[CH2:38][N:39]3[C:43]([CH3:44])=[CH:42][C:41]([C:45]([F:48])([F:47])[F:46])=[N:40]3)[CH2:33][CH2:32]2)[CH:28]=[CH:29][CH:30]=1.N1(C2CCCCCCCCCC2)CCCN=CCCCCC1>C(#N)C>[Cl:1][C:2]1[C:3]([OH:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[CH2:32][CH2:33][N:34]([C:37](=[O:49])[CH2:38][N:39]3[C:43]([CH3:44])=[CH:42][C:41]([C:45]([F:48])([F:47])[F:46])=[N:40]3)[CH2:35][CH2:36]2)[CH:26]=1)=[O:7]
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCN(c2cccc(N)c2)CC1
Reactant: O=C(O)c1cccc(Cl)c1O
Agent: C1=NCCCN(C2CCCCCCCCCC2)CCCCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCN(c2cccc(NC(=O)c3cccc(Cl)c3O)c2)CC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 3-chloro-2-hydroxy-benzoic acid (0.11 g, 0.65 mmol) in acetonitrile (10 mL) is added carbodiimidazole (0.11 g, 0.71 mmol). After stirring the reaction mixture at 60° C. for 2 h, 1-[4-(3-amino-phenyl)-piperazin-1-yl]-2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone (0.20 g, 055 mmol) is added, followed by 1,8-diazabicycloundec-7-ene (0.1 mL, 0.82 mmol). After stirring overnight at 60° C., the reaction mixture is cooled down to RT and then solvent is evaporated and the resulting yellow oil is dissolved in ethylacetate (20 mL), washed with saturated aqueous sodium bicarbonate solution (20 mL), 1N HCl (20 mL) and brine (20 mL). The organic layer is dried over sodium sulfate, filtered, and evaporated under reduced pressure. Cyclohexane is added dropwise to a solution of crude mixture in 1 mL ethylacetate to give after filtration 3-chloro-2-hydroxy-N-(3-{4-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperazin-1-yl}-phenyl)-benzamide (Compound No. I.ao.003) (0.090 g, 26%). 1H-NMR (400 MHz, MeOD): δ=2.31 (s, 3H), 3.21-3.28 (m, 2H), 3.31-3.39 (m, 2H), 3.77-3.83 (m, 4H), 5.25 (s, 2H), 6.47 (s, 1H), 6.87-6.89 (m, 1H), 6.92-6.99 (m, 1H), 7.17-7.22 (m, 1H), 7.28-7.33 (m, 1H), 7.41-7.42 (m, 1H), 7.57-7.61 (m, 1H), 7.90-7.92 (m, 1H). MS: m/z=522 (M+1).
Reaction SMILES: Cl[C:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)=[O:3].[F:14][C:15]([F:28])([F:27])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2NN=[N:24][N:23]=2)=[CH:18][CH:17]=1.N1C=CC=CC=1>O>[F:14][C:15]([F:27])([F:28])[C:16]1[CH:17]=[CH:18][C:19]([C:22]2[O:3][C:2]([C:4]3[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=3)=[N:24][N:23]=2)=[CH:20][CH:21]=1
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: FC(F)(F)c1ccc(-c2nnn[nH]2)cc1
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)c1ccc(-c2nnc(-c3ccc(C(F)(F)F)cc3)o2)cc1
Yield: 3487.1 %

Procedure:
A mixture of methyl 4-chloroformylbenzoate (1.39 g), 5-(4-trifluoromethylphenyl)-1H-tetrazol (1.50 g) and pyridine (30 ml) was heated under reflux for 1 hr. After cooling, water was added to the mixture. The crystals were collected by filtration and purified by silica gel column chromatography (hexane:tetrahydrofuran=1:9, volume ratio) to give methyl 4-[5-(4-trifluoromethylphenyl)-1,3,4-oxadiazol-2-yl]benzoate (1. 85 g, yield 76%). Recrystallization from hexane-ethyl acetate gave colorless prism crystals. melting point: 216–217° C.
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.[NH2:7][OH:8].[N+:9]([C:12]1[O:16][C:15]([C:17]2[C:21]([CH:22]=O)=[CH:20][N:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[N:18]=2)=[CH:14][CH:13]=1)([O-:11])=[O:10].O>CN(C)C=O>[N+:9]([C:12]1[O:16][C:15]([C:17]2[C:21]([CH:22]=[N:7][OH:8])=[CH:20][N:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[N:18]=2)=[CH:14][CH:13]=1)([O-:11])=[O:10]
Reactant: NO
Reactant: O=Cc1cn(-c2ccccn2)nc1-c1ccc([N+](=O)[O-])o1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(-c2nn(-c3ccccn3)cc2C=NO)o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
Add 1.18 g of anhydrous sodium acetate and 1.0 g of hydroxylamine hydrochloride to 3.9 g of 3-(5-nitro-2-furyl)-1-(2-pyridyl)pyrazole-4-carboxaldehyde in 12 ml of dimethylformamide, whereupon the temperature of the formed mixture rises slightly. Stir the resulting mixture at room temperature for 4 hours before pouring onto ice and water to obtain a 99% yield of 3-(5-nitro-2-furyl)-1-(2-pyridyl)pyrazole-4-carboxaldehydeoxime [m.p. 234.5° to 235° C].
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:29])=[C:5]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][OH:22])[CH:16]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[O:9].[CH:30](=O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH3:1][C:2]1[NH:3][C:4]([CH3:29])=[C:5]([C:23]([O:25][CH:26]([CH3:27])[CH3:28])=[O:24])[CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21](=[O:22])=[CH:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:16]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[O:9]
Reactant: O=Cc1ccccc1
Reactant: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc(NO)c1
Agent: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc(/[N+]([O-])=C/c2ccccc2)c1
Product: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc([N+]([O-])=Cc2ccccc2)c1

Procedure:
The reaction of hydroxylamine 55 (0.80 g, 2 mmol) with benzaldehyde (56)(0.21 g, 2 mmol) afforded, after workup, a yellow oil. The crude product was purified by flash chromatography with 1:1 ethyl acetate/hexane as the eluant to obtain 0.85 g (1.72 mmol, 86%) of 67 as a light yellow gum; IR (CH2Cl2) 3440, 2975, 1692, 1620, 1552, 1470, 1298, 1212, 1100 cm-1 ; 1H NMR (CDCl3, 60 MHz) δ 1.16 (t, J=6 Hz, 6H), 2.26 (s, 6H), 3.30 (s, 3H), 3.50 (t, J=5 Hz, 2H), 4.16 (t, J=5 Hz, 2H), 4.70-5.06 (m, 2H), 6.86 (bs, 1H), 7.30-8.46 (m, 10H). Anal. Calcd for C28H32N2O6 : C, 68.29; H, 6.50. Found: C, 68.16; H, 6.31.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18](C)([C:24](OCC)=O)[C:19]([O:21]CC)=[O:20])=[CH:10][C:9]1=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O.Cl>C(O)C>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH:18]([CH3:24])[C:19]([OH:21])=[O:20])=[CH:10][C:9]1=[O:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(C(=O)OCC)c1cc(=O)n(Cc2ccccc2)c2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C(=O)O)c1cc(=O)n(Cc2ccccc2)c2ccccc12
Yield: 66.3 %

Procedure:
A solution of diethyl α-(1-benzyl-1,2-dihydro-2-oxoquinol-4-yl)-α-methylmalonate (3.0 g.) in ethanol (20 ml.) containing sodium hydroxide (3.0 g.) and water (3.0 ml.) was heated under reflux for 1 hour. The solution was then cooled and poured into water (200 ml.). The resultant solution was acidified to pH 3 by addition of concentrated hydrochloric acid to give α-(1-benzyl-1,2-dihydro-2-oxoquinol-4-yl)propionic acid 1.5 g., m.p. 179°-180° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.[OH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21](=[O:23])[CH3:22]>>[OH:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:22][C:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[OH:14])=[O:23])[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10]
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: CC(=O)c1ccccc1O
Product: O=C(C=Cc1cc(O)c(O)c([N+](=O)[O-])c1)c1ccccc1O

Procedure:
The procedure described in Example 8 was repeated using 1.0 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 0.74 g of 2'-hydroxyacetophenone. Yield 0.2 g (12%), m.p. 231°-234° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[CH:4]=[CH:3]1.ClC(Cl)(Cl)C(=N)O[C:12]([CH3:15])([CH3:14])[CH3:13].B(F)(F)F.CCOCC.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:12]([O:7][CH:5]1[CH2:6][C:2](=[O:1])[CH:3]=[CH:4]1)([CH3:15])([CH3:14])[CH3:13]
Reactant: O=C1C=CC(O)C1
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC1C=CC(=O)C1
Temperature: 6.5 °C
Reaction time: 2 h
Yield: 19.7 %

Procedure:
A solution of 4-hydroxy-2-cyclopentenone (1.15 g, 11.7 mmol) in methylene chloride is cooled to 3° C. and treated sequentially with tert-butyl trichloroacetimidate (4.2 mL, 23.7 mmol) and boron trifluoride diethyl etherate (0.15 mL). The reaction mixture is stirred at 3-10° C. for 2 hours and then allowed to warm to room temperature and stirred for 22 hours. The reaction mixture is then treated with sodium bicarbonate (250 mg) and filtered. The filtrate is concentrated under vacuum and the residue is purified by chromatography (silica gel, 39 g, 20% ethyl acetate/hexane, 600 mL) to provide the title compound (355 mg, 40%) as a yellow oil; 1H NMR (CDCl3)δ7.44 (dd, 1H, J=18 Hz), 6.2 (d, 1H, J=5.4 Hz), 4.8 (m, 1H), 2.68 (dd, 1H, J=5.8, 18 Hz), 2.25 (d, 1H, J=18 Hz), 1.27 (s, 9H); IR (neat) νmax 2976, 2936, 1721, 1368, 1352, 1188, 1103, 1161 cm-1 ; MS (CI) m/e (% relative intensity) 155 (M+H+, 22), 99 (100).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.C(O)C.[H][H]>[Pd].C(O)(=O)C>[C:19]([OH:21])(=[O:20])[CH3:18].[NH:11]1[CH2:12][CH2:13][CH:14]([O:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:16]1
Reactant: [H][H]
Reactant: CCOC(=O)COC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)COC1CCNCC1
Yield: 192.1 %

Procedure:
In a similar manner to Example 2, starting material step (c), the product from step (a) (2.3 g), ethanol (200 ml), glacial acetic acid (0.6 ml), 10% Pd on C (200 mg) and hydrogen gas were reacted to give ethyl piperidin-4-yloxyacetate, acetate salt (1.7 g), as a brown oil: NMR Spectrum (DMSO-d6) 1.20 (3H, t), 1.41 (2H, m), 1.82 (3H, s), 1.86 (2H, m), 2.58 (2H, m), 2.95 (2H, m), 3.46 (1H, m), 4.11 (4H, m); Mass Spectrum m/Z 188 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([CH2:20][C:21](OCC)=[O:22])[N:9]=1.[NH2:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][OH:32]>>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([CH2:20][C:21]([NH:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][OH:32])=[O:22])[N:9]=1
Reactant: NCCOCCO
Reactant: CCOC(=O)Cn1nc(-c2ccccc2O)nc1-c1ccccc1O
Product: O=C(Cn1nc(-c2ccccc2O)nc1-c1ccccc1O)NCCOCCO

Procedure:
2.0 g of ethyl [3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]acetate (Example 2) and 10 ml of 2-(2-aminoethoxy)ethanol are stirred at room temperature for 2 h. The mixture is poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is crystallized from isopropanol. After drying, 2-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]-N-[2-(2-hydroxy-ethoxy)ethyl]acetamide remains as colorless crystals of m.p. 173-174° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=3)[CH:11]=[C:10]([C:22]([F:25])([F:24])[F:23])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:26]([NH:30][S:31]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)(=[O:33])=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([NH:30][S:31]([C:34]1[CH:35]=[CH:36][CH:37]=[C:38]([C:2]2[CH:7]=[C:6]([C:8]3[N:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=4)[CH:11]=[C:10]([C:22]([F:25])([F:24])[F:23])[N:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:39]=1)(=[O:33])=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: Fc1ccc(-c2cc(C(F)(F)F)nc(-c3ccnc(Cl)c3)n2)cc1F
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(F)c(F)c4)cc(C(F)(F)F)n3)ccn2)c1

Procedure:
3-{4-[4-(3,4-Difluoro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonic acid tert-butylamide was prepared from 2-(2-chloro-pyridin-4-yl)-4-(3,4-difluoro-phenyl)-6-trifluoromethyl-pyrimidine (example E.104) (0.25 g, 0.67 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.21 g, 0.82 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.25 g), which was subsequently deprotected.
Reaction SMILES: [C@@H:1]12[CH2:7][NH:6][C@@H:5]1[CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:2]2.Br[C:19]1[CH:20]=[N:21][CH:22]=[C:23]([O:25][CH3:26])[CH:24]=1>>[CH3:26][O:25][C:23]1[CH:24]=[C:19]([N:6]2[CH2:7][C@@H:1]3[C@H:5]2[CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:2]3)[CH:20]=[N:21][CH:22]=1
Reactant: O=C(OCc1ccccc1)N1C[C@@H]2CN[C@@H]2C1
Reactant: COc1cncc(Br)c1
Product: COc1cncc(N2C[C@H]3CN(C(=O)OCc4ccccc4)C[C@H]32)c1
Yield: 36.4 %

Procedure:
The product of Example 52D (940 mg, 4.05 mmol) and 3-bromo-5-methoxypyridine (1.13 g, 6.07 mmol) were processed according to the procedure described in Example 1E. The crude product was purified by chromatography (SiO2, ethyl acetate:hexane, 1:1) to provide the title compound (0.50 g, 37% yield). MS (DCI/NH3) m/z 340 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:22])[N:10]([CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][CH2:20][OH:21])[CH2:15][CH2:14]2)[CH3:11])=[CH:4][CH:3]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]([N:10]([CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][CH2:20][O:21][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:15][CH2:14]2)[CH3:11])=[O:22])=[CH:6][CH:7]=1
Reactant: CN(C[C@H]1CC[C@H](CCO)CC1)C(=O)Oc1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Product: CN(C[C@H]1CC[C@H](CCOS(C)(=O)=O)CC1)C(=O)Oc1ccc(Cl)cc1

Procedure:
In analogy to the procedure described in example 3.4, trans-[4-(2-hydroxy-ethyl)-cyclohexylmethyl]-methyl-carbamic acid 4-chloro-phenyl ester was treated with methanesulfonyl chloride to yield trans-methanesulfonic acid 2-(4-{[(4-chloro-phenoxycarbonyl)-methyl-amino]-methyl}-cyclohexyl)-ethyl ester as colorless viscous oil, MS: 404 (MH+, 1Cl).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:25])[CH:9]2[C:13]3([CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10]2)[CH:5]=[CH:4][N:3]=1.Cl.[CH3:27][N:28]1[CH:32]=[C:31]([NH2:33])[CH:30]=[N:29]1.CCN(C(C)C)C(C)C>CCCCO>[CH3:25][N:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:33][C:31]2[CH:30]=[N:29][N:28]([CH3:27])[CH:32]=2)[N:7]=1)[CH:9]1[C:13]2([CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10]1
Reactant: Cn1cc(N)cn1
Reactant: CN(c1ccnc(Cl)n1)C1CN(C(=O)OC(C)(C)C)CC12CCCC2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CN(c1ccnc(Nc2cnn(C)c2)n1)C1CN(C(=O)OC(C)(C)C)CC12CCCC2
Temperature: 150 °C
Yield: 55.3 %

Procedure:
To a suspension of tert-butyl 4-((2-chloropyrimidin-4-yl)(methyl)amino)-2-azaspiro[4.4]nonane-2-carboxylate (0.34 g, 0.93 mmol) in n-BuOH (5.0 mL) was added 1-methyl-1H-pyrazol-4-amine hydrochloride (0.25 g, 1.85 mmol) and DIPEA (0.48 g, 3.71 mmol). The mixture was stirred in a sealed tube and heated to 150° C. overnight, then concentrated in vacuo. The residue was purified by silica gel column chromatography (EA) to give the product as a yellow solid (0.22 g, 55%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][CH2:9][CH2:10][NH2:11])=[CH:5][CH:4]=1.[OH:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O.O.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][CH2:9][CH2:10][NH:11][CH2:18][C:17]2[CH:20]=[CH:21][CH:22]=[C:15]([OH:14])[CH:16]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(OCCCN)cc1
Reactant: O=Cc1cccc(O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(OCCCNCc2cccc(O)c2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
3-(4-Methoxyphenoxy)propylamine (10.0 g) was dissolved in methanol (50 mL) at room temperature, a solution of 3-hydroxybenzaldehyde (6.7 g) in methanol (50 mL) was added dropwise within 5 minutes at water temperature (about 20° C.), and then the resulting mixture was stirred at room temperature for 20 hours. Then, sodium borohydride (2.1 g)/water (100 mL) was added dropwise at water temperature (about 20° C.) for 5 minutes, and the mixture was stirred at room temperature for 12 hours. Precipitates were removed, washed with water and then dried under reduced pressure at 80° C. for 5 hours. Pale yellow crystals were obtained (13.9 g, 87.4%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([NH:12][C@H:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18](O)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([NH:12][C@H:13]2[CH2:17][CH2:16][N:15]([C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14]2)[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(N[C@H]2CCNC2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(N[C@H]2CCN(C(=O)c3ccccc3)C2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.1 %

Procedure:
To a solution of compound 5c (1 g, 4.14 mmol), compound 4a (0.557 g, 4.56 mmol), and Et3N (1.27 mL, 8.28 mmol) in CH2Cl2 (20 mL) was added HATU (2.05 g, 5.38 mmol). The reaction mixture was stirred at room temperature for 18 h. The resultant mixture was diluted with CH2Cl2 and washed with aq. NaHCO3. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 5% MeOH/EtOAc+0.5 TEA %) gave compound 5d (0.96 g). MS m/z (M+Na+) 368.0.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:26])=[C:11]([C:14]4[CH:19]=[C:18]([CH:20]=O)[CH:17]=[C:16]([O:22][CH3:23])[C:15]=4[O:24][CH3:25])[CH:12]=3)[C:7](=[O:27])[C:6]([C:28]([OH:30])=[O:29])=[CH:5]2)[CH2:3][CH2:2]1.[NH:31]([CH2:38][CH2:39][C:40]#[N:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CC([O-])(C)C.[K+].Cl>CS(C)=O.O>[C:40]([C:39](=[CH:38][NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:20][C:18]1[CH:17]=[C:16]([O:22][CH3:23])[C:15]([O:24][CH3:25])=[C:14]([C:11]2[CH:12]=[C:13]3[C:8]([C:7](=[O:27])[C:6]([C:28]([OH:30])=[O:29])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[CH:9][C:10]=2[F:26])[CH:19]=1)#[N:41]
Reactant: N#CCCNc1ccccc1
Reactant: COc1cc(C=O)cc(-c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)c1OC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(CC(C#N)=CNc2ccccc2)cc(-c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
A suspension of 310 mg of 1-cyclopropyl-6-fluoro-7-(5-formyl-2,3-dimethoxy-phenyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (Example 8a)) in 3 ml of dimethyl sulphoxide is treated with 110 mg of 3-anilinopropionitrile and 185 mg of potassium tert-butylate. The resulting solution is stirred at room temperature for one hr. The reaction mixture is poured into 30 ml of water, adjusted to pH 5 with 2N aqueous HCl and extracted twice with 50 ml of methylene chloride each time. The combined organic phases are washed with 50 ml of water and with 50 ml of saturated, aqueous sodium chloride solution, dried over magnesium sulphate and concentrated. 400 mg (98%) of 7-[5-(2-cyano-3-phenylamino-allyl)-2,3-dimethoxy-phenyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid are obtained as a yellow foam.
Reaction SMILES: [CH2:1]1[C@@H:5]2[C@@H:6]3[C:11](=[O:12])[O:10][C:8](=[O:9])[C@@H:7]3[C@H:2]1[CH:3]=[CH:4]2.C1(C)C=CC=CC=1.COC1C=CC2N=CC=C([C@@H](O)[C@H]3N4C[C@H](C=C)[C@@H](CC4)C3)C=2C=1.[CH3:44][OH:45]>C(Cl)(Cl)(Cl)Cl>[CH3:44][O:45][C:11]([C@@H:6]1[C@@H:5]2[CH2:1][C@@H:2]([CH:3]=[CH:4]2)[C@@H:7]1[C:8]([OH:10])=[O:9])=[O:12]
Reactant: CO
Reactant: O=C1OC(=O)[C@H]2[C@@H]1[C@@H]1C=C[C@H]2C1
Agent: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccc(OC)cc12
Solvent: Cc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)[C@H]1[C@@H](C(=O)O)[C@@H]2C=C[C@H]1C2
Temperature: -55 °C
Reaction time: 0.17 h
Yield: 99.5 %

Procedure:
The starting material (a) was prepared as described in J. Org. Chem. 2000, 65, 6984-6991. cis-5-Norbornene-exo-2,3-dicarboxylic anhydride (5 g, 30.45 mmol) was suspended in a 1:1 mixture of toluene and carbon tetrachloride (610 mL). The mixture was stirred for 10 min. Quinine (10.87 g, 33 5 mmol) was added and the flask was degassed and backfilled with nitrogen. The solution was cooled to −55° C. While stirring, methanol (3.7 mL, 91.35 mmol) was added. The mixture was stirred at −55° C. for 16 h. Upon warming to 25° C., the mixture was concentrated in vacuo to a foam. The foam was dissolved in a mixture of ethyl acetate (400 mL) and 1.0 M aqueous hydrochloric acid solution (400 mL). The layers were separated and the organic layer was further washed with 1.0 M aqueous hydrochloric acid solution (2×200 mL), saturated aqueous brine solution (100 mL) and dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the desired product, (1S,2S,3R,4R)-3-(methoxycarbonyl)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid (5.95 g, 30.3 mmol, 99%), as a clear oil. 1H NMR (400 MHz, DMSO-d6) δ: 1.31 (1H, d, J=8.5 Hz), 1.98 (1H, d, J=8.6 Hz), 2.51 (2H, d, J=1.6 Hz), 2.95 (2H, bs), 3.52 (3H, s), 6.17-6.21 (2H, m), 12.16 (1H, s).