Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[CH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].[H][H]>C(O)C.[Ni]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: [H][H]
Reactant: CCOC(=O)C=Cc1ccc(F)cc1F
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(F)cc1F

Procedure:
42.4 g (0.20 mol) of ethyl 3-(2,4-difluorophenyl)-2-propenoate are dissolved in 400 ml of ethanol, 4 g of Raney nickel in ethanol are added, and the mixture is hydrogenated at 20°-25° C. using hydrogen gas. When the theoretical amount of hydrogen has been taken up, the solution is filtered and evaporated on a vacuum rotary evaporator. 41.4 g of a pale brown oil which is subjected to fractional distillation at 120° C. in vacuo (20 mbar) are obtained. 33 g (77% of theory) of a colourless oil are obtained.
Reaction SMILES: [CH2:1]([C@@:8]([OH:28])([C:12]([N:14]1[C@H:18]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:25][C@H:17]2[O:16][C:15]1([CH3:27])[CH3:26])=[O:13])[CH2:9][CH:10]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][O:30][C:31]([NH:33][C@H:34]([C:39]([NH:41][NH2:42])=[O:40])[C:35]([CH3:38])([CH3:37])[CH3:36])=[O:32].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1>[CH3:29][O:30][C:31](=[O:32])[NH:33][C@H:34]([C:39]([NH:41][NH:42][CH2:10][CH2:9][C@:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([OH:28])[C:12]([N:14]1[C@H:18]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:25][C@H:17]2[O:16][C:15]1([CH3:27])[CH3:26])=[O:13])=[O:40])[C:35]([CH3:38])([CH3:37])[CH3:36]
Reactant: CC1(C)O[C@@H]2Cc3ccccc3[C@@H]2N1C(=O)[C@@](O)(CC=O)Cc1ccccc1
Reactant: COC(=O)N[C@H](C(=O)NN)C(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)NNCC[C@@](O)(Cc1ccccc1)C(=O)N1[C@H]2c3ccccc3C[C@H]2OC1(C)C)C(C)(C)C
Reaction time: 8 h

Procedure:
(S)-3-Benzyl-4-((3aS,8aR)-2,2-dimethyl-8,8a-dihydro-3 aH-indeno[1,2-d]oxazol-3-yl)-3-hydroxy-4-oxo-butyraldehyde (21h) (0.082 g, 0.21 mmol) and [N-(methoxycarbony)-L-tert-leucinyl]hydrazine (0.048 g, 0.23 mmol, prepared as reported JMC, 41, 3387, 1998) in dry THF (10 mL) was stirred for 3 h and [the LCMS (ESI+) shows 565 (M+)], then Na(OAc)3BH (0.137 g, 0.64 mmol) was added and stirred overnight. The reaction mixture was quenched with water and evaporated. The residue was dissolved in dichloromethane and washed with water, brine and dried. The crude product was analysed by LCMS (ESI+) which showed 567 (M+) the title compound with a minor quantity of the compound lacking the protection group on the indanol moiety [MS (ESI+): 527 (M+)]. This mixture was alkylated by the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([C:18]([CH:23]=O)=[CH:19]N(C)C)[O:11][N:10]=1.Cl.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][NH2:34]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([C:18]2[CH:19]=[N:34][N:33]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[F:26])[CH:23]=2)[O:11][N:10]=1
Reactant: NNc1ccccc1F
Reactant: COC(=O)c1c(-c2c(F)cccc2Cl)noc1C(C=O)=CN(C)C
Agent: Cl
Solvent: CCO
Product: COC(=O)c1c(-c2c(F)cccc2Cl)noc1-c1cnn(-c2ccccc2F)c1
Temperature: 57.5 °C
Yield: 60.1 %

Procedure:
To a solution of raw methyl 3-(2-chloro-6-fluorophenyl)-5-[2-(dimethylamino)-1-formylvinyl]isoxazole-4-carboxylate (36 mg, 0.102 mmol) in ethanol (460 mg), 2-fluorophenyl hydrazine hydrochloride (16 mg, 0.100 mmol) was added. The mixture was warmed to 55-60° C. until a TLC sample showed no starting enamine. The solution was evaporated to dryness in vacuum, the reside was extracted with 3×10 ml of boiling hexane, and the hexane extracts were combined and concentrated and cooled to room temperature. Crystallization gave 25 mg of desired product (example I-89) (yield 60%). Result of LC/MS MH+: 416.05; 1H NMR (CDCl3): 3.67 (s, 3H), 7.30 (t, 1H), 7.45 (m, 4H), 7.57 (m, 1H), 7.93 (t, 1H), 8.50 (s, 1H), 9.13 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16](=[O:21])[CH2:17][CH:18]3[CH2:20][CH2:19]3)[N:14]=2)[N:11]=1.[CH3:25][N:26]1[C:30]([C:31](Cl)=[O:32])=[CH:29][C:28]([CH3:34])=[N:27]1>CN(C)C(=O)C>[CH:18]1([CH2:17][C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:31]([C:30]5[N:26]([CH3:25])[N:27]=[C:28]([CH3:34])[CH:29]=5)=[O:32])[CH:24]=[CH:23][CH:22]=4)=[N:11][N:10]3[CH:12]=2)=[O:21])[CH2:19][CH2:20]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)CC4CC4)cn3n2)c1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Solvent: CC(=O)N(C)C
Product: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)CC5CC5)cn4n3)c2)n(C)n1
Yield: 61.8 %

Procedure:
Using N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]-2-cyclopropylacetamide (100 mg, 0.309 mmol), 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (64 mg, 0.404 mmol) and N,N-dimethylacetamide (5.0 mL), and by a reaction in the same manner as in Example 148, the title compound (85 mg, 62%) was obtained as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15]([NH2:19])[CH2:16][CH2:17][CH3:18].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C)C=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:19][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCNC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
To a solution of 1-t-butoxycarbonylpyperidin-4-one (10.0 g) in dimethylformamide (200 mL) were added n-butylamine (6.0 mL) and triethylamine (7.0 mL) and the solution was stirred. To the reaction solution was added sodium triacetoxyborohydride (16.0 g) and the solution was stirred for 1.5 hours. After finishing the reaction, water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to give the title compound having the following physical data.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][O:7][CH2:8][C:9]([NH:11][NH2:12])=[O:10].[Cl:13][C:14]1[CH:31]=[CH:30][C:17]2[O:18][C:19]3[CH:29]=[CH:28][CH:27]=[CH:26][C:20]=3[CH2:21][N:22]([C:23](Cl)=[O:24])[C:16]=2[CH:15]=1>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][O:7][CH2:8][C:9]([NH:11][NH:12][C:23]([N:22]1[CH2:21][C:20]2[CH:26]=[CH:27][CH:28]=[CH:29][C:19]=2[O:18][C:17]2[CH:30]=[CH:31][C:14]([Cl:13])=[CH:15][C:16]1=2)=[O:24])=[O:10]
Reactant: NNC(=O)COCc1cccs1
Reactant: O=C(Cl)N1Cc2ccccc2Oc2ccc(Cl)cc21
Product: O=C(COCc1cccs1)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21

Procedure:
8-chlorodibenz[b,f][1,41oxazepine-10(11H)-carboxylic acid, 2-[(2-thienylmethoxy)acetyl]hydrazide (21) was prepared in the manner described in Example 6 from 1 mmol of 2-(2-thienylmethoxy)acetic acid, hydrazide (20), prepared as described above in Example 20, and 1.0 mmol of 8-chlorodibenz[b,f][1,41oxazepine-10(11H)-carbonyl chloride (2), prepared as described above in Example 2, to yield 0.28 g (64%) of product. Analysis calculated for C21H18N3O4SCl (M.W. 443.91): C, 56.82; H, 4.09; N, 9.47. Found: C, 56.55; H, 4.08; N, 9.28.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:11]=1[C:12](O)=[O:13].CCCCCCC>CCOC(C)=O>[F:9][C:10]1[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:11]=1[C:12]([O:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:13]
Reactant: Cc1ccc(O)cc1
Reactant: O=C(O)c1cc(F)c(F)cc1F
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccc(OC(=O)c2cc(F)c(F)cc2F)cc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
The title compound can also be prepared according to the following method: 4-methylphenol (80.0 g, 739.8 mmol) was added to a suspension of 2,4,5-trifluorobenzoic acid (136.8 g, 776.8 mmol) and 1,1-carbonyldiimidazole (83-85% wt, 163.6 g, 849.7 mmol) in EtOAc (1.20 L) at 40° C. The reaction mixture was stirred at 40° C. for 2 hours, then cooled to 20° C. and washed with water (480 mL), a 0.5 M aqueous solution of sodium hydroxide (2×400 mL) and water (400 mL). The organics were concentrated in vacuo and azeotroped with heptane to give a yellow oil. Heptane (640 mL) was added and the reaction was stirred at room temperature for 16 hours. A seed was used to facilitate the formation of a suspension. The resulting suspension was cooled to 10° C. and filtered. The residue was washed with cold heptane (80 mL) and dried to afford the title compound as an off white solid (147.5 g, 75%):
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]([C:8]1[CH:20]=[CH:19][C:18]2[C:17]3[C:12](=[CH:13][C:14]([C:21](=O)[CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:15][CH:16]=3)[CH2:11][C:10]=2[CH:9]=1)=O)([OH:3])=[O:2].[OH-].[Na+].O.NN.Cl>C(O)COCCO.O>[C:24]([CH2:23][CH2:22][CH2:21][C:14]1[CH:15]=[CH:16][C:17]2[C:18]3[C:10](=[CH:9][C:8]([CH2:6][CH2:5][CH2:4][C:1]([OH:3])=[O:2])=[CH:20][CH:19]=3)[CH2:11][C:12]=2[CH:13]=1)([OH:26])=[O:25]
Reactant: O=C(O)CCC(=O)c1ccc2c(c1)Cc1cc(C(=O)CCC(=O)O)ccc1-2
Agent: Cl
Agent: NN
Agent: [Na+]
Solvent: OCCOCCO
Solvent: O
Product: O=C(O)CCCc1ccc2c(c1)Cc1cc(CCCC(=O)O)ccc1-2
Temperature: 110 °C

Procedure:
In an argon-purged flask 2,7-di(3-carboxy-propionyl)fluorene (12.8 g, 0.035 mol) was suspended in diethylene glycol (150 mL). The flask was placed in a room temperature oil bath then NaOH (14 g, 0.35 mol) and an 80% solution of hydrazine hydrate (13.1 mL, 0.21 mol) were added successively. The reaction mixture was slowly heated to 110° C. and refluxed for approximately two hours. The reaction temperature was raised to 200° C. with removal of water during the heating process. After three hours at 200° C. reaction temperature the reaction was cooled to approximately 60° C. The reaction mixture was carefully poured into water (500 mL) and the mixture was acidified to pH 2 with concentrated HCl. The product was filtered and washed with water. The product was dissolved in warm NaOH solution (0.5M) and precipitated by acidification to pH 2 with HCl. The product was filtered and washed with water (Yield 10.9 g, 92%). 1H-NMR (d6-DMSO): δ (ppm) 12.0 (s, 2H, COOH); 7.8 (m, 2H, Ar); 7.4 (s, 2H, Ar); 7.2 (m, 2H, Ar); 3.9 (s, 2H, CH2); 2.7 (t, 4H, CH2); 2.3 (t, 4H, CH2); 1.8 (m, 4H, CH2).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@:13]([CH2:24][OH:25])([N:21]=[N+:22]=[N-:23])[O:12]1.C[Si](Cl)(C)C.[C:31](Cl)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:32].CO>N1C=CC=CC=1>[N:21]([C@@:13]1([CH2:24][OH:25])[C@H:14]2[O:18][C:17]([CH3:20])([CH3:19])[O:16][C@H:15]2[C@H:11]([N:6]2[CH:5]=[N:4][C:3]3[C:7]2=[N:8][CH:9]=[N:10][C:2]=3[NH:1][C:31](=[O:32])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:12]1)=[N+:22]=[N-:23]
Reactant: CC1(C)O[C@H]2[C@H](n3cnc4c(N)ncnc43)O[C@@](CO)(N=[N+]=[N-])[C@H]2O1
Reactant: O=C(Cl)c1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: CO
Solvent: c1ccncc1
Product: CC1(C)O[C@H]2[C@H](n3cnc4c(NC(=O)c5ccccc5)ncnc43)O[C@@](CO)(N=[N+]=[N-])[C@H]2O1
Reaction time: 1 h
Yield: 91.8 %

Procedure:
Compound 36.2 (300 mg, 0.86 mmol) was dissolved in 8.6 mL anhydrous pyridine, and treated with TMSCl (1.09 mL, 8.6 mmol). The mixture was stirred for 1 h, and then treated with BzCl (1.0 mL, 8.6 mmol), stirred for overnight. MeOH was added to the mixture after the reaction was completed. The mixture was stirred for another 5 min and then concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with sat. NaHCO3 twice and the organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography eluting with 50% EtOAc in hexane to give compound 36.3 (357 mg, 74% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:7][C:6]2[CH:8]=[CH:9][C:10]([CH:12]=O)=[CH:11][C:5]=2[C:4](=[O:14])[O:3]1.[CH2:16]([NH2:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[CH2:16]([NH:22][CH2:12][C:10]1[CH:9]=[CH:8][C:6]2[O:7][C:2]([CH3:15])([CH3:1])[O:3][C:4](=[O:14])[C:5]=2[CH:11]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCN
Reactant: CC1(C)OC(=O)c2cc(C=O)ccc2O1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCCCCCNCc1ccc2c(c1)C(=O)OC(C)(C)O2
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.1 %

Procedure:
To a solution of 2,2-dimethyl-4-oxo-4H-1,3-benzodioxine-6-carbaldehyde (510 mg, 2.47 mmol) in anhydrous DCE (20 mL) was added n-hexylamine (392 μL, 2.97 mmol), acetic acid (212 μL) and sodium triacetoxyborohydride (786 mg, 3.71 mmol) and the resulting mixture was stirred at rt for 3 hrs. The reaction mixture was diluted with DCM and washed with a saturated aqueous solution of NaHCO3 and brine. The organic layer was dried over MgSO4 and the solvents were removed under reduced pressure. Purification by flash chromatography on silicagel (EtOAc/c-Hex (20/80)) gave 627 mg (87%) of the title compound. HPLC, Rt: 2.70 min purity: 86.4% ). 1H NMR (CDCl3) δ: 0.85 (t, J=6.8 Hz, 3H), 1.28 (m, 6H), 1.48 (m, 2H), 1.70 (s, 6H), 2.41 (m, 1H), 2.58 (t, J=7.3 Hz, 2H), 3.74 (s, 2H), 6.90 (d, J=8.5 Hz, 1H), 7.53 (dd, J=8.5, 2.3 Hz, 1H), 7.86 (d, J=2.1 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:14]=O)[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:16]#[N:17])[CH3:2].[S:18]1[CH2:24][C:22](=[O:23])[NH:21][C:19]1=[S:20].C([O-])(=O)C.[NH4+]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](/[CH:14]=[C:24]3/[C:22](=[O:23])[NH:21][C:19](=[S:20])[S:18]/3)[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:16]#[N:17])[CH3:2]
Reactant: O=C1CSC(=S)N1
Reactant: CCOc1c(C#N)cnc2ccc(C=O)cc12
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: CCOc1c(C#N)cnc2ccc(/C=C3\SC(=S)NC3=O)cc12
Temperature: 25 °C
Yield: 100 %

Procedure:
The suspension of 4-ethoxy-6-formyl-quinoline-3-carbonitrile (example 14e, 1.13 g, 5 mmol) and rodahnine (2-thioxo-thiazolin-4-one) (1.0 g, 7.5 mmol) in anhydrous toluene (50 mL) was added ammonium acetate (0.77 g, 10 mmol). The mixture was stirred under reflux for 6 h. After cooling to room temperature, the solid was collected by filtration, washed with water, toluene and dried to obtain 4-ethoxy-6-[4-oxo-2-thioxo-thiazolidin-(5Z)-ylidenemethyl]-quinoline-3-carbonitrile (1.7 g, 100%) as a grey solid. LC-MS m/e 342 (MH+)
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[C:15]2[C:16]4[C:21]([CH:22]=[C:23]5[C:28]=2[CH:27]=[CH:26][CH:25]=[CH:24]5)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[Br:29]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:29][C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:13]2[C:14]3[C:5]([CH:6]=[C:7]4[C:12]=2[CH:11]=[CH:10][CH:9]=[CH:8]4)=[CH:4][CH:3]=[CH:2][CH:1]=3)=[C:28]2[C:23]=1[CH:24]=[CH:25][CH:26]=[CH:27]2
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc2c(-c3c4ccccc4cc4ccccc34)c3ccccc3cc2c1
Solvent: O
Solvent: CN(C)C=O
Product: Brc1c2ccccc2c(-c2c3ccccc3cc3ccccc23)c2ccccc12
Temperature: 0 °C
Reaction time: 4 h
Yield: 36.8 %

Procedure:
9,9′-bianthracene (10 g, 28.2 mmol) was dissolved in DMF (200 mL), protected from light and N-bromosuccinimide (5.5 g, 31 mmol) diluted in DMF (20 ml) was added to the solution at 0° C. The reaction mixture was maintained at 0° C. for 1 hour. The solution was then warmed slowly to room temperature and stirred for 4 h. After the reaction completion, water was added to the mixture to terminate the reaction. The reaction mixture was extracted with ethyl acetate and water, dried with anhydrous magnesium sulfate, the solvent was removed and the residue was purified by column chromatography on silica(hexane-dichloromethane) to give product 4.5 g (37%) as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-])=O)[CH:8]=2)[N:3]=1.[F:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[CH:21]([NH2:25])[CH2:20][CH2:19]2>>[F:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[CH:21]([NH:25][C:2]1[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([NH2:12])[CH:8]=3)[N:3]=1)[CH2:20][CH2:19]2
Reactant: NC1CCc2cc(F)ccc21
Reactant: O=[N+]([O-])c1ccc2nc(Cl)ccc2c1
Product: Nc1ccc2nc(NC3CCc4cc(F)ccc43)ccc2c1

Procedure:
The title compound was prepared in accordance with the general method described in example 2 from 2-chloro-6-nitro-quinoline and rac-5-fluoro-indan-1-ylamine (CAS no: 148960-33-2); MS: m/e=294.3 (M+H+).
Reaction SMILES: [NH:1]1[CH2:3][CH2:2]1.C(=O)([O-])O.[Na+].[F:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[C:12]([O:19][CH3:20])[CH:11]=1.[OH-].[Na+]>O.ClC(Cl)Cl>[F:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([N:1]2[CH2:3][CH2:2]2)=[O:15])=[C:12]([O:19][CH3:20])[CH:11]=1
Reactant: C1CN1
Reactant: COc1cc(F)ccc1C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc(F)ccc1C(=O)N1CC1
Temperature: 0 °C
Reaction time: 0.62 h

Procedure:
To 231 parts of a aziridine solution 0.95M in water are added 16 parts of sodium hydrogen carbonate while stirring vigorously at 0° C. Then there is added dropwise, during a 45 minutes-period, a solution of 36 parts of 4-fluoro-2-methoxybenzoyl chloride in 150 parts of trichloromethane while still cooling at 0° C. Upon completion, stirring is continued for 30-45 minutes without cooling. The reaction mixture is adjusted to pH 8 with a diluted sodium hydroxide solution and the product is extracted three times with trichloromethane. The combined extracts are washed three times with water, dried, filtered and evaporated, yielding 40.5 parts of 1-(4-fluoro-2-methoxybenzoyl)-aziridine as a residue.
Reaction SMILES: CN.Cl[C:4]1[C:13]([C:14]([C:16](=[CH:22][N:23](C)[CH3:24])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:15])=[CH:12][C:11]2[C:6](=[CH:7][C:8]([F:27])=[C:9]([F:26])[CH:10]=2)[N:5]=1>C(O)C>[CH2:20]([O:19][C:17]([C:16]1[C:14](=[O:15])[C:13]2[CH:12]=[C:11]3[CH:10]=[C:9]([F:26])[C:8]([F:27])=[CH:7][C:6]3=[N:5][C:4]=2[N:23]([CH3:24])[CH:22]=1)=[O:18])[CH3:21]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc2cc(F)c(F)cc2nc1Cl
Agent: CN
Solvent: CCO
Product: CCOC(=O)c1cn(C)c2nc3cc(F)c(F)cc3cc2c1=O
Reaction time: 1 h
Yield: 83.1 %

Procedure:
A solution of methylamine (11.3 g) at approximately 0° C. in ethanol (50 cc) is added in the course of 10 minutes at between 0° and 5° C. to a stirred suspension, maintained at a temperature in the region of 0° C., of ethyl 2-(2-chloro-6,7-difluoro-3-quinolinecarbonyl)-3-(dimethylamino)acrylate (22.3 g) in ethanol (480 cc), the mixture is stirred for 1 hour at between 0° and 5° C., the temperature is allowed to rise to approximately 25° C. and the mixture is stirred for a further 16 hours at the same temperature. The insoluble matter is drained and washed with ethanol (3×100 cc) and ethyl ether (2×100 cc). After 1 recrystallization in dimethylformamide (250 cc), 3-ethoxycarbonyl-7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (16 g) is obtained in the form of a yellow solid, m.p. 323° -324° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[C:23]3[C:18](=[C:19]([CH2:24][S:25][CH3:26])[CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:9][C:10](OCC)=[O:11])=[C:4]([CH3:27])[CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[C:23]3[C:18](=[C:19]([CH2:24][S:25][CH3:26])[CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:9][CH2:10][OH:11])=[C:4]([CH3:27])[CH:3]=1
Reactant: CCOC(=O)CC(c1ccc(F)cc1C)c1c[nH]c2c(CSC)cccc12
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CSCc1cccc2c(C(CCO)c3ccc(F)cc3C)c[nH]c12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 585 mg (1.52 mmol) of the compound from Example 43A in 15 ml of tetrahydrofuran was added dropwise to 5.3 ml (5.31 mmol) of a 1N solution of lithium aluminum hydride in tetrahydrofuran in 30 ml of tetrahydrofuran at RT under argon. The mixture was stirred at RT for 15 min and then, while cooling in ice, 1N hydrochloric acid was added. The mixture was extracted with ethyl acetate, and the organic phase was dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 369 mg (71% of theory) of the title compound.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.[Na].[CH2:22]([SH:24])[CH3:23].CN(C=O)C>O>[CH2:22]([S:24][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1)[CH3:23]
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Reactant: CCS
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
A mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.20 g of ethyl mercaptan sodium salt and 2 ml of DMF was stirred at room temperature for one hour. Water was added to the reaction mixture, and was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.28 g of 2-(3-ethylthio pyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 41”).
Reaction SMILES: [F:1][C:2]([F:16])([CH:13]([F:15])[F:14])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1.C([CH2:19][C:20]([OH:22])=[O:21])#N.FC(F)(C(F)F)COC1C=CC(/C=C\C#N)=CC=1.N1CCCCC1>N1C=CC=CC=1.C1(C)C(C)=CC=CC=1>[F:1][C:2]([F:16])([CH:13]([F:15])[F:14])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH:19][C:20]([OH:22])=[O:21])=[CH:7][CH:6]=1
Reactant: O=Cc1ccc(OCC(F)(F)C(F)F)cc1
Reactant: N#CCC(=O)O
Agent: N#C/C=C\c1ccc(OCC(F)(F)C(F)F)cc1
Solvent: Cc1ccccc1C
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1ccc(OCC(F)(F)C(F)F)cc1
Temperature: 110 °C
Yield: 135.1 %

Procedure:
735.0 g (3.12 mol) of 4-(2,2,3,3-tetrafluoropropoxy)benzaldehyde, 269 g of cyanoacetic acid, 660 g of cis-4-(2,2,3,3-tetrafluoropropoxy)cinnamonitrile (main fractions containing 80 to 85% by weight of cis isomer) are admixed with 750 g of xylene, 750 ml of pyridine and 750 ml of piperidine and heated to 110° C. with stirring. The mixture is allowed to react for 2 hours, and 53.8 g of cyanoacetic acid are added again and the mixture is allowed to react for a further 30 minutes. After cooling, the reaction mixture is distilled under reduced pressure and 1173 g of 4-(2,2,3,3-tetrafluoropropoxy)cinnamic acid (yield: 87% purity>95% by weight) are obtained in the form of a mixture of isomers which contains cis-4-(2,2,3,3-tetrafluoropropoxy)cinnamonitrile and trans-4-(2,2,3,3-tetrafluoropropoxy)cinnamonitrile in a molar ratio of about 1.8:1 and , in addition, about 3% by weight of piperidine and up to 2% by weight of unidentifiable impurities.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[C:14]([C@:19]2([CH3:25])[CH2:23][O:22]C(=O)[NH:20]2)[CH:13]=[CH:12]3)[CH2:4][CH2:3]1.[OH-].[Li+].C(O)C.O>>[NH2:20][C@@:19]([C:14]1[CH:13]=[CH:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([O:8][CH:5]3[CH2:6][CH2:7][C:2]([CH3:26])([CH3:1])[CH2:3][CH2:4]3)[CH:10]=2)[CH:15]=1)([CH3:25])[CH2:23][OH:22]
Reactant: CC1(C)CCC(Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1(C)CCC(Oc2ccc3cc([C@@](C)(N)CO)ccc3c2)CC1

Procedure:
The mixture of (R)-4-(6-(4,4-dimethylcyclohexyloxy)naphthalen-2-yl)-4-methyloxazolidin-2-one and lithium hydroxide (45 mg, 0.0019 mol) in ethanol (1.1 mL, 0.019 mol) and water (0.37 mL, 0.021 mol) was heated to reflux for overnight. The crude product was partitioned between ethyl acetate and water and the ethyl acetate layer was concentrated and the crude was brought up in methanol and purified by HPLC. MS: m/z=311.2 [M-NH2]+