Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[C:5]([C:11]([F:14])([F:13])[F:12])[CH:4]=1.Cl.Cl.[NH:17]1[CH2:22][CH2:21][CH:20](/[CH:23]=[C:24]2/[C:25]([NH:30][CH2:31][C:32]#[CH:33])=[N:26][C:27](=[O:29])[S:28]/2)[CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:17]2[CH2:22][CH2:21][CH:20](/[CH:23]=[C:24]3/[C:25]([NH:30][CH2:31][C:32]#[CH:33])=[N:26][C:27](=[O:29])[S:28]/3)[CH2:19][CH2:18]2)=[C:5]([C:11]([F:14])([F:13])[F:12])[CH:4]=1
Reactant: COc1ccc(CBr)c(C(F)(F)F)c1
Reactant: C#CCNC1=NC(=O)S/C1=C\C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(OC)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.9 %

Procedure:
To a solution of 4-methoxy-2-(trifluoromethyl)benzyl bromide (516 mg) in DMF (5 mL) were added (5Z)-5-(piperidin-4-ylmethylidene)-4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one dihydrochloride (500 mg) and potassium carbonate (862 mg). The reaction mixture was stirred at room temperature overnight, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (468 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:31])[C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:18][CH2:17][C@H:16]([O:19][C:20]4[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][C:21]=4[F:29])[C:15]3=[O:30])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH3:65][NH:66][CH2:67][CH2:68][OH:69]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([F:31])[C:5]([N:8]2[CH2:9][CH2:10][CH:11]([N:14]3[CH2:18][CH2:17][C@H:16]([O:19][C:20]4[CH:28]=[CH:27][C:23]([C:24]([N:66]([CH2:67][CH2:68][OH:69])[CH3:65])=[O:26])=[CH:22][C:21]=4[F:29])[C:15]3=[O:30])[CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: CNCCO
Reactant: O=C(O)c1ccc(O[C@H]2CCN(C3CCN(c4ncc(Cl)cc4F)CC3)C2=O)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CN(CCO)C(=O)c1ccc(O[C@H]2CCN(C3CCN(c4ncc(Cl)cc4F)CC3)C2=O)c(F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 29.1 %

Procedure:
To a solution of (S)-4-(1-(1-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yloxy)-3-fluorobenzoic acid (Example 153, Step B; 0.1 g, 0.22 mmol) in DMF (2 mL) was added HATU (0.17 g, 0.44 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.12 mL, 0.66 mmol) and the reaction was stirred for 20 minutes at ambient temperature. 2-(Methylamino)ethanol (0.050 g, 0.66 mmol) was added, and the reaction was stirred for 2 hours at ambient temperature. The reaction was diluted with EtOAc (30 mL) and washed with HCl (1 N, 10 mL), NaOH (1 N, 10 mL), water (10 mL), and brine (10 mL), and the combined organic phases were dried over MgSO4, filtered and concentrated under vacuum. The crude material was purified by reverse phase HPLC. The combined fractions were diluted with EtOAc (50 mL) and washed with 1 N NaOH (10 mL), water (10 mL), and brine (10 mL), and the combined organic phases were dried over MgSO4, filtered and concentrated under vacuum to give (S)-4-(1-(1-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yloxy)-3-fluoro-N-(2-hydroxyethyl)-N-methylbenzamide (0.033 g, 0.064 mmol, 29% yield). Mass spectrum (apci) m/z=509.0 (M+H).
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5])C.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[F:26][C:23]1[CH:22]=[CH:21][C:20]([C:15]2[C:14]([CH2:13][O:12][C:9]3[N:8]=[N:7][C:6]([C:4]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[O:5])=[CH:11][CH:10]=3)=[C:18]([CH3:19])[O:17][N:16]=2)=[CH:25][CH:24]=1
Reactant: C1COCCN1
Reactant: CCOC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2C)nn1
Product: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)N2CCOCC2)nn1
Yield: 83 %

Procedure:
As described for example 59, 6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridazine-3-carboxylic acid ethyl ester (143 mg, 0.4 mmol) was converted, using morpholine instead of aminomethylcyclopropane, to the title compound (132 mg, 83%) which was obtained as a light yellow solid. MS: m/e=399.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@:15]3([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]3)[C:14]3[CH:13]=[C:12]([Cl:22])[N:11]=[CH:10][C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[F:23][C:24]1[C:29](B(O)O)=[CH:28][CH:27]=[CH:26][N:25]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>>[Cl:22][C:12]1[N:11]=[CH:10][C:9]2[O:8][C:5]3[C:4]([C@:15]4([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]4)[C:14]=2[CH:13]=1)=[CH:3][C:2]([C:29]1[C:24]([F:23])=[N:25][CH:26]=[CH:27][CH:28]=1)=[CH:7][CH:6]=3
Reactant: OB(O)c1cccnc1F
Reactant: NC1=N[C@@]2(COC1)c1cc(Br)ccc1Oc1cnc(Cl)cc12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: NC1=N[C@@]2(COC1)c1cc(-c3cccnc3F)ccc1Oc1cnc(Cl)cc12
Temperature: 90 °C
Yield: 89.6 %

Procedure:
A vial was charged with (S)-7-bromo-3-chloro-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (546.36 mg, 1.435 mmol), 2-fluoropyridin-3-ylboronic acid (303 mg, 2.153 mmol), potassium phosphate (914 mg, 4.31 mmol), and bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II) (50.8 mg, 0.072 mmol). The vial was flushed with Argon, and then dioxane (5383 μL) and water (1794 μL) were added. The vial was sealed and heated in a Biotage Initiator microwave reactor for 20 min at 90° C. The reaction mixture was diluted with water and extracted with EtOAc (3×). The combined organic extracts were dried over sodium sulfate, concentrated under reduced pressure. The residue was purified by chromatography (0-100% EtOAc/Hexane) to give (S)-3-chloro-7-(2-fluoropyridin-3-yl)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (510.4 mg, 95% purity) as an off-white solid.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([O:6][C:7]2[CH:12]=[CH:11][C:10]([I:13])=[CH:9][N:8]=2)[CH2:3]1.C(N(CC)CC)C.[CH:21]1[CH:26]=[N:25][CH:24]=[C:23]([N:27]=[C:28]=[O:29])[CH:22]=1>ClCCl>[N:25]1[CH:26]=[CH:21][CH:22]=[C:23]([NH:27][C:28]([N:2]2[CH2:3][CH:4]([O:6][C:7]3[CH:12]=[CH:11][C:10]([I:13])=[CH:9][N:8]=3)[CH2:5]2)=[O:29])[CH:24]=1
Reactant: Ic1ccc(OC2CNC2)nc1
Reactant: O=C=Nc1cccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cccnc1)N1CC(Oc2ccc(I)cn2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.1 %

Procedure:
2-(Azetidin-3-yloxy)-5-iodo-pyridine hydrochloride (4.2 g, 13 mmol) was suspended in anhydrous dichloromethane (50 mL) and triethylamine (5.5 mL) was added. Pyridine-3-isocyanate (1.45 g, 11.7 mmol) was added and the reaction mixture was stirred at ambient temperature for 16 hr. The suspension solvents were removed in vacuo and the residue partitioned between ethyl acetate (400 mL) and sat. aqueous sodium bicarbonate solution (400 mL). The mixture was filtered through a pad of celite and the filtrate phases were separated. The organic phase was washed with sat. aqueous sodium bicarbonate solution (250 mL), then sat aqueous sodium chloride solution (250 mL) and dried over sodium sulphate and filtered. The filtrate solvents were removed in vacuo to afford a yellow solid which was purified by flash chromatography on silica gel (100 g), eluting with a 1:19 mix of 7N ammonia in methanol solution:dichloromethane. This affords the title compound (2.0 g, 42%) as a colourless solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1)[CH3:2].C(Cl)(=O)C([Cl:16])=O>ClCCl.CN(C)C=O>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([Cl:16])=[O:12])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(CC(=O)O)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCc1ccc(CC(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
4-Ethylphenylacetic acid (3.0 g) (see Japanese Unexamined Patent Publication 63-233975) was dissolved in dichloromethane (15 ml), and thereto were added oxalyl chloride (6.0 ml) and N,N-dimethylformamide (one drop). The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was evaporated under reduced pressure, and the residue was subjected to azeotropic distillation with toluene to give a crude 4-ethylphenylacetyl chloride, which was used in the subsequent step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@H:4]([NH2:17])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[CH3:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[C:24]([CH3:27])[C:25]=1[F:26].C(N(CC)CC)C>ClCCl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:1][O:2][C:3](=[O:18])[C@H:4]([NH:17][C:22]1[CH:23]=[C:24]([CH3:27])[C:25]([F:26])=[C:20]([CH3:19])[CH:21]=1)[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11]
Reactant: Cc1cc(B(O)O)cc(C)c1F
Reactant: COC(=O)[C@H](N)CCCCNC(=O)OC(C)(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H](CCCCNC(=O)OC(C)(C)C)Nc1cc(C)c(F)c(C)c1
Temperature: 25 °C
Reaction time: 87 h
Yield: 79.8 %

Procedure:
To a suspension of (R)-2-Amino-6-tert-butoxycarbonylamino-hexanoic acid methyl ester (3.000 g, 10.108 mmol), 3,5-dimethyl-4-fluorophenylboronic acid (3.398 g, 20.216 mmol), Cu(OAc)2 (2.019 g, 11.119 mmol), and molecular sieves 4 Å (7.591 g) in 45 mL of dichloromethane, was added triethylamine (2.8 mL, 20.216 mmol). After stirring at room temperature under O2 (1 atm) for 87 h, the reaction mixture was filtered through a pad of Celite and washed with dichloromethane. The filtrate was concentrated under reduced pressure. The product was isolated by Flash column chromatography (silica gel column) eluting with 0-30% ethyl acetate/hexanes to give the title compound as colorless oil (3.084 g, 80% yield). LC-MS: tR=9.8 min; m/z 383 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])[C:8](=[O:16])[NH:7][CH2:6][CH2:5]2.Br[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[C:24]([F:27])([F:26])[F:25].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([F:14])([F:13])[F:15])[C:8](=[O:16])[N:7]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[C:24]([F:27])([F:26])[F:25])[CH2:6][CH2:5]2
Reactant: FC(F)(F)c1ccncc1Br
Reactant: O=C1NCCc2cc(Cl)c(C(F)(F)F)cc21
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C1c2cc(C(F)(F)F)c(Cl)cc2CCN1c1cnccc1C(F)(F)F
Yield: 9.5 %

Procedure:
6-Chloro-7-(trifluoromethyl)-3,4-dihydroisoquinolin-1(2H)-one (I-85e: 100 mg, 0.4 mmol) was reacted with 3-bromo-4-(trifluoromethyl)-pyridine (117.6 mg, 0.520 mmol), 1,4-dioxane (5 mL), copper iodide (7.6 mg, 0.04 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (5.6 mg, 0.04 mmol) and potassium phosphate (255.6 mg, 1.2 mmol) to afford the crude product. Purification by preparative HPLC afforded 15 mg of the product (10% yield).
Reaction SMILES: [CH3:1][C@:2]12[C@H:12]([CH2:13]/[CH:14]=[C:15]3\[C@H:16]([OH:21])[CH2:17][O:18][C:19]\3=[O:20])[C:10](=[CH2:11])[CH2:9][CH2:8][C@@H:7]1[C@@:6]([CH2:23][OH:24])([CH3:22])[C@H:5]([OH:25])[CH2:4][CH2:3]2.[C:26]1(C)[CH:31]=CC(S([O-])(=O)=O)=C[CH:27]=1.[NH+]1C=CC=CC=1.C1(C)C=CC=CC=1.CS(C)=O>COC(OC)(C)C>[CH3:1][C@:2]12[C@H:12]([CH2:13]/[CH:14]=[C:15]3\[C@H:16]([OH:21])[CH2:17][O:18][C:19]\3=[O:20])[C:10](=[CH2:11])[CH2:9][CH2:8][C@@H:7]1[C@:6]1([CH3:22])[CH2:23][O:24][C:26]([CH3:31])([CH3:27])[O:25][C@@H:5]1[CH2:4][CH2:3]2
Reactant: C=C1CC[C@@H]2[C@](C)(CO)[C@H](O)CC[C@@]2(C)[C@@H]1C/C=C1/C(=O)OC[C@H]1O
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: COC(C)(C)OC
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: C=C1CC[C@@H]2[C@]3(C)COC(C)(C)O[C@@H]3CC[C@@]2(C)[C@@H]1C/C=C1/C(=O)OC[C@H]1O
Temperature: 80 °C
Reaction time: 1 h
Yield: 2788.6 %

Procedure:
Andrographolide (150 mg, 0.43 mmol) was dissolved in a mixture solution of 2,2-dimethoxypropane (0.2 mL), pyridinium p-toluene-sulfonate (3 mg) and toluene/DMSO (3 mL/0.4 mL), stirred at 80° C. for 1 hour, and cooled to room temperature at the end. The reaction was terminated by using triethylamine (0.1 mL), the reaction mixture was diluted with toluene (20 mL), washed with water (3×5 mL), the organic layer was dried using anhydrous Na2SO4 and concentrated, and the obtained white solid was washed with ethyl ether and filtrated to obtain the compound 1 (130 mg, 78%) (Srinivas et al., Bioorg. Med. Chem. Lett. 2004, 14, 4711-4717).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:9]1.[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>CN(C)C(=O)C>[CH3:29][N:15]([CH2:14][C@H:11]1[CH2:12][CH2:13][C@H:8]([CH2:7][O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:9][CH2:10]1)[S:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)(=[O:18])=[O:17]
Reactant: C1CCNCC1
Reactant: CN(C[C@H]1CC[C@H](COCCCCBr)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Solvent: CC(=O)N(C)C
Product: CN(C[C@H]1CC[C@H](COCCCCN2CCCCC2)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to the method described in example 12.1, trans-N-[4-(4-bromo-butoxymethyl)-cyclohexylmethyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide was reacted with piperidine in N,N-dimethylacetamide at room temperature to yield trans-N-methyl-N-[4-(4-piperidin-1-yl-butoxymethyl)-cyclohexylmethyl]-4-trifluoromethyl-benzenesulfonamide as light yellow solid, MS: 505 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[CH2:23][CH2:24][C:25]([O:27]CC)=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[CH2:23][CH2:24][C:25]([OH:27])=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 84.4 %

Procedure:
To a solution of ethyl 3-(2,4-dibenzyloxyphenyl)propionate (12.0 g) in ethanol (300 ml), sodium hydroxide (10.3 g) was added, followed by stirring at room temperature for 6 hours. The reaction mixture was adjusted to pH 4.0 with addition of 5N hydrochloric acid solution. Ethanol was distilled off and to the residue was added water. The precipitated crystal was collected by filtration, washed with water and dried to obtain as colorless crystal 3-(2,4-dibenzyloxyphenyl)propionic acid (9.4 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][N:41]=[C:40]([CH:44]3[CH2:48][CH2:47][CH2:46][CH2:45]3)[CH:39]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][N:41]=[C:40]([CH:44]3[CH2:45][CH2:46][CH2:47][CH2:48]3)[CH:39]=2)[CH:33]=1)=[O:31])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(C3CCCC3)c2)c1
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C4CCCC4)c3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-ethoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J8) (240 mg, 0.75 mmol) and 3-[3-(2-cyclopentyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K61) (274 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow solid (366 mg, 80%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[F:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)=[CH:4][CH:3]=1.Cl.[CH3:26][O:27][C:28]([C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[CH2:35][NH:34][CH2:33]2)=[O:29].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH3:26][O:27][C:28]([C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[CH2:35][N:34]([C:15]1[C:16]([F:18])=[C:17]3[C:12]([C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9][N:8]3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:13][C:14]=1[F:20])[CH2:33]2)=[O:29]
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(F)c(F)cc2c1=O
Reactant: COC(=O)c1ccc2c(c1)CNC2
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)CN(c1c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)cc4)c3c1F)C2
Yield: 9.6 %

Procedure:
170 mg of 1-(4-fluorophenyl)-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 109 mg of 5-methoxycarbonylisoindoline hydrochloride, 228 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 24 mg of the target compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:9][CH:10]2[CH2:12][CH2:11]2)[CH:5]=[C:6]([F:8])[CH:7]=1.O1CCCC1.C([Li])CCC.[CH2:23]([O:25][C:26](Cl)=[O:27])[CH3:24]>CCOCC.[Cl-].[Na+].O>[CH:10]1([O:9][C:4]2[CH:3]=[C:2]([F:1])[C:7]([C:26]([O:25][CH2:23][CH3:24])=[O:27])=[C:6]([F:8])[CH:5]=2)[CH2:12][CH2:11]1
Reactant: CCOC(=O)Cl
Reactant: Fc1cc(F)cc(OC2CC2)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)c1c(F)cc(OC2CC2)cc1F
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 87.6 %

Procedure:
To a 250 ml round bottom flask was added cyclopropyl 3,5-difluorophenyl ether (3.6 g, 21.2 mmol) and 60 ml tetrahydrofuran. n-Butyllithium (nBuLi) (2.5 M, 8.9 ml, 22.2 mmol) was added via a syringe at −78° C. The resulting solution was stirred at −78° C. for 20 minutes. Ethylchloroformate (3.05 ml, 31.7 mmol) was added by a syringe. The resulting solution was left stirring for 5 more minutes. The reaction mixture was diluted with 100 ml ether and 60 ml brine. The layers were separated, and the organic portion was dried over sodium sulfate, filtered and concentrated. The crude product was purified on silica gel column eluted with hexane to 1:9 ethyl acetate/hexane gradient solvent to give 4.5 g desired product as yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH3:12])=[CH:9][O:10]C.Cl(O)(=O)(=O)=O>CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:12])[CH:9]=[O:10]
Reactant: COC=C(C)c1ccccc1Cl
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCOCC
Product: CC(C=O)c1ccccc1Cl
Reaction time: 1 h

Procedure:
To a solution of 2-(2-chlorophenyl)-1-methoxypropene (712 mg, 3.9 mmol) in ether (8 ml) at 0° C. was added perchloric acid (70%, 3 ml). After stirring for 1 h the solution was diluted with ether (8 ml) and washed with water (2×20 ml). The organic phase was separated, dried (Na2SO4) and evaporated. The crude 2-(2-chlorophenyl)propanal was isolated as a colourless oil and used without further purification.
Reaction SMILES: [F:1][P-:2]([F:7])([F:6])([F:5])([F:4])[F:3].[C:8]1([CH3:27])[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S+:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[O-][O-].[Na+].[Na+].ClC(Cl)(Cl)C(Cl)=[O:35]>CO>[F:1][P-:2]([F:7])([F:6])([F:5])([F:4])[F:3].[C:8]1([CH3:27])[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S+:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:35]
Reactant: Cc1ccccc1[S+](c1ccccc1)c1ccccc1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Agent: [O-][O-]
Solvent: CO
Product: Cc1ccccc1[S+](=O)(c1ccccc1)c1ccccc1
Yield: 0.1 %

Procedure:
(Tolyl)diphenylsulphonium hexafluorophosphate (1.08 g, 2.57 mol) is dissolved in methanol (40 ml) with cooling in an ice-water bath. Sodium peroxide (2.42 g, 31 mmol) is added slowly. After 15 mins a solution of trichloro- acetyl chloride (1.4 ml, 12.5 mol) in methanol (30 ml) is added over 20 mins. After a further 30 mins the reaction mixture is filtered under vacuum and the filtrate evaporated in vacuo. Water is added and the resulting solid collected, washed with water and ether to give (tolyl)diphenylsulphoxonium hexafluorophosphate (0.72 g, 64% ) with spectra identical to those of authentic material.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[C:13](=[O:27])[NH:14][N:15]=[C:16]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH2:25][CH3:26])[N:19]=2)[CH:17]=1)=O>C(O)(=O)C>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]2[NH:9][C:10]([C:12]3[C:13](=[O:27])[NH:14][N:15]=[C:16]([C:18]4[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH2:25][CH3:26])[N:19]=4)[CH:17]=3)=[N:1][C:2]=2[CH:7]=1
Reactant: CCNc1nccc(-c2cc(C(=O)Nc3ccc(Cl)cc3N)c(=O)[nH]n2)n1
Solvent: CC(=O)O
Product: CCNc1nccc(-c2cc(-c3nc4cc(Cl)ccc4[nH]3)c(=O)[nH]n2)n1

Procedure:
6-(2-Ethylaminopyrimidin-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (2-amino-4-chlorophenyl)amide (50 mg) are stirred in 1 ml of glacial acetic acid at 100° C. for 3 hours. After cooling, the precipitate is filtered off with suction, stirred with aqueous sodium bicarbonate solution and again filtered off with suction, washed with water and dried in vacuo.
Reaction SMILES: [C:1]([O:14]CC)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:17]([NH2:20])[CH2:18][NH2:19]>O1CCCC1>[NH2:19][CH2:18][CH2:17][NH:20][C:1](=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)OCC
Reactant: NCCN
Solvent: C1CCOC1
Product: CCCCCCCCCCCC(=O)NCCN
Temperature: 100 °C
Yield: 44.6 %

Procedure:
A solution of 23 g of ethyl dodecanoate and 62.7 g of ethylenediamine in 100 ml of tetrahydrofuran (THF) was refluxed for 3 hours and the excess THF was distilled off. The reaction mixture was heated at 100° C. for 16 hours, cooled to room temperature, poured into cold water and extracted with ether. After drying, the organic solution was concentrated to give 15.7 g of crude product and this was recrystallized from ether-hexane to give 10.9 g of pure product, m.p. 64°-66° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20])[C:7]([OH:9])=[O:8].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C1COCC1.CS(C)=O>C(Cl)Cl.N1C=CC=CC=1>[CH:2]([CH2:3][CH2:4][CH2:5][C@H:6]([N:10]1[C:11](=[O:20])[C:12]2=[CH:19][CH:18]=[CH:17][CH:16]=[C:13]2[C:14]1=[O:15])[C:7]([OH:9])=[O:8])=[O:1]
Reactant: O=C(O)[C@H](CCCCO)N1C(=O)c2ccccc2C1=O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=CCCC[C@@H](C(=O)O)N1C(=O)c2ccccc2C1=O
Reaction time: 8 h

Procedure:
6-Hydroxy-2(S)-phthalimidohexanoic acid (1.94 g) was dissolved in 145 ml of CH2Cl2 containing 2.26 ml of pyridine. Pyridinium dichromate (1.95 g) was added and the mixture stirred overnight under nitrogen. By addition to 200 ml of ethyl acetate and filtration, chromium salts were removed. The filtrate was concentrated under vacuum. The residue was redissolved in 250 ml of ethyl acetate and the solution refiltered. The filtrate was finally passed through a MgSO4 pad to remove trace amounts of chromium salts and concentrated to afford a white solid, 0.475 g; m.p. 219°-22°; [α]D25° =-41.6° (THF, c=1.5). Tlc on silica (4:1 ethyl acetate:acetic acid) indicated a single spot at Rf =0.79. 'H NMR spectrum (d6 -DMSO) showed triplets at δ9.65 (1H) and δ4.85 (1H, J=7.5 Hz), a singlet at δ7.95 (4H), and a broad multiplet at δ0.9-2.50 (6H) ppm. 13C NMR spectrum (d6 -DMSO) showed single absorptions at 202.9, 170.5, 167.5, 134.9, 131.3, 123.5, 51.7, 42.4, 27.8, and 18.7 ppm.