Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:24])([CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)[CH2:10][C:11](=[O:17])[NH:12][CH2:13][CH2:14][S:15][CH3:16].ClC1C=CC=C(C(OO)=[O:33])C=1>C(O)(C)C.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:24])([CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)[CH2:10][C:11](=[O:17])[NH:12][CH2:13][CH2:14][S:15]([CH3:16])=[O:33]
Reactant: CSCCNC(=O)CC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CC(C)O
Product: CS(=O)CCNC(=O)CC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl

Procedure:
2-(2,4-Dichlorophenyl)-1-[N-(2-[methylthio]ethyl)carbamoyl]-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (0.8 g) and m-chloroperbenzoic acid (85%, 0.35 g, 1 equiv.) were stirred at room temperature in a mixture of isopropanol and methylene chloride (1:1, v/v, 40 ml) for two days. The solvents were then removed under reduced pressure, and the residue was chromatographed on silica (Merck, "Kieselgel 60 ", 25 g), eluting with a mixture of chloroform, methanol and ammonia (sp. gr. 0.880) (160:20:5, v/v). A portion of the isomer which was eluted first was obtained pure, 116 mg, m.p. 168°-170° C.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:24])[CH2:18][CH2:19][C:20]([O:22]C)=[O:21])=[CH:13][CH:12]=1>>[C:1]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([C:17](=[O:24])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:16]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Product: O=C(O)CCC(=O)c1ccc(NC(=O)c2ccccc2)cc1
Yield: 53.8 %

Procedure:
In a manner similar to that described in Example 3, benzoyl chloride (0.047 g, 0.00033 mol) was allowed to react with 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester (0.052 g, 0.00025 mol), and the resulting intermediate was hydrolyzed to give 0.040 g of 4-[4-(benzoylamino)-phenyl]-4-oxo-butyric acid as an off-white solid; MS-(AP+) MH+332.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH:13]=[CH2:14])[C@H:9]1[CH2:15][OH:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)=[O:19].OS(O)(=O)=O.O=[Cr](=O)=O.OS(O)(=O)=O.O>CC(C)=O.C(O)(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH:13]=[CH2:14])[C@H:9]1[C:15]([OH:19])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C[C@H]1CCN(C(=O)OC(C)(C)C)[C@@H]1CO
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)O
Product: C=C[C@H]1CCN(C(=O)OC(C)(C)C)[C@@H]1C(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 73.9 %

Procedure:
600 mg of alcohol 165 (2.64 mmol) was dissolved in 15 ml of acetone, cooled to 0° C. and added dropwise with 5 ml of Jones reagent (7.40 mmol, 2.8 eq.) (freshly prepared from 2 g of CrO3, 2.7 g of conc. H2SO4, 12 ml of H2O) and stirred for 2 h at RT, the course of the reaction being monitored using TLC (EE/CH 1:1). This was followed by addition of 4 ml of isopropanol, during which the orange color of the reaction mixture gradually turned green-brown. Filtration over Celite was followed by washing with 5 ml of an acetone/glacial acetic acid mixture (20:1) and concentrating to dryness. The remaining greenish residue was purified using silica gel column chromatography (CH2Cl2/MeOH 20:1), thereby obtaining 470 mg of vinylproline 166 (1.95 mmol, 74%) in the form of white crystals suitable for X-ray crystallographic analysis.
Reaction SMILES: C([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[N:7]=1)C.Br[CH2:15][CH2:16]Br>>[Br:12][C:8]1[N:7]=[C:6]([C:5]2([C:4]([OH:3])=[O:13])[CH2:16][CH2:15]2)[CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)Cc1cccc(Br)n1
Reactant: BrCCBr
Product: O=C(O)C1(c2cccc(Br)n2)CC1
Yield: 57 %

Procedure:
The title compound was prepared from (6-bromo-pyridin-2-yl)-acetic acid ethyl ester and 1,2-dibromoethane following a procedure analogous to that described in Step 3 for Intermediate 4; under these conditions the ester group was hydrolyzed. Yield: 57% of theory; LC (method 3): tR=2.60 min; Mass spectrum (ESI+): m/z=242/244 (Br) [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:32])[N:14]([CH3:31])[N:15]=[C:16]([CH2:26][O:27]COC)[C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:2].Cl.O.[OH-].[Na+]>CO>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:32])[N:14]([CH3:31])[N:15]=[C:16]([CH2:26][OH:27])[C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1-c1c(OCc2ccccc2)c(COCOC)nn(C)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCc1cc(C)cc(CC)c1-c1c(OCc2ccccc2)c(CO)nn(C)c1=O
Temperature: 65 °C
Reaction time: 1.25 h
Yield: 85.1 %

Procedure:
To a solution of 4-(2,6-diethyl-4-methylphenyl)-6-methoxymethoxymethyl-5-benzyloxy-2-methyl-3(2H)-pyridazinone (2.3 g, 4.91 mmol) in methanol (15 ml) was added concentrated hydrochloric acid (2 ml) and water (1 ml), and stirred at 65° C. for 75 minutes. After cooling to room temperature, the mixture was neutralized with 2N aqueous sodium hydroxide solution, and extracted with ethyl acetate 2 times. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give 1.64 g of Compound (I-29) (yield: 85%) as solid.
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[C:7]([C:8](Cl)=[O:9])=[CH:6][N:5]([CH3:11])[N:4]=1.[CH:13]1([NH:16][CH:17]([CH3:27])[CH2:18][N:19]([CH3:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][CH2:14]1.C(N(CC)CC)C.CCCCCCC.C(OCC)(=O)C>O1CCCC1>[CH:13]1([N:16]([CH:17]([CH3:27])[CH2:18][N:19]([CH3:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]([C:7]2[C:3]([CH:2]([F:12])[F:1])=[N:4][N:5]([CH3:11])[CH:6]=2)=[O:9])[CH2:15][CH2:14]1
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Reactant: CC(CN(C)c1ccccc1)NC1CC1
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(CN(C)c1ccccc1)N(C(=O)c1cn(C)nc1C(F)F)C1CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 40.2 %

Procedure:
At ambient temperature, a solution of 220 mg (1.13 mmol) of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride in 1 ml of tetrahydrofurane is added dropwise to a solution of 210 mg (1.03 mmol) of N2-cyclopropyl-N1-methyl-N1-phenylpropane-1,2-diamine and 0.16 ml (1.13 mmol) of triethylamine in 5 ml of tetrahydrofurane. The reaction mixture is stirred for 15 hrs at room temperature. The solvent to is removed under vacuum and 100 ml of water are then added to the residue. The watery layer is extracted twice with ethyl acetate (2×150 ml) and the combined organic layers are successively washed by a 1 N solution of HCl, a saturated solution of potassium carbonate and brine and filtered over a ChemElut cartridge to yield after concentration 180 mg of a brown oil. Column chromatography (gradient heptane/ethyl acetate) yielded 150 mg (38% yield) of N-cyclopropyl-3-(difluoromethyl)-1-methyl-N-{1-[methyl(phenyl)-amino]propan-2-yl}-1H-pyrazole-4-carboxamide as a yellow oil (M+H=363).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([SH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)#[N:13]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[N:13][C:7](=[O:9])[C:6]=2[CH:10]=1
Reactant: N#Cc1ccccn1
Reactant: O=C(O)c1cc(Cl)ccc1S
Solvent: c1ccncc1
Product: O=c1nc(-c2ccccn2)sc2ccc(Cl)cc12
Yield: 27 %

Procedure:
A mixture of 5-chloro-2-mercaptobenzoic acid (2.00 g, 10.6 mmol), 2-cyanopyridine (1.10 g, 10.5 mmol) and pyridine (50.0 ml) was refluxed for 9 hrs. After cooling, the precipitated crystals were collected by filtration and recrystallized from hexane-chlorobenzene to give the titled compound (0.78 g, 27%)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.C([Li])CCC.CN([CH:17]=[O:18])C.O>C(OCC)C.CCCCCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:17]=[O:18])=[CH:4][N:3]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: CCOCC
Product: O=Cc1ccc(Br)nc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
According to a procedure described in literature (Xin Wang et al., Tetrahedron. Lett., 2000, vol. 41, p. 4335], a solution of 2,5-dibromopyridine (3.17 g) in anhydrous diethyl ether (140 ml) was added dropwise with a 1.6 M solution of n-butyl lithium in hexane (11 ml) with cooling at −78° C. under argon gas atmosphere over 5 minutes, and stirred for 20 minutes. This reaction mixture was added dropwise with dehydrated DMF (1 ml) over 3 minutes, stirred for 30 minutes, then warmed to room temperature, and further stirred for 1 hour. The reaction mixture was added with water (20 ml), and extracted with ethyl acetate (30 ml×2). The organic layer was washed with saturated brine, and dried, and then the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Quad, hexane:ethyl acetate=6:1) to obtain the title compound (Intermediate Int. n-44, 1.46 g).
Reaction SMILES: [CH:1]1([C:4]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][O:18]COC)[CH:12]=2)=[CH:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1>C(O)(=O)C.[Zn]>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][OH:18])[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:2][CH2:3]1
Reactant: CCOC(=O)C=C(c1ccnc(COCOC)c1)C1CC1
Agent: [Zn]
Solvent: CC(=O)O
Product: CCOC(=O)CC(c1ccnc(CO)c1)C1CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57.2 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(2-((methoxymethoxy)methyl)pyridin-4-yl)acrylate (1.28 g) in acetic acid (20 mL) was added zinc powder (2.87 g) at 20° C., and the mixture was stirred at room temperature for 10 min. The reaction mixture was filtered, and the solvent of the filtrate was evaporated under reduced pressure. The residue was dissolved in THF (30 mL), and conc. sulfuric acid (3.51 mL) was added. The reaction mixture was stirred at 60° C. for 1 hr, and further heated under reflux for 5 min. The reaction mixture was basified with aqueous potassium carbonate solution at 0° C., and extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (626 mg) as a colorless oil.
Reaction SMILES: [O:1]=[C:2]([NH:25][C:26]1[NH:30][C:29]([C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)=[N:28][N:27]=1)[C@@H:3]([N:11]([CH2:19][C:20]1[N:21]=[CH:22][S:23][CH:24]=1)C(=O)OC(C)(C)C)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl.C([O-])(O)=O.[Na+]>O1CCOCC1.O>[C:5]1([CH2:4][C@H:3]([NH:11][CH2:19][C:20]2[N:21]=[CH:22][S:23][CH:24]=2)[C:2]([NH:25][C:26]2[NH:30][C:29]([C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)=[N:28][N:27]=2)=[O:1])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)N(Cc1cscn1)[C@@H](Cc1ccccc1)C(=O)Nc1nnc(-c2ccncc2)[nH]1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(Nc1nnc(-c2ccncc2)[nH]1)[C@H](Cc1ccccc1)NCc1cscn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 34 %

Procedure:
To a rt solution of 2.E (147 mg, 0.29 mmol) in dioxane (3.0 mL) was added concentrated HCl (0.5 mL). After stirring at rt for 1.5 hr, the reaction mixture was poured into saturated NaHCO3, diluted with water and extracted with 30% iPrOH/chloroform. The organic solvent was removed under reduced pressure. After purification of the residue by preparative HPLC (10-90% CH3CN/water, 45 min), the combined product fractions was treated with saturated NaHCO3, and extracted with 30% i PrOH/CHCl3. After removal of solvent under reduced pressure, the title product 2 (40 mg, 37%) was obtained as colorless solid. MS ESI (positve.) m/e: 406.1 (M+H); 1H NMR (400 MHz, CD3OD) δ ppm 3.22-3.43 (m, 3H), 3.47-(dd, J=13.50, 6.06 Hz, 1H), 4.40-4.63 (m, 3H), 7.21-7.41 (m, 5H), 7.80 (d, J=1.96 Hz, 1H), 8.50 (d, J=6.65 Hz, 2H), 8.86 (d, J=6.65 Hz, 2H), 9.10 (d, J=1.96 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]([S:16]([CH3:19])(=[O:18])=[O:17])[C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N+:13]([O-])=O)[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].CO>[Pd].C(OCC)(=O)C>[NH2:13][C:11]1[CH:10]=[C:5]([CH:4]=[C:3]([N:2]([CH3:1])[S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(N(C)S(C)(=O)=O)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(N)cc(N(C)S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99 %

Procedure:
A mixture of methyl 3-[methyl(methylsulfonyl)amino]-5-nitrobenzoate obtained in Reference Example 95.76 g (20 mmol), 10% Pd/C (50% wet) (1.50 g), methanol (80 mL) and ethyl acetate (80 mL) was stirred at room temperature under hydrogen atmosphere for 1.5 hours. The reaction solution was filtered on Celite and the solvent was evaporated to give 5.11 g (19.8 mmol) of the title compound (yield: 99%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:28]3[CH2:33][CH2:32][N:31](C(OCC)=O)[CH2:30][CH2:29]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C@H:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:21])[N:14]=2)=[CH:4][CH:3]=1.[Si](I)(C)(C)C.Cl.[OH-].[Na+]>C(Cl)(Cl)Cl.C(O)CC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C@H:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:21])[N:14]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)N1CCC(c2nc(-c3ccc(F)cc3)c(-c3ccnc(N[C@@H](C)c4ccccc4)n3)s2)CC1
Agent: C[Si](C)(C)I
Agent: Cl
Agent: [Na+]
Solvent: CCCO
Solvent: ClC(Cl)Cl
Product: C[C@H](Nc1nccc(-c2sc(C3CCNCC3)nc2-c2ccc(F)cc2)n1)c1ccccc1
Yield: 87 %

Procedure:
4-(4-Fluorophenyl)-2-(1-ethoxycarbonylpiperidin-4-yl)-5-(2-(1-(S)-phenylethyl)amino-4-pyrimidinyl)thiazole (2.4 g 4.5 mmol) was dissolved in CHCl3 (45 ml) and treated with Me3SiI (1.8 ml 13.5 mmol) at 60° C. for 6 h. The reaction mixture was combined with 6M HCl in propanol (18.5 ml), homogenized by vigorous stirring, poured on 2N NaOH and extracted twice with CH2Cl2. The combined organic phases were dried over Na2SO4, filtered, evaporated to dryness and purified by SiO2 chromatography (tert.butyl methyl ether/MeOH/NH3conc. 95/4.5/0.5 to 80/18/2) to yield the title compound (1.8 g 87%) as a white foam.
Reaction SMILES: CCN(CC)CC.Br[C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([N:17]3[CH:23]4[CH2:24][CH2:25][N:20]([CH2:21][CH2:22]4)[CH2:19][CH2:18]3)=[N:14][C:13]=2[CH:26]=1.[C:27]1([CH3:36])[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1.[F-].[Cs+]>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C1C=CC=CC=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1)C>[C:27]1([CH3:36])[CH:32]=[CH:31][CH:30]=[C:29]([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([N:17]4[CH:23]5[CH2:24][CH2:25][N:20]([CH2:21][CH2:22]5)[CH2:19][CH2:18]4)=[N:14][C:13]=3[CH:26]=2)[CH:28]=1
Reactant: Cc1cccc(B(O)O)c1
Reactant: Brc1ccc2oc(N3CCN4CCC3CC4)nc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: Cc1cccc(-c2ccc3oc(N4CCN5CCC4CC5)nc3c2)c1
Temperature: 80 °C
Yield: 75.5 %

Procedure:
Et3N (5 μL) was added to a solution of palladium (II) acetate (0.7 mg, 3.1 μmol) and 2-(N,N-dimethylamino)-2′-dicylohexylphosphinobiphenyl (1.8 mg, 4.65 μmol) in 1,2-dimethoxyethane (0.5 mL) under a nitrogen atmosphere at RT. 4-(-5Bromo-benzooxazol-2-yl)-1,4-diaza-bicyclo[3.2.2]nonane (50 mg, 0.155 mmol, prepared in example 9), m-tolylboronic acid (32 mg, 0.233 mmol) and CsF (70 mg, 0.465 mmol) were added to the solution and the mixture was heated in an oil bath (temp=80° C.) for a period of 16 h. The reaction mixture was cooled to RT, filtered through a pad of celite and concentrated in vacuo. The crude residue was purified by chromatography (Biotage, 12L) eluting with 4% MeOH in CHCl3 with 1 mL of NH4OH per L to give 39 mg (75%) of the title compound as a film: 1H NMR (CDCl3, 400 MHz) δ 7.55 (d, 1H, J=1.7 Hz), 7.40-7.38 (m, 2H), 7.33-7.26 (m, 2H), 7.22-7.19 (m, 1H), 7.14 (d, 1H, J=7.4 Hz), 4.54-4.52 (m, 1H), 3.94 (t, 2H, J=5.8 Hz), 3.19-3.12 (m, 4H), 3.06-2.99 (m, 2H), 2.41 (s, 3H), 2.20-2.13 (m, 2H), 1.86-1.78 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 162.2, 148.6, 144.3, 141.9, 138.5, 138.0, 128.9, 128.4, 127.8, 124.6, 119.8, 114.8, 108.7, 57.3, 60.4, 46.5, 44.4, 27.0, 21.8; MS (Cl) m/z 334.1 (M+1).
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][C:6](Cl)=[O:7])[CH3:4].Cl.Cl.[Cl:11][C:12]1[C:13]([F:38])=[C:14]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH:32]4[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]4)=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)[CH:15]=[CH:16][CH:17]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:11][C:12]1[C:13]([F:38])=[C:14]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH:32]4[CH2:37][CH2:36][N:35]([C:6](=[O:7])[CH2:5][N:3]([CH3:4])[CH3:2])[CH2:34][CH2:33]4)=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: CN(C)CC(=O)Cl
Reactant: COc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC1CCN(C(=O)CN(C)C)CC1
Yield: 44.9 %

Procedure:
N,N-Dimethylaminoacetyl chloride hydrochloride (100 mg) was added portionwise to a stirred solution of N-(3-chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine dihydrochloride (250 mg, 0.57 mmol) and diisopropylethylamine (300 μl) in methylene chloride (25 ml) at 0° C. The reaction mixture was allowed to stir for 2 hours to room temperature. The reaction mixture was washed with saturated sodium bicarbonate solution (25 ml), dried (MgSO4), filtered and evaporated. The residues were purified by column chromatography eluting with increasingly polar mixtures of methylene chloride/methanol (100/0 to 90/10), followed by methylene chloride/methanol (saturated with ammonia) (90/10). The fractions containing the desired product were combined and evaporated under vacuum to give the title product as a white foam (0.125 g, 45%); 1H NMR Spectrum: (DMSO d6) 1.50-1.65 (m, 1H); 1.65-1.80 (m, 1H); 1.95-2.15 (m, 2H); 2.25 (s, 6H); 3.10-3.50 (m, 4H); 3.75-4.05 (m, 2H); 3.95 (s, 3H); 4.90 (m, 1H); 7.30 (m, 1H); 7.35 (s, 1H); 7.40-7.60 (m, 2H); 7.85 (s, 1H); 8.40 (s, 1H); 9.65 (s, 1H); Mass Spectrum: (M+H)+ 488.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:22][CH3:23])=[C:6]([CH:8]2[C:16](=[O:17])[CH:15]3[CH:10]([C:11]4([CH3:20])[O:18][C:14]3([CH3:19])[CH:13]=[CH:12]4)[C:9]2=[O:21])[CH:7]=1>CO.[Pd]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:22][CH3:23])=[C:6]([CH:8]2[C:9](=[O:21])[CH:10]3[CH:15]([C:14]4([CH3:19])[O:18][C:11]3([CH3:20])[CH2:12][CH2:13]4)[C:16]2=[O:17])[CH:7]=1
Reactant: CCc1ccc(Br)cc1C1C(=O)C2C(C1=O)C1(C)C=CC2(C)O1
Agent: [Pd]
Solvent: CO
Product: CCc1ccc(Br)cc1C1C(=O)C2C(C1=O)C1(C)CCC2(C)O1

Procedure:
A solution of (1RS,2SR,6RS,7SR)-4-(5-bromo-2-ethylphenyl)-1,7-dimethyl-10-oxatricyclo[5.2.1.02,6]dec-8-en-3,5-dione (1.63 g, 4.3 mmol) in methanol (200 ml) is hydrogenated at 3.5 bar over 5% palladium on carbon for 1 hour and 30 minutes at room temperature. The catalyst is removed by filtration through diatomaceous earth and the solvent is evaporated under reduced pressure. Trituration with diethyl ether gives (1RS,2SR,6RS,7SR)-4-(5-bromo-2-ethylphenyl)-1,7-dimethyl-10-oxatricyclo[5.2.1.02,6]decane-3,5-dione.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:35]=[CH:36]/[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([F:52])([F:51])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[C@@:22]([OH:34])([CH2:30][CH2:31][O:32][CH3:33])[C:23]([O:25]C(C)(C)C)=[O:24])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:35]=[CH:36]/[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([F:51])([F:52])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[C@@:22]([OH:34])([CH2:30][CH2:31][O:32][CH3:33])[C:23]([OH:25])=[O:24])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCCC(F)(F)CCCCCC/C=C/[C@H](C(=O)N[C@@H](Cc1ccc(OCCCC)cc1)C(=O)OC)[C@@](O)(CCOC)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCC(F)(F)CCCCCC/C=C/[C@H](C(=O)N[C@@H](Cc1ccc(OCCCC)cc1)C(=O)OC)[C@@](O)(CCOC)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 44 %

Procedure:
tert-Butyl (E)-(2S,3S)-3-[(S)-2-(4-butoxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-12,12-difluoro-2-hydroxy-2-(2-methoxy-ethyl)-nonadec-4-enoate (No. 5552820; 13.9 mg, 0.0188 mmol) was dissolved in dichloromethane (2.1 mL), and trifluoroacetic acid (TFA, 0.7 mL) was added to the solution. The mixture was stirred at room temperature for 16 hours, and the solvent was distilled off. To the residue was added dichloromethane, and the solvent was again distilled off. This operation was repeated twice. Subsequently, HPLC purification (water with 0.05% TFA-acetonitrile with 0.05% TFA) was performed to obtain (E)-(2S,3S)-3-[(S)-2-(4-butoxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-12,12-difluoro-2-hydroxy-2-(2-methoxy-ethyl)-nonadec-4-enoic acid (No. 5514403; 5.6 mg, 44% yield, white powder).
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([CH3:3])[CH3:2].[Br:9][C:10]1[CH:15]=[CH:14][C:13](I)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CNCCNC>CN(C)C=O.[Cu]I.O>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([N:6]2[CH:7]=[CH:8][C:4]([CH:1]([CH3:3])[CH3:2])=[N:5]2)=[CH:12][CH:11]=1
Reactant: Brc1ccc(I)cc1
Reactant: CC(C)c1cc[nH]n1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1ccn(-c2ccc(Br)cc2)n1
Temperature: 100 °C
Yield: 95.2 %

Procedure:
3-Isopropylpyrazole (588 mg, 5.43 mmol), 1-bromo-4-iodobenzene (15.11 g, 53.4 mmol), cesium carbonate (5.22 g, 16.0 mmol), copper(I)iodide (1.02 g, 5.34 mmol) and N,N′-dimethylethylenediamine (570 uL, 5.34 mmol) are combined in dry N,N-dimethylformamide (100 mL) and heated at 100° C. for 3 hours under a nitrogen atmosphere. The mixture is cooled, poured into water and extracted with diethyl ether. The organic phase is dried and the solvent removed. The residue is purified by flash chromatography (30% dichloromethane in cyclohexane) to give the title compound (Yield 1.37 g) LC (METHOD 5): tR=1.47 min; Mass spectrum (ES+): m/z=265/267 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH2:11][CH2:12][C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[CH:24]=[CH2:25]>CC(C)=O>[CH2:25]([O:8][C:7]1[C:6]([Cl:9])=[CH:5][C:4]([C:10]2[CH2:11][CH2:12][C:13](=[O:16])[NH:14][N:15]=2)=[CH:3][C:2]=1[Cl:1])[CH:24]=[CH2:23]
Reactant: O=C1CCC(c2cc(Cl)c(O)c(Cl)c2)=NN1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1c(Cl)cc(C2=NNC(=O)CC2)cc1Cl
Yield: 93 %

Procedure:
In 50 ml. of acetone was mixed 5 g. of 6-(3,5-dichloro-4-hydroxyphenyl)-4,5-dihydro-3(2H)-pyridazinone obtained in Example 5 and 3.3 g. of anhydrous potassium carbonate and to the resulting mixture was added dropwise 2.4 g. of allyl bromide at room temperature while stirring. After completion of the addition, the mixture was heated under reflux for 4 hours. After cooling, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure and the residue was recrystallized from ethanol to give 5.3 g. of the desired product of m.p. 137° C. (Yield 93%).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][CH:10]1[CH2:14][CH2:13][NH:12][CH2:11]1>C1(C)C=CC=CC=1>[C:2]1([CH:1]=[N:9][CH:10]2[CH2:14][CH2:13][NH:12][CH2:11]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1CCNC1
Reactant: O=Cc1ccccc1
Solvent: Cc1ccccc1
Product: C(=NC1CCNC1)c1ccccc1
Temperature: 25 °C
Yield: 60.3 %

Procedure:
Benzaldehyde (21.2 g; 0.20 mol) was added, dropwise, to a solution of 3-aminopyrrolidine (17.2 g; 0.20 mol) in toluene (80 ml). The solution thus obtained was stirred at room temperature. After 3 h the solvent was removed by evaporation at reduced pressure and the residue was taken up twice with toluene. 21 g N-(phenylmethylene)pyrrolidine-3-amine was thus obtained, and was used in subsequent reactions without further purification.