Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:7]3[CH2:15][CH:10]([C:11](=O)[C:12]=2[CH:13]=1)[CH:9]=[CH:8]3.[OH-].[K+].O.NN>C(O)CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:7]3[CH2:15][CH:10]([CH2:11][C:12]=2[CH:13]=1)[CH:9]=[CH:8]3
Reactant: COc1ccc2c(c1)C(=O)C1C=CC2C1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: COc1ccc2c(c1)CC1C=CC2C1
Temperature: 25 °C

Procedure:
5-Methoxytricyclo[7.2.1.02.7]dodeca-2(7),3,5,10-tetraene-8-one (9.41 g, 47 mmol) and pulverized potassium hydroxide (KOH) (6.17 g, 110 mmol) were warmed in ethylene glycol (50 mL) until solution occurred. The mixture was cooled to rt, treated with hydrazine hydrate (6 mL, 190 mmol) and heated to reflux for 2 hours. The reflux condenser was replaced with a distilling head and distillates were collected from 120-190° C. The distillates were diluted with H2O (100 mL) and extracted with EiOAc (4×40 mL). The organic layer was washed with H2O (4×30 mL), brine (25 mL), dried (MgSO4), filtered and concentrated to an oil (8.2 g, 94%). (TLC 25%EtOAc/hexanes Rf 0.68). 1H NMR (CDCl3) δ 8.92 (d, J=8.0 Hz, 1H), 6.88 (m, 2H), 6.25 (dd, J=5.1,2.5 Hz, 1H), 5.79 (dd, J=5.1,2.4 Hz, 1H), 3.77 (s, 3H), 3.31 (br s, 1H), 3.01-2.94 (2H), 2.56 (d, J=16.5 Hz, 1H), 2.22 (m, 1H), 1.85 (d, J=10.0 Hz, 1H), GCMS m/e 186 (M+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]2[C:24]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32]4[CH:41]=C5C(CCCN5C(=O)C(F)(F)F)=[CH:34][CH:33]=4)[N:26]=3)=[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][N:18]3[N:17]=2)[CH:11]=1)=[O:8].[Li+].[OH-]>CO>[CH2:19]1[C:20]2[C:21](=[CH:34][CH:33]=[C:32]([NH:31][C:27]3[N:26]=[C:25]([C:24]4[C:16]([C:12]5[CH:11]=[C:10]([NH:9][C:7](=[O:8])[CH2:6][C:2]6[S:1][CH:5]=[CH:4][CH:3]=6)[CH:15]=[CH:14][CH:13]=5)=[N:17][N:18]5[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=45)[CH:30]=[CH:29][N:28]=3)[CH:41]=2)[CH2:22][CH2:23][NH:18]1
Reactant: O=C(Cc1cccs1)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)N(C(=O)C(F)(F)F)CCC4)n2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(Cc1cccs1)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CNCC4)n2)c1
Yield: 42 %

Procedure:
A solution of 2-(2-thienyl)-N-{3-[3-(2-{[1-(trifluoroacetyl)-1,2,3,4-tetrahydro-7-quinolinyl]amino}-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}acetamide (0.075 g, 0.11 mmol) and LiOH (50 mg, 1.2 mmol) in MeOH (10 mL) was stirred for 30 min. The reaction mixture was evaporated down and the crude taken up in DCM and washed with brine. Purification via column chromatography using a 0-30% gradient of EtOAc/MeOH generated the product as a yellow solid in 42% yield. 1H NMR (400 MHz, d6-DMSO): δ 10.36 (s, 1H), 9.41 (s, 1H), 8.83 (d, 1H), 8.48 (d, 1H), 8.22 (d, 1H), 7.89 (s, 1H), 7.75 (d, 2H), 7.43 (m, 5H), 7.28 (d, 1H), 7.12 (t, 1H), 6.97 (m, 3H), 6.44 (d, 1H), 3.88 (s, 2H), 3.77 (s, 2H), 2.93 (t, 2H), 2.62 (m, 2H). ES-LC/MS m/z=558 [M+H]+.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[CH2:11][CH2:12][NH2:13].O>C1(C)C=CC=CC=1>[CH2:1]([NH:13][CH2:12][CH2:11][C:10]([OH:9])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCC(O)(COc1ccc(Cl)cc1)c1ccccc1
Reactant: O=Cc1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: OC(CCNCc1ccccc1)(COc1ccc(Cl)cc1)c1ccccc1
Yield: 67.9 %

Procedure:
34 g of benzaldehyde were added to a solution of 35 g (0.32 mole) of the 3-hydroxy-3-phenyl-4-(4-chlorophenoxy)-butylamine obtained as described in (b), in 700 ml of toluene, and the mixture was boiled in a water separator until the water had been removed. The solution was evaporated down, the residue was dissolved in 500 ml of methanol, and 25 g of sodium borohydride were added a little at a time. The reaction mixture was evaporated down, 2N sodium hydroxide solution was added to the residue and the mixture was extracted with 3 times 200 ml of ether. The ether was removed, and the resulting residue was dissolved in isopropanol, from which it was obtained in crystalline form. 83 g (68%) of N-benzyl-3-hydroxy-3-phenyl-4-(4-chlorophenoxy)-butylamine of melting point 84°-85° C. were obtained.
Reaction SMILES: [CH3:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([OH:12])([CH2:5]3)[CH2:3]1)[CH2:9]2.[C:13](OC(=O)C)(=[O:15])[CH3:14].S(=O)(=O)(O)O.O.C(=O)(O)[O-].[Na+]>CCCCCCC.C1CCCCC1.CCOCC>[C:13]([O:12][C:4]12[CH2:5][CH:6]3[CH2:7][CH:8]([CH2:9][C:2]([CH3:1])([CH2:11]3)[CH2:3]1)[CH2:10]2)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: CC12CC3CC(C1)CC(O)(C3)C2
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCCCC
Solvent: O
Product: CC(=O)OC12CC3CC(CC(C)(C3)C1)C2
Temperature: 25 °C
Reaction time: 20.5 h

Procedure:
121 mg (0.728 mmoles) of 3-methyl-1-adamantanol are dissolved in 0.2 mL n-heptane and 0.2 mL cyclohexane. A mixture of 0.2 mL (2.25 mmoles) of acetic anhydride and 2 microliters (0.036 mmoles) of concentrated sulfuric acid is added, and the mixture is stirred at ambient temperature for 20.5 hours. The solution is dissolved in 10L of ether and extracted with 10 mL of water. The aqueous layer is extracted with 10 mL ether. The ether layers are combined, extracted with 2×mL of water followed by 40 mL of aqueous sodium bicarbonate (10 g/liter), dried over magnesium sulfate, and stripped of solvent in vacuo. The product is a colorless oil with Rf 0.55 (silica: eluant hexane 75%, ethyl acetate 25%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:69][NH:70][CH:71]1[CH2:76][CH2:75][CH2:74][CH2:73][CH2:72]1>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:15](=[O:17])[N:70]([CH:71]2[CH2:76][CH2:75][CH2:74][CH2:73][CH2:72]2)[CH3:69])[CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:22]1[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CNC1CCCCC1
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)C1CCCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (0.039 g), TBTU (0.064 g) and HOBt (0.027 g) in DMF (1 ml) was added DIPEA (0.036 ml) followed by N-methylcyclohexylamine (0.027 ml) after 15 min. The reaction mixture was stirred at room temperature for 18 h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.036 g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])[C:3]=1[CH3:21].[I:22][C:23]1[CH:31]=[C:30]2[C:26]([C:27]([CH3:33])([CH3:32])[CH2:28][NH:29]2)=[CH:25][CH:24]=1.Cl.O1CCOCC1>CN1C(=O)CCC1>[F:20][C:14]1[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=1[C:4]1[C:3]([CH3:21])=[C:2]([N:29]2[C:30]3[C:26](=[CH:25][CH:24]=[C:23]([I:22])[CH:31]=3)[C:27]([CH3:33])([CH3:32])[CH2:28]2)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=1
Reactant: CC1(C)CNc2cc(I)ccc21
Reactant: Cc1c(-c2cc(F)ccc2F)nc2cc(F)ccc2c1Cl
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: Cc1c(-c2cc(F)ccc2F)nc2cc(F)ccc2c1N1CC(C)(C)c2ccc(I)cc21
Temperature: 150 °C

Procedure:
Prepared according to procedure L using 4-chloro-2-(2,5-difluorophenyl)-7-fluoro-3-methylquinoline (150 mg, 0.49 mmol) (described herein), 6-iodo-3,3-dimethylindoline (160 mg, 0.59 mmol) (described herein), and 4.0 hydrochloric acid in 1,4-dioxane (120 μL, 0.49 mmol) in NMP (810 μL). The reaction mixture was stirred and heated at 150° C. for 3 h. Purification afforded 2-(2,5-difluorophenyl)-7-fluoro-4-(6-iodo-3,3-dimethylindolin-1-yl)-3-methylquinoline as a yellow solid. Mass Spectrum (ESI) m/e=545 (M+1).
Reaction SMILES: O.Cl.C1(C)C=CC=CC=1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23](=O)[CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:19][CH:18]=2)=[CH:13][C:12]=1[Br:30]>[Zn].O1CCOCC1>[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:21][CH:22]=2)=[CH:13][C:12]=1[Br:30]
Reactant: Nc1ccc(-c2ccc(C(=O)CCC(=O)O)cc2)cc1Br
Agent: Cl
Agent: [Zn]
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: Nc1ccc(-c2ccc(CCCC(=O)O)cc2)cc1Br
Yield: 25 %

Procedure:
A mixture of 6 ml of water, 8 gm of amalgamated zinc, 14 ml of concentrated hydrochloric acid, 20 ml of toluene and 4 gm of 4-(4'-amino-3'-bromo-4-biphenylyl)-4-oxo-butyric acid was refluxed for 6 hours, while stirring. Subsequently, 10 ml of dioxane were added and the toluene/dioxane phase was separated. The residue remaining after evaporation of the solvent was admixed with water, covered with ether, and adjusted with sodium bicarbonate solution to pH 6. The ether solution was separated, washed with water, dried over sodium sulfate and evaporated. The thus obtained 4-(4'-amino-3'-bromo-4-biphenylyl)-butyric acid was dissolved in ethyl acetate and converted into its cyclohexylamine salt by addition of cyclohexylamine. Yield: 25% of theory. Melting point of the cyclohexylamine salt: 182° C. (decomp.).
Reaction SMILES: [F:1][C:2]1[C:24]([S:25][CH:26]2[CH2:31][CH2:30][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:28][CH2:27]2)=[CH:23][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([CH3:22])[N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.C(O)(C(F)(F)F)=[O:36].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl>[F:1][C:2]1[C:24]([S:25]([CH:26]2[CH2:27][CH2:28][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:30][CH2:31]2)=[O:36])=[CH:23][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:20])[CH3:21])[N:17]=[C:16]([CH3:22])[N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(SC4CCN(C(C)C)CC4)c(F)cc2OCC3)n(C(C)C)n1
Reactant: O=C(O)C(F)(F)F
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1nc(-c2cn3c(n2)-c2cc(S(=O)C4CCN(C(C)C)CC4)c(F)cc2OCC3)n(C(C)C)n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of 8-fluoro-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-9-(1-isopropylpiperidin-4-ylsulfanyl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene 209 (194 mg, 0.40 mmol) in DCM (15 mL) was added TFA (93 μL, 1.20 mmol) followed by a solution of m-CPBA (76 mg, 0.440 mmol) in DCM (2 mL). The resulting mixture was stirred for 15 min at 0° C. then volatiles were removed under reduced pressure. The crude material was purified by column chromatography (C18, gradient 20-45% MeOH in 0.5% TFA/H2O) and then loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 0.5M NH3 in MeOH affording 210 as a white solid (167 mg, 83%). LCMS: RT 2.61 min [M+H]+ 501.1. 1H NMR (DMSO, 400 MHz): δ 8.71 (1H, d, J=7.99 Hz), 7.93 (1H, s), 7.15 (1H, d, J=10.69 Hz), 5.69-5.57 (1H, m), 4.66-4.51 (4H, m), 2.89-2.76 (3H, m), 2.72-2.60 (1H, m), 2.26 (3H, s), 2.20-2.06 (2H, m), 1.94-1.85 (1H, bd, J=12.30 Hz), 1.59-1.40 (9H, m), 0.91 (6H, d, J=6.53 Hz)
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16](=[O:35])[CH2:17][CH2:18][N:19]([C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[C:25]([Cl:34])[CH:24]=1)[CH2:20][CH2:21][OH:22])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C.OP([O-])(O)=O.[K+]>C(Cl)Cl>[C:11]([O:15][C:16](=[O:35])[CH2:17][CH2:18][N:19]([C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:32])([F:33])[F:31])=[C:25]([Cl:34])[CH:24]=1)[CH2:20][CH:21]=[O:22])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)CCN(CCO)c1ccc(OC(F)(F)F)c(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCN(CC=O)c1ccc(OC(F)(F)F)c(Cl)c1
Temperature: -5 °C
Reaction time: 0.08 h

Procedure:
To a solution of 0.55 ml (6.3 mmol) of oxalyl chloride in 21 ml CH2Cl2 at −50 to −60° C. was added a solution of 0.93 ml (13.1 mmol) dimethylsulfoxide in 7 ml of CH2Cl2 within 20 min. The solution was stirred for 5 min, then a solution of 2.10 g (5.5 mmol) of 3-[(3-chloro-4-trifluoromethoxy-phenyl)-(2-hydroxy-ethyl)-amino]-propionic acid tert-butyl ester in 14 ml CH2Cl2 was added within 20 min. The mixture was stirred for 15 min and 3.81 ml (27.4 mmol) of triethylamine were added within 20 min. The suspension was stirred for 3 h and slowly warmed to −5° C. The reaction was neutralized with cold aqueous 10% KH2PO4 (adjusted with solid KH2PO4 to pH 4-5) and extracted with EtOAc (3×). The organic phases were washed with aqueous saturated NaHCO3 (freshly prepared), aqueous 10% NaCl, dried over Na2SO4 evaporated to yield 2.21 g (quantitative) of the title compound as yellow oil. MS: 381 (M+, Cl).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:13]=[C:14]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)[S:15][C:16]=1[CH2:17][O:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([NH:25][OH:26])=[NH:24])=[C:21]([O:29][CH3:30])[CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:42](OC1C=CC=CC=1)=[O:43].C(N(C(C)C)CC)(C)C>O1CCCC1>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:13]=[C:14]([C:31]2[CH:32]=[CH:33][C:34]([C:37]([F:39])([F:40])[F:38])=[CH:35][CH:36]=2)[S:15][C:16]=1[CH2:17][O:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]2[NH:24][C:42](=[O:43])[O:26][N:25]=2)=[C:21]([O:29][CH3:30])[CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CCCOCc2ccccc2)ccc1C(=N)NO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CCCOCc2ccccc2)ccc1-c1noc(=O)[nH]1
Temperature: 150 °C

Procedure:
To a solution of 1.05 g of 4-[4-(3-benzyloxy-propyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-N-hydroxy-2-methoxy-benzamidine in 5 mL of tetrahydrofuran were added 254 μL of phenyl chloroformate and 607 μL of diisopropylethylamine. The resulting mixture was heated to 150° C. under microwave irradiation for 20 minutes. After allowing it to cool down to room temperature, the mixture was concentrated under reduced pressure and dichloromethane/water were added to the residue. The organic layer was separated and the aqueous layer extracted three times with dichloromethane. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Diisopropyl ether was added to the residue and the solid was collected by filtration and washed with diisopropyl ether to give 558 mg of 3-{4-[4-(3-benzyloxy-propyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methoxy-phenyl}-4H-[1,2,4]oxadiazol-5-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[C:10]1[CH:22]=[CH:21][C:13]([C:14]([O:16]C(C)(C)C)=[O:15])=[C:12]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH:11]=1>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[C:10]1[CH:22]=[CH:21][C:13]([C:14]([OH:16])=[O:15])=[C:12]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[CH:11]=1
Reactant: CC(C)(C)OC(=O)c1ccc(/C=C/c2ccccc2Cl)cc1Nc1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(/C=C/c2ccccc2Cl)cc1Nc1ccc(F)cc1

Procedure:
Trifluoroacetic acid 10 mL solution of the obtained tert-butyl 4-((E)-2-(2-chlorophenyl)vinyl)-2-(4-fluoroanilino)benzoate was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, the obtained residue was refined by reversed-phase silica gel column chromatography [eluent; 85-100% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to give 4-((E)-2-(2-chlorophenyl)vinyl)-2-(4-fluoroanilino)benzoic acid 4.6 mg of a yellow solid.
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4](=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].C(N(CC)CC)C.C(O[CH:22]=[CH:23][C:24](=O)[C:25]([F:28])([F:27])[F:26])C.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:9]([O:8][C:6](=[O:7])[C:5]1[CH:22]=[CH:23][C:24]([C:25]([F:28])([F:27])[F:26])=[C:3]([S:2][CH3:1])[C:4]=1[OH:11])[CH3:10]
Reactant: CCOC=CC(=O)C(F)(F)F
Reactant: CCOC(=O)CC(=O)CSC
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(C(F)(F)F)c(SC)c1O
Temperature: 0 °C
Reaction time: 5 h

Procedure:
100 g of ethyl 4-(methylsulphanyl)-3-oxobutanoate and 27.8 g of triethylamine were initially charged in 260 ml of toluene and cooled to 0° C. under nitrogen. Then 102.8 g of 4-ethoxy-1,1,1-trifluorobut-3-en-2-one were added dropwise at 0-7° C. within 30 minutes and the mixture was stirred for a further 5 h. After 16 hours, the reaction was warmed up to 18° C. The reaction mixture was concentrated, admixed with 150 ml of acetonitrile and concentrated at 5 mbar. The crude product was admixed with 2 equivalents of 10% sodium hydroxide solution while stirring and cooling with ice-water and stirred for 1 h, and the solids were filtered off with suction, washed three times with 50 ml of 3.5% sodium hydroxide solution and dried by suction. The solids were then admixed with 150 ml of water and 150 ml of toluene, and adjusted to pH 1 with about 150 ml of 10% HCl, and further HCl was metered in with continued stirring until the pH remains below 3. Then the filtered phases were separated and the water phase was extracted once more with toluene. The combined toluene phases were dried and concentrated: Yield 122.3 g (78% of theory). 1H NMR (CDCl3, 400 MHz): δ=11.77 ppm (1H, s), 7.93 ppm (1H, d), 7.23 ppm (1H, d), 4.47 ppm (2H, q), 2.44 ppm (3H, s), 1.45 ppm (3H, t).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([O:20][CH3:21])=[C:7]([O:18][CH3:19])[CH:8]=2)[N:3]=1.[CH2:22]([O:24][C:25]1[CH:26]=[C:27]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH2:28][N:29]1[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]1)[CH3:23]>C(O)CO>[CH3:19][O:18][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[O:20][CH3:21])[N:3]=[C:2]([NH:35][CH:32]1[CH2:33][CH2:34][N:29]([CH2:28][C:27]3[CH:36]=[CH:37][C:38]([O:39][CH3:40])=[C:25]([O:24][CH2:22][CH3:23])[CH:26]=3)[CH2:30][CH2:31]1)[N:11]=[C:10]2[N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: COc1cc2nc(Cl)nc(N3CCCCC3)c2cc1OC
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1OC
Solvent: OCCO
Product: CCOc1cc(CN2CCC(Nc3nc(N4CCCCC4)c4cc(OC)c(OC)cc4n3)CC2)ccc1OC
Yield: 16 %

Procedure:
A solution of 2-chloro-6,7-dimethoxy-4-piperidin-1-yl-quinazoline (30.8 mg, 0.10 mmol 1.0 equiv; commercially available) and 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (39.7 mg, 0.15 mmol, 1.5 equiv; intermediate A1) in ethylene glycol (2 mL) was heated by microwave irradiation to 220° C. for 20 min. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 8.7 mg (16%) of the title compound. MS (ISP): 391.4 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[CH2:12][S:11](=O)[CH:10]2[N:7]([C:8](=[O:46])[CH:9]2[NH:14][C:15](=[O:45])[C:16](=[N:42][O:43][CH3:44])[C:17]2[N:18]=[C:19]([NH:22][C:23]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[S:20][CH:21]=2)[C:6]=1[C:47]([O:49][CH:50]([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:48])[C:2]([CH3:4])=[O:3].P(Cl)(Cl)Cl>C(Cl)Cl.CN(C)C(=O)C.C(OCC)(=O)C>[CH2:1]([C:5]1[CH2:12][S:11][CH:10]2[N:7]([C:8](=[O:46])[CH:9]2[NH:14][C:15](=[O:45])[C:16](=[N:42][O:43][CH3:44])[C:17]2[N:18]=[C:19]([NH:22][C:23]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[S:20][CH:21]=2)[C:6]=1[C:47]([O:49][CH:50]([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)=[O:48])[C:2]([CH3:4])=[O:3]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CC(C)=O)CS(=O)C12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CC(C)=O)CSC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: -10 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
A solution of 3-acetonyl-2-benzhydryloxycarbonyl-7-[2-methoxyimino-2-(2-tritylaminothiazol-4-yl)-acetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-5-oxide (5 g) in a mixture of methylene chloride (60 cc) and N,N-dimethylacetamide (2.3 cc) is cooled to -10° C. Phosphorus trichloride (1.01 cc) is then added and the mixture is stirred for one hour at -10° C. The reaction mixture is diluted with ethyl acetate (300 cc), washed successively with a saturated solution of sodium bicarbonate (50 cc) and distilled water (300 cc), dried over sodium sulphate and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 20° C. This yields the syn isomer of 3-acetonyl-2-benzhydryloxycarbonyl-7-[2-methoxyimino-2-(2-tritylaminothiazol-4-yl)-acetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (4.5 g) in the form of a hard yellow foam.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[N:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])=[C:14]([NH:29][S:30]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][N:34]=3)(=[O:32])=[O:31])[N:13]=2)[CH:7]=1.[Cl-].[Cl-].[Ca+2].[BH4-].[Na+]>CCO.C1COCC1>[OH:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[N:13]=[C:14]([NH:29][S:30]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][N:34]=3)(=[O:31])=[O:32])[C:15]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])=[C:16]([O:18][CH3:19])[N:17]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)COc1cccc(-c2nc(NS(=O)(=O)c3ccc(C)cn3)c(Oc3ccccc3OC)c(OC)n2)c1
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2cccc(OCCO)c2)nc1OC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
70 mg of {3-[4-methoxy-5-(2-methoxy-phenoxy)-6-(5-methyl-pyridine-2-sulfonylamino)-pyrimidin-2-yl]-phenoxy}-acetic acid methyl ester, product of example 2, were dissolved in a mixture of EtOH/THF (each 3 ml) on gentle warming and subsequently treated with 27.4 mg of CaCl2 and 18.7 mg of NaBH4 at RT. The reaction mixture was stirred at RT for 1.5 h until which time starting material was consumed according to TLC analysis (CH2Cl2/EtOAc: 3/1). The mixture was partitioned between 10% citric acid and EtOAc. The organic layer was dried over Na2SO4 and the solvent removed in vacuo. The residue was purified on a silica gel chromatography column (eluted with Me2Cl2EtOAc: 3/1). Combination of the purified fractions and evacuation in vacuo afforded 5-methyl-pyridine-2-sulfonic acid [2-[3-(2-hydroxy-ethoxy)-phenyl]-6-methoxy-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-amide as a white solid. ISP mass spectrum, m/e 539.3 (M+1 calculated for C26H26N4O7S: 539).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11](=[O:29])[NH:12][C:13]1[C:14]([CH3:28])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]#[C:25][CH2:26]O)=[CH:20][CH:19]=1)[CH3:9].[NH:30]1[CH:34]=[C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:32]=[N:31]1>>[CH2:38]([O:37][C:35]([C:33]1[CH:34]=[N:30][N:31]([CH2:26][C:25]#[C:24][C:21]2[CH:22]=[CH:23][C:18]([C:17]3[O:16][N:15]=[C:14]([CH3:28])[C:13]=3[NH:12][C:11]([O:10][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH3:9])=[O:29])=[CH:19][CH:20]=2)[CH:32]=1)=[O:36])[CH3:39]
Reactant: Cc1noc(-c2ccc(C#CCO)cc2)c1NC(=O)OC(C)c1ccccc1Cl
Reactant: CCOC(=O)c1cn[nH]c1
Product: CCOC(=O)c1cnn(CC#Cc2ccc(-c3onc(C)c3NC(=O)OC(C)c3ccccc3Cl)cc2)c1

Procedure:
Prepared according to the procedure described in Example 5, Step 2, using the following starting materials: {5-[4-(3-hydroxy-prop-1-ynyl)-phenyl]-3-methyl-isoxazol-4-yl}-carbamic acid 1-(2-chloro-phenyl)-ethyl ester and ethyl 4-pyrazolecarboxylate.