Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[CH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[N+:16]([O-])=O)C>CO.[Pd]>[O:3]=[C:4]1[CH2:5][CH2:6][C:7]2[C:8](=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[CH:14][CH:15]=2)[NH:16]1
Reactant: CCOC(=O)C=Cc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: O=C1CCc2ccc(C(=O)O)cc2N1
Reaction time: 12 h

Procedure:
To 10% Pd—C (100 mg) under nitrogen atmosphere was added a solution of 4-(3-ethoxy-3-oxoprop-1-enyl)-3-nitrobenzoic acid (45) (29 g, 0.11 mol) in 75 mL methanol and kept at 50 psi H2 atmosphere for 12 h. The reaction mixture was filtered through a sintered funnel and the filtrate was concentrated to give the pure compound 22. Off-white solid (20.9 g, 96%). 1H NMR (400 MHz, CDCl3): δ 2.44 (t, J=6.8 Hz, 2H); 2.90 (t, J=6.8 Hz, 2H); 7.25 (d, J=7.6 Hz, 1H); 7.44 (s, 1H); 7.47 (dd, J=7.6, 1.6 Hz, 1H); 10.22 (broad s, 1H); 12.85 (broad s, 1H). 13C NMR (75 MHz, CDCl3): δ 24.8, 30.0, 115.1, 123.5, 127.8, 127.9, 129.0, 139.0, 167.5, 169.0.
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1Br.[C:8](=[O:10])=[O:9].CC(C)=O.C([Li])CCC.C(=O)=O>C(OCC)C>[Cl:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:8]([OH:10])=[O:9]
Reactant: O=C=O
Reactant: Clc1sccc1Br
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: CCOCC
Product: O=C(O)c1ccsc1Cl
Temperature: 25 °C
Yield: 90 %

Procedure:
To a round bottomed flask were added 2-chloro-3-bromothiophene (26.2 g, 132.7 mmole) along with diethyl ether (390 mL). The reaction was cooled to -78° C. (dry ice/acetone) and 1.6M n-butyllithium (87.0 mL, 139.0 mmole) was added dropwise. The reaction was stirred for 1.5 hours after which an excess of CO2 (~25.0 g) was added all at once. The reaction was warmed to room temperature and poured onto ice/water. The mixture was extracted with 10% sodium carbonate solution and the basic aqueous layer was washed with methylene chloride. The basic solution was then acidified to a pH 3.0 and extracted with diethyl ether. The organic layer was washed with water, brine, and dried (MgSO4). Solvent removal yielded 19.32 g of an off-white solid (90%) which was used as is.
Reaction SMILES: Cl.[F:2][C:3]([F:25])([F:24])[C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[CH:6]([O:15][CH:16]1[CH2:19][NH:18][CH2:17]1)[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[C:30]12([N:40]=[C:41]=[O:42])[CH2:39][CH:34]3[CH2:35][CH:36]([CH2:38][CH:32]([CH2:33]3)[CH2:31]1)[CH2:37]2>C(Cl)Cl>[F:25][C:3]([F:2])([F:24])[C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[CH:6]([O:15][CH:16]1[CH2:19][N:18]([C:41]([NH:40][C:30]23[CH2:39][CH:34]4[CH2:33][CH:32]([CH2:38][CH:36]([CH2:35]4)[CH2:37]2)[CH2:31]3)=[O:42])[CH2:17]1)[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1
Reactant: CSc1ccc(C(OC2CNC2)c2ccccc2C(F)(F)F)cc1
Reactant: O=C=NC12CC3CC(CC(C3)C1)C2
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CSc1ccc(C(OC2CN(C(=O)NC34CC5CC(CC(C5)C3)C4)C2)c2ccccc2C(F)(F)F)cc1

Procedure:
To a solution of 3-[2-(trifluoromethyl)-4′-(methylthio)benzhydryloxy]azetidine hydrochloride (118) (100 mg, 0.26 mmol) in anhydrous DCM (5 mL) was added MP-carbonate (3.10 mmol/g; 250 mg, 0.84 mmol) and 1-adamantyl isocyanate (47 mg, 0.26 mmol). The resultant mixture was shaken at ambient temperature for 16 h, after which time it was poured onto a DCM-wetted SCX-2 (1 g) cartridge. The sample was eluted with DCM (18 mL), then evaporated to afford the desired product as a white, crystalline solid (70 mg, 51%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]#[N:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].O1CCC[CH2:14]1.[H-].[Na+].CI>CN(C)C=O.O>[CH3:14][N:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[C:11]#[N:12]
Reactant: N#CNc1cccc([N+](=O)[O-])c1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CN(C#N)c1cccc([N+](=O)[O-])c1
Temperature: -20 °C
Reaction time: 0.13 h

Procedure:
To a cooled (-20° C.) and stirred solution of 3-nitrophenyl cyanamide (1 g) in a mixture of anhydrous tetrahydrofuran and anhydrous dimethylformamide (3:1; 20 ml) was added sodium hydride (60% dispersion in oil; 294 mg) in one portion, under a nitrogen atmosphere. After 8 minutes of stirring at -20° C., methyl iodide (1.14 ml) was added and the red mixture was allowed to warm to room temperature and diluted with anhydrous dimethylformamide (5 ml). After a further 45 minutes of stirring, water (75 ml; CAUTION| hydrogen evolution) was added and products were extracted with ethyl acetate (2×100 ml). The combined organic phases were washed with brine (1×50 ml), dried (MgSO4) and concentrated. The remaining solid was dissolved in ethyl acetate (30 ml) and hexane (100 ml) was added to give the title compound (880 mg) as fine needles; δH (250 MHz, DMSO-d6) 7.98 (1H, m, Ar--H), 7.85 (1H,t, J=2.2 Hz, Ar--H), 7.73 (1H, t, J=7.7 Hz, Ar--H), 7.60 (1H, m, Ar--H), 3.45 (3H, s, --NMe);m/z (CI) 177 (M-).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:26])[CH3:25])[CH:18]=3)=[C:11]3[N:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.[BH4-].[Na+].O>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:26])[CH3:25])[CH:18]=3)=[C:11]3[NH:12][CH2:13][CH2:14][CH2:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1cc(-c2c(-c3ccc(F)cc3)nn3cccnc23)ccn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=O)Nc1cc(-c2c(-c3ccc(F)cc3)nn3c2NCCC3)ccn1
Yield: 25.1 %

Procedure:
To a mixture of N-{4-[2-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidin-3-yl]pyridin-2-yl}acetamide (120 mg, 0.34 mmol, 1 eq) in 2 mL of ethanol is added sodium borohydride (29 mg, 0.76 mmol, 2.2 eq). The mixture is refluxed for 1 h. The mixture is then poured into water, extracted with dichloromethane (3×20 mL), dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The crude material is purified by column chromatography using silica gel in heptane and ethyl acetate (1:0 to 0:1) as eluent and 30 mg (25%) of N-{4-[2-(4-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl]pyridin-2-yl}acetamide are obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][O:12][CH2:13][CH3:14])=[CH:9][N:10]=2)[N:7]=1.[NH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1.Cl>CCOCC>[ClH:1].[CH2:13]([O:12][CH2:11][C:8]1[N:6]2[N:7]=[C:2]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1)[CH3:14]
Reactant: NCc1ccccn1
Reactant: CCOCc1cnc2ccc(Cl)nn12
Agent: Cl
Solvent: CCOCC
Product: CCOCc1cnc2ccc(NCc3ccccn3)nn12
Yield: 18 %

Procedure:
Prepared from 6-chloro-3-(ethoxymethyl)imidazo[1,2-b]pyridazine (8b) and 2-(aminomethyl)pyridine according to general procedure 4 (step B). The free-base was converted to the HCl salt with 2N HCl in Et2O to provide the title compound (35 mg, 18%) as a white solid; 1H NMR (500 MHz, CD3OD) δ 8.53-8.52 (m, 1H), 7.90 (d, J=9.7 Hz, 1H), 7.86 (dt, J=1.7, 9.5 Hz, 1H), 7.78 (s, 1H), 7.56 (d, J=9.8 Hz, 1H), 7.38-7.36 (m, 1H), 7.26 (d, J=9.8 Hz, 1H), 4.73 (s, 2H), 4.68 (s, 2H), 3.49 (q, J=7.0 Hz, 2H), 1.10 (t, J=7.1 Hz, 3H); 13C NMR (125 MHz, CD3OD) δ 158.9, 156.6, 149.3, 139.6, 134.7, 128.7, 124.2, 123.6, 123.0, 122.5, 119.9, 67.5, 60.9, 47.4, 15.4; HPLC tR=7.4 min (Luna), 98.5%; ES-MS: (M+H)=284 m/z.
Reaction SMILES: [C:1]12(CCO)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(N(C(C)C)CC)(C)C.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[C:38]([N:41]1[C:45]([CH2:46][O:47][C:48](=[O:50])[CH3:49])=[CH:44][N:43]=[C:42]1[CH2:51][CH2:52][CH2:53][CH3:54])(=O)[CH3:39]>ClCCl.C(Cl)(Cl)Cl.CO>[C:48]([O:47][CH2:46][C:45]1[N:41]([CH2:38][CH2:39][C:1]23[CH2:10][CH:5]4[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]4)[CH2:8]2)[CH2:2]3)[C:42]([CH2:51][CH2:52][CH2:53][CH3:54])=[N:43][CH:44]=1)(=[O:50])[CH3:49]
Reactant: CCCCc1ncc(COC(C)=O)n1C(C)=O
Reactant: OCCC12CC3CC(CC(C3)C1)C2
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCCc1ncc(COC(C)=O)n1CCC12CC3CC(CC(C3)C1)C2
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
A mixture of 2-(1-adamantyl)ethanol (10.7 g and diisopropylethylamine (11 ml) in dichloromethane (70 ml) was added to triflic anhydride (16.75 g) in dichloro methane (70 ml) at -78° C. under argon. After stirring the mixture at -78° C. for 45 minutes, 1-acetyl-2-n-butyl-5-(acetoxymethyl)imidazole in dichloromethane (50 ml) was added and the mixture was allowed to stand at room temperature for 4 days, then concentrated and heated on a steam bath with 10% sodium hydroxide (250 ml), diluted with 300 ml of water, extracted with dichloromethane, dried, filtered and concentrated to give an oil. Chromatography (silica gel) in methanol chloroform gives 5-acetoxymethyl-1-[2-(1-adamantyl)ethyl]-2-n-butylimidazole.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:22])=[C:17]([CH:21]=1)[C:18]([OH:20])=[O:19]>C(O)(=O)C>[Cl:22][C:16]1[CH:15]=[CH:14][C:13]([NH:12][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[CH:21][C:17]=1[C:18]([OH:20])=[O:19]
Reactant: Clc1ccc2ccccc2n1
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Solvent: CC(=O)O
Product: O=C(O)c1cc(Nc2ccc3ccccc3n2)ccc1Cl

Procedure:
A solution of 2-chloro-quinoline (0.50 g, 3.1 mmol) and 5-amino-2-chloro-benzoic acid (0.53 g, 3.1 mmol) in acetic acid (10 mL) was heated at 100° C. for 2 h. Acetic acid was removed and the residue triturated in ethyl acetate. The title compound was obtained as a white solid (0.55 g, 59%) after the filtration. MS (ES+): m/z 299 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([O:17][CH3:18])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15]Br)[CH:7]=1.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[OH:27].CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][CH2:15][CH2:14][CH2:13][O:12][C:8]1[CH:7]=[C:6]([CH2:5][CH:4]([O:17][CH3:18])[C:3]([OH:2])=[O:19])[CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)C(Cc1cccc(OCCCBr)c1)OC
Reactant: Oc1ccccc1Cl
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: COC(Cc1cccc(OCCCOc2ccccc2Cl)c1)C(=O)O

Procedure:
The title compound was prepared from 3-[3-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid methyl ester (Example 323, Step 1) and 2-chlorophenol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1). The enatiomers were separated by chiral HPLC. 1H-NMR (CDCl3, 200.15 MHz): 7.35 (dd, 1H, J=8.1, 1.9), 7.24–7.16 (m, 2H), 6.97–6.80 (m, 5H), 4.22 (t, 2H, J=5.9), 4.20 (t, 2H, J=5.9), 4.02 (dd, 1H, J=7.3, 4.0), 3.39 (s, 3H), 3.13 (dd, 1H, J=14.2, 3.8), 2.97 (dd, 1H, J=14.0, 7.8), 2.30 (qn, 2H, J=6.2).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH:13]=2)[N:8]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[C:7]=1[CH2:33][C:34]([O:36]CC)=[O:35])=[O:5])C.[OH-].[Na+].O1CCOCC1.Cl>O>[C:34]([CH2:33][C:7]1[N:8]([C:26]2[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=2)[C:9]2[C:14]([C:6]=1[C:4]([OH:5])=[O:3])=[CH:13][C:12]([O:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:20][CH:21]=1)=[CH:11][CH:10]=2)([OH:36])=[O:35]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(C(F)(F)F)cc3)ccc2n1-c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)Cc1c(C(=O)O)c2cc(Oc3ccc(C(F)(F)F)cc3)ccc2n1-c1ccc(Cl)cc1
Temperature: 120 °C

Procedure:
A mixture of 1-(4-chlorophenyl)-2-ethoxycarbonylmethyl-5-(4-trifluoromethylphenoxy)indole-3-carboxylic acid ethyl ester (140 mg, 0.25 mmol, see step (c) Example 2), NaOH (aq, 2M, 2 mL) and dioxane (2 mL) were heated at 120° C. for 4.5 h, cooled, diluted with H2O, acidified to pH 2 with HCl (aq, 1 M) and extracted with EtOAc. The combined extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was treated with CH2Cl2 (2 mL) to give the title compound as a white solid which was recrystallised from CH2Cl2/EtOH (9:1). Yield 45 mg (37%), mp 974-276° C.
Reaction SMILES: F[C:2]1[N:18]=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([N:6]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[CH3:7])=[O:5].[ClH:19].[NH:20]1[C:24]2=[N:25][CH:26]=[CH:27][C:28]([O:29][C:30]3[CH:35]=[CH:34][C:33]([NH:36]C4C(C(NC5C=CC(F)=CC=5F)=O)=CN=CC=4)=[CH:32][C:31]=3[F:54])=[C:23]2[CH:22]=[CH:21]1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>CC(N(C)C)=O>[ClH:19].[ClH:19].[NH:20]1[C:24]2=[N:25][CH:26]=[CH:27][C:28]([O:29][C:30]3[CH:35]=[CH:34][C:33]([NH:36][C:2]4[N:18]=[CH:17][CH:16]=[CH:15][C:3]=4[C:4]([N:6]([C:8]4[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=4)[CH3:7])=[O:5])=[CH:32][C:31]=3[F:54])=[C:23]2[CH:22]=[CH:21]1
Reactant: O=C(Nc1ccc(F)cc1F)c1cnccc1Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Reactant: CN(C(=O)c1cccnc1F)c1ccc(F)cc1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CC(=O)N(C)C
Product: CN(C(=O)c1cccnc1Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1)c1ccc(F)cc1
Temperature: 160 °C
Yield: 10.1 %

Procedure:
A mixture of 2-fluoro-N-(4-fluorophenyl)-N-methylnicotinamide (50 mg, 0.2 mmol) and 4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluoroaniline (122 mg, 0.5 mmol, Compound C of Example 1) in DMA (0.8 mL) was heated in a microwave at 160° C. for 20 min. The product was purified by preparative (RP) HPLC to afford the title compound as a beige solid (11 mg, 11% yield)—dihydrochloride salt. 1H NMR (CD3OD) δ 8.56 (d, 1H, J=3.5 Hz), 8.23 (dd, 1H, J=7.6, 1.0 Hz), 8.19 (d, 1H, J=7.1 Hz), 7.58 (m, 3H), 7.32 (dd, 1H, J=11.2, 2.5 Hz), 7.22 (d, 1H, J=8.6 Hz), 7.04 (d, 1H, J=4.1 Hz), 6.96 (d, 1H, J=7.9 Hz), 6.47 (m, 4H), 3.27 (s. 3H). MS(ESI+) m/z 472 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[C:4](=[O:19])[CH2:3]1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>>[CH3:20][C:2]1([CH3:1])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([C:22]([F:33])([F:32])[F:21])[CH:28]=3)[CH:9]=2)[C:4](=[O:19])[CH2:3]1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CC1(C)CC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc21
Product: CC1(C)CC(=O)c2ccc(-c3cccc(C(F)(F)F)c3)cc21

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester and 3-trifluoromethylphenyl boronic acid according to the procedure described in example 21. MS m/z 305; HRMS: calcd for C18H15F3O+H+, 305.11478; found (ESI, [M+H]+), 305.1142.
Reaction SMILES: [F:1][CH:2]([CH:8]([O:11][C:12](=[O:16])[C:13]([CH3:15])=[CH2:14])[CH2:9][CH3:10])[C:3]([O:5]CC)=[O:4].[OH-].C[N+](C)(C)C>C1COCC1>[F:1][CH:2]([CH:8]([O:11][C:12](=[O:16])[C:13]([CH3:15])=[CH2:14])[CH2:9][CH3:10])[C:3]([OH:5])=[O:4]
Reactant: C=C(C)C(=O)OC(CC)C(F)C(=O)OCC
Agent: C[N+](C)(C)C
Agent: [OH-]
Solvent: C1CCOC1
Product: C=C(C)C(=O)OC(CC)C(F)C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.9 %

Procedure:
Under a nitrogen atmosphere, 5.81 g (25 mmol) of the ethyl 2-fluoro-3-(methacryloyloxy)pentanoate, and 250 mL of THF were cooled in a 1 L reaction vessel on an ice bath to an ice temperature, and thereto was added 250 g of a 2.38 weight % aqueous tetramethylammoniumhydroxide solution. The temperature of the mixture was elevated to the room temperature, followed by stirring the mixture at a room temperature for 5 hrs. After disappearance of the raw material was confirmed by thin layer chromatography, the solvent of the reaction liquid was distilled off under a reduced pressure. Water was added to the reaction mixture thus obtained, and the mixture was extracted three times with ethyl acetate. The organic layer was washed with water twice, and the solvent was distilled off under a reduced pressure to obtain 4.59 g of 2-fluoro-3-(methacryloyloxy)pentanoic acid represented by the following formula (yield: 90%).
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.[Br-].[CH3:12][C:13]1[C:14]([Zn+])=[N:15][CH:16]=[CH:17][CH:18]=1.CCOC(C)=O.O>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[C:3]([C:14]2[C:13]([CH3:12])=[CH:18][CH:17]=[CH:16][N:15]=2)=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1
Reactant: CSc1ncc(Cl)c(I)n1
Reactant: Cc1cccnc1[Zn+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CSc1ncc(Cl)c(-c2ncccc2C)n1
Temperature: 25 °C
Yield: 64 %

Procedure:
A solution of 5-chloro-4-iodo-2-(methylthio)pyrimidine (5 g, 17.4 mmol) and Pd(PPh3)4 (1 g, 0.87 mmol) in dry THF (120 mL) was degassed under N2 three times. Then a solution of (3-methylpyridin-2-yl)zinc(II) bromide in THF (0.5 M, 53 mL, 26.3 mmol) was added. The resulting mixture was heated at reflux overnight. The mixture was then cooled to room temperature and was treated with EtOAc (80 mL) and H2O (100 mL). The layers were separated and the aqueous layer was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4 and filtered. The filtrate was concentrated and filtered. The filtrate was concentrated and the residue was purified via column chromatography (petroleum ether: EtOAc=9:1) to give the title compound (2.8 g, 64%) as a yellow syrup.
Reaction SMILES: [OH:1][CH2:2][CH2:3]OC1C2C(=O)C3C(=CC=CC=3)SC=2C=CC=1.[OH:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25](=[O:37])[CH:26]=[C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:28]2)=[CH:23][CH:22]=1.C1(=O)OCCO1>C(N(CC)CC)C>[OH:1][CH2:2][CH2:3][O:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25](=[O:37])[CH:26]=[C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:28]2)=[CH:23][CH:22]=1
Reactant: O=c1cc(-c2ccccc2)oc2cc(O)ccc12
Reactant: O=c1c2ccccc2sc2cccc(OCCO)c12
Solvent: O=C1OCCO1
Solvent: CCN(CC)CC
Product: O=c1cc(-c2ccccc2)oc2cc(OCCO)ccc12
Yield: 83 %

Procedure:
In an analogous fashion to 2-hydroxyethoxythioxanthone in Example 29, 7-hydroxyflavone (Aldrich) was reacted with ethylene carbonate and triethylamine to obtain 7-hydroxyethoxyflavone (83% yield). This product was dissolved in THF. One equivalent of VDM and several drops of DBU were added. The reaction mixture was stirred overnight.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]([C:6]([C@H:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]2[C:14]([O:16][CH3:17])=[O:15])=[O:7])=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C([O-])([O-])=O.[Na+].[Na+].ClCCl>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CCO.C1(C)C=CC=CC=1>[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[CH:19]=[CH:18][C:5]([C:6]([C@H:8]3[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]3[C:14]([O:16][CH3:17])=[O:15])=[O:7])=[CH:4][CH:3]=2)=[CH:23][CH:22]=1
Reactant: Nc1ccc(B(O)O)cc1
Reactant: COC(=O)[C@@H]1CCCC[C@@H]1C(=O)c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCO
Product: COC(=O)[C@@H]1CCCC[C@@H]1C(=O)c1ccc(-c2ccc(N)cc2)cc1
Temperature: 85 °C

Procedure:
Methyl cis-2-(4-bromobenzoyl)cyclohexanecarboxylate (1.76 g, 5.41 mmol) and 4-amino phenyl boronic acid (1.13 g, 6.49 mmol) were added to a clean dry flask under argon. Toluene (50 mL), EtOH (20 mL), and 3 M aqueous Na2CO3 (14 mL, 43 mmol) were added, and resulting solution was degassed for 30 minutes by using a flow of argon. Then [1,1′-bis(diphenylphosphino)-ferrocene]dichloro palladium(II), 1:1 complex with dichloromethane (442 mg, 0.54 mmol) was added and the resulting mixture was heated at 85° C. for 16 h. The mixture was cooled to rt, and then diluted with EtOAc and passed through a Celite® pad. The solvent was removed by rotary evaporation. Water and EtOAc were added, and the aqueous layer was extracted with EtOAc. The combined organic phases were washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (Biotage Flash 40M) using 33 to 40% ethyl acetate in hexane to afford methyl cis-2-[(4′-amino-1,1′-biphenyl-4-yl)carbonyl]cyclohexanecarboxylate.(1.54 g, 84%). LC-MS ret. time 3.99; m/z 338 (MH+); 1H NMR (400 MHz, CD2Cl2) δ 1.37–1.53 (m, 3H), 1.74–1.88 (m, 2H), 1.90–1.99 (m, 1H), 2.04–2.22 (m, 2H), 2.75 (m, 1H), 3.59 (s, 3H), 3.90 (q, 1H), 6.79 (m, 2H), 7.48 (m, 2H), 7.63 (m, 2H), 7.89 (m, 2H).
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[S:26][C:16]=2[N:17]=[C:18]([C:20]2[CH:25]=[N:24][CH:23]=[CH:22][N:21]=2)[N:19]=1>>[N:21]1[CH:22]=[CH:23][N:24]=[CH:25][C:20]=1[C:18]1[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:1][O:2][C:3]=3[CH:4]=2)[C:15]2[CH:28]=[C:27]([C:29]([F:31])([F:32])[F:30])[S:26][C:16]=2[N:17]=1
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3cnccn3)nc2s1
Reactant: NCCc1ccc2c(c1)OCO2
Product: FC(F)(F)c1cc2c(NCCc3ccc4c(c3)OCO4)nc(-c3cnccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(pyrazin-2-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(3,4-methylenedioxyphenethylamino)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].S(=O)(=O)(O)O.[CH3:20]O>>[OH:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([O:14][CH3:20])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CO
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])c(O)c1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc([N+](=O)[O-])c(O)c1
Temperature: 25 °C

Procedure:
To 3-hydroxy-4-nitrophenylacetic acid (5.45 g, 27.6 mol) and methanol (100 ml) was added concentrated sulfuric acid (0.5 ml). The mixture was then heated under reflux for 4 hours under stirring. After cooling to room temperature, the reaction mixture was distilled under reduced pressure to remove the solvent. Water (100 ml) was added to the residue, followed by extraction with ether (300 ml). The extract was washed successively with a saturated aqueous solution (100 ml) of sodium bicarbonate and saturated brine (100 ml), dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent, whereby the title compound (4.90 g, 84%) was obtained as a yellow crystalline powder.
Reaction SMILES: [N:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[S:3][C:2]=1[NH:10][C:11](=[O:13])[CH3:12].Cl[C:15]1[CH:20]=[N:19][CH:18]=[CH:17][N:16]=1.O>CN1C(=O)CCC1>[N:16]1[CH:17]=[CH:18][N:19]=[CH:20][C:15]=1[N:6]1[CH2:7][CH2:8][C:9]2[N:1]=[C:2]([NH:10][C:11](=[O:13])[CH3:12])[S:3][C:4]=2[CH2:5]1
Reactant: CC(=O)Nc1nc2c(s1)CNCC2
Reactant: Clc1cnccn1
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(=O)Nc1nc2c(s1)CN(c1cnccn1)CC2
Temperature: 250 °C
Yield: 9.7 %

Procedure:
As shown in step 10-iv of Scheme 10, to a solution of 50 mg of Compound 1035 in 3 mL of NMP was added 100 mg of 2-chloro pyrazine. The reaction mixture was warmed to 250° C. for 10 minutes under microwave irradiation. The reaction was poured into water (10 mL) and the crude product collected by filtration. The crude solid was purified by silica gel chromatography (CH2Cl2 to EtOH) to provide N-(5-(pyrazin-2-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)acetamide (Compound 1, 6.8 mg): ESMS (M+H) 276.16.