Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]([CH2:19]C)([N:7]1[C:12]2[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=[O:18])C)[CH3:2].[C:22]([O:26][C:27]([N:29]1[CH2:32][CH:31](OS(C)(=O)=O)[CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[C:22]([O:26][C:27]([N:29]1[CH2:32][CH:31]([O:17][C:14]2[CH:15]=[CH:16][C:11]3[O:10][CH2:9][C:8](=[O:18])[N:7]([CH:5]([C:4]([O:3][CH2:1][CH3:2])=[O:21])[CH3:19])[C:12]=3[CH:13]=2)[CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Reactant: CCOC(=O)C(C)(CC)N1C(=O)COc2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)N1C(=O)COc2ccc(OC3CN(C(=O)OC(C)(C)C)C3)cc21
Temperature: 90 °C
Reaction time: 3 h
Yield: 40.9 %

Procedure:
A mixture of ethyl 2-(6-hydroxy-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (1.08 g, 4.07 mmol), 3-methanesulfonyloxy-azetidine-1-carboxylic acid tert-butyl ester (1.12 g, 4.48 mmol) and Cs2CO3 (2.65 g, 8.12 mmol) in DMF (20 mL) was stirred at 90° C. for 3 h. The reaction mixture was cooled to ambient temperature and poured into water (150 mL). The aqueous mixture was extracted with EtOAc (3×20 mL) and the combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and evaporated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 10% EtOAc in petroleum ether) to give 3-[4-(1-ethoxycarbonyl-ethyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yloxy]-azetidine-1-carboxylic acid tert-butyl ester as a white solid (0.7 g, 41%). 1H NMR (CDCl3, 400 MHz): δ 6.94 (d, J=8.4 Hz, 1H), 6.30 (m, 2H), 5.30 (q, J=7.2 Hz, 1H), 4.78 (m, 1H), 4.59 (d, J=15.2 Hz, 2H), 4.27 (m, 4H), 3.95 (m, 2H), 1.62 (d, J=7.2 Hz, 3H), 1.45 (s, 9H), 1.21 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.O[C@@H:31]1[CH:36]2[CH2:37][CH2:38][N:33]([CH2:34][CH2:35]2)[CH2:32]1>>[N:33]12[CH2:38][CH2:37][CH:36]([CH2:35][CH2:34]1)[C@H:31]([N:19]1[C:18](=[O:23])/[C:17](=[CH:16]/[C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][C:4]=3[C:26]([F:27])([F:29])[F:28])[N:8]=[CH:9]4)/[S:21][C:20]1=[O:22])[CH2:32]2
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: O[C@H]1CN2CCC1CC2
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1[C@@H]1CN2CCC1CC2

Procedure:
(5Z)-3-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and (3R)-3-hydroxy-1-azabicyclo[2.2.2]octane following General Procedure J.
Reaction SMILES: C(OC([N:6]1[C:14]2[C:9](=[C:10]([Br:15])[CH:11]=[CH:12][CH:13]=2)[C:8]([O:16][CH3:17])=[N:7]1)=O)C.O.[Li+].[OH-]>C1COCC1>[Br:15][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[C:8]([O:16][CH3:17])=[N:7][NH:6]2
Reactant: CCOC(=O)n1nc(OC)c2c(Br)cccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1n[nH]c2cccc(Br)c12
Reaction time: 15 h

Procedure:
To a stirring solution of 4-Bromo-3-methoxy-indazole-1-carboxylic acid ethyl ester CLXXXV (1.27 g, 4.14 mmol) in THF (28 ml) and H2O (9 ml) was added LiOH (397 mg, 16.6 mmol). The reaction mixture was stirred at reflux for 2 hours then at room temperature for 15 hours. The mixture was concentrated. The residue was diluted with EtOAc (50 ml), washed with HCl (1M) and brine, dried over MgSO4, filtered and concentrated affording 4-Bromo-3-methoxy-1H-indazole CLXXXVI as an off-white solid (98% yield), which was used without further purification in the next step.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1([CH3:11])[CH2:8][CH:7]([Cl:9])[CH2:6][C:5]1=[O:10].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1>C(O)C>[CH3:3][C:4]1([CH3:11])[CH2:8][CH:7]([Cl:9])[C:6](=[CH:17][C:16]2[CH:19]=[CH:20][C:13]([F:12])=[CH:14][CH:15]=2)[C:5]1=[O:10]
Reactant: CC1(C)CC(Cl)CC1=O
Reactant: O=Cc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)CC(Cl)C(=Cc2ccc(F)cc2)C1=O
Reaction time: 0.5 h
Yield: 69 %

Procedure:
10% strength aqueous sodium hydroxide solution (50 cc) is added to a mixture of 2,2-dimethyl-4-chloro-1-cyclopentanone (10 g) and 4-fluorobenzaldehyde (8.4 g) in ethanol (100 cc) at 0° C. After 30 minutes, a thick slurry is filtered and the solid washed and then dried. 2,2-Dimethyl-4-chloro-5-(4-fluorobenzylidene)-1-cyclopentanone (11.8 g), m.p. 69° C., is obtained. Sodium hydride (3.1 g; 80% strength dispersion in mineral oil) in anhydrous DMSO (50 cc) is heated to 80° C. until the solid is dissolved completely. The solution is then diluted with THF (100 cc) and thereafter cooled to -10° C. A solution of trimethylsulphonium iodide (11.5 g) in dimethyl sulphoxide (80 cc) is added to the mixture in the course of 10 minutes and the mixture is stirred for 15 minutes at -10° C. A solution of 2,2-dimethyl-4-chloro-5-(4-fluorobenzylidene)-1-cyclopentanone (11.8 g) is then added in THF (100 cc). The mixture thereby produced is left at room temperature, then poured into water and extracted with ether, washed with water, dried and distilled. 7-(4-Fluorobenzylidene)-4,4-dimethyl-1-oxaspiro[2.4]hept-5-ene, used directly for the next step, is obtained.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][OH:6])[CH3:2].F[C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1>>[CH2:1]([N:3]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1)[CH2:4][CH2:5][OH:6])[CH3:2]
Reactant: CCNCCO
Reactant: O=Cc1ccc(F)cc1
Product: CCN(CCO)c1ccc(C=O)cc1

Procedure:
Following the procedure of Example I, 2-(ethylamino)ethanol is reacted with 4-fluorobenzaldehyde to provide 4-[N-ethyl-N-(2-hydroxyethyl)amino]benzaldehyde starting material.
Reaction SMILES: C1(C(C2C=CC=CC=2)([C@@H]2CCCN2)O)C=CC=CC=1.COB(OC)OC.CSC.B.[Br:31][C:32]1[N:37]=[C:36]([C:38](=[O:43])[CH2:39][CH2:40][CH2:41][CH3:42])[CH:35]=[CH:34][CH:33]=1>C1COCC1>[Br:31][C:32]1[N:37]=[C:36]([C@H:38]([OH:43])[CH2:39][CH2:40][CH2:41][CH3:42])[CH:35]=[CH:34][CH:33]=1
Reactant: CCCCC(=O)c1cccc(Br)n1
Agent: B
Agent: COB(OC)OC
Agent: OC(c1ccccc1)(c1ccccc1)[C@@H]1CCCN1
Solvent: CSC
Solvent: C1CCOC1
Product: CCCC[C@@H](O)c1cccc(Br)n1
Reaction time: 0.08 h
Yield: 88.6 %

Procedure:
To a stirring solution of (S)-(−)-α,α-diphenyl-2-pyrrolidinemethanol (α,α-diphenyl-L-prolinol) (840 mg, 3.32 mmol) in THF (3 mL) was added drop-wise trimethylborate (0.45 mL, 3.97 mmol) at ambient temperature under nitrogen. After stirring for 1 h at this temperature, borane dimethylsulfide (2M in THF, 2.5 mL, 5.00 mmol) drop-wise over 3-4 minutes. After the effervescence had stopped, 1-(6-bromo-2-pyridinyl)-1-pentanone (797 mg, 3.29 mmol) in THF (3.6 mL) was added over 1 h using a syringe pump. The mixture was stirred for an additional 5 minutes and the reaction was then quenched with aqueous HCl (2N, 5 mL) and the reaction mixture stirred overnight at ambient temperature. The mixture was then reduced under vacuum and the residue partitioned between EtOAc (30 mL) and water (30 mL) and the layers separated. The aqueous was then re-extracted with EtOAc (30 mL) and the combined organic layer washed with brine (50 mL) and then reduced under vacuum to give an oil. Purification by SPE (silica, 20 g cartridge) eluting with cyclohexane:EtOAc (gradient 100:1 to 3:1) afforded the title compound as an oil (712 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]2[C:14]3[N:15]=[C:16]([NH:19][C:20]4[CH:21]=[C:22]([CH2:26][CH2:27]OS(C)(=O)=O)[CH:23]=[CH:24][CH:25]=4)[N:17]=[CH:18][C:13]=3[CH:12]([CH3:33])[N:11]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)[C:10]2=[O:42])[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH3:43][NH:44][CH3:45]>>[CH3:43][N:44]([CH3:45])[CH2:27][CH2:26][C:22]1[CH:21]=[C:20]([NH:19][C:16]2[N:15]=[C:14]3[N:9]([C:5]4[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=4)[C:1]#[N:2])[C:10](=[O:42])[N:11]([C:34]4[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=4)[CH:12]([CH3:33])[C:13]3=[CH:18][N:17]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: COc1ccc(N2C(=O)N(c3cccc(C#N)c3)c3nc(Nc4cccc(CCOS(C)(=O)=O)c4)ncc3C2C)cc1
Reactant: CNC
Product: COc1ccc(N2C(=O)N(c3cccc(C#N)c3)c3nc(Nc4cccc(CCN(C)C)c4)ncc3C2C)cc1
Temperature: 100 °C

Procedure:
A mixture of (±)-methanesulfonic acid (2-{3-[8-(3-cyano-phenyl)-6-(4-methoxy-phenyl)-5-methyl-7-oxo-5,6,7,8-tetrahydro-pyrimido[4,5-d]pyrimidin-2-ylamino]-phenyl}-ethyl)-ester (0.19 g; 0.32 mmol) (from Example 5a supra) and dimethylamine (2.0 M in tetrahydrofuran; 2.00 mL; 4.00 mmol) (Aldrich) in a bomb bottle and heated at 100° C. overnight. Upon cooling, the mixture was concentrated and the residue was partitioned between ethyl acetate and water. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate and concentrated. At this point, the crude material was combined with material from an earlier run and purified by flash chromatography (Biotage, 12S; 100:0 to 50:50 ethyl acetate-methanol). This material was then crystallized from ethyl acetate and ether to give (±)-3-[7-[3-(2-dimethylamino-ethyl)-phenylamino]-3-(4-methoxy-phenyl)-4-methyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-benzonitrile as a solid. (Yield 0.12 g; 26.8%).
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:13]1[C:18]([C:19]2[CH:20]=[CH:21][C:22]([F:26])=[CH:23][C:24]=2[F:25])=[CH:17][C:16]([C:27]([OH:29])=[O:28])=[C:15]([OH:30])[CH:14]=1.[CH:31](O)([CH3:33])[CH3:32].O>CN(C=O)C>[F:25][C:24]1[CH:23]=[C:22]([F:26])[CH:21]=[CH:20][C:19]=1[C:18]1[CH:13]=[CH:14][C:15]([OH:30])=[C:16]([C:27]([O:29][CH:31]([CH3:33])[CH3:32])=[O:28])[CH:17]=1
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)ccc1O
Reactant: CC(C)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)OC(=O)c1cc(-c2ccc(F)cc2F)ccc1O
Temperature: 50 °C
Reaction time: 2 h
Yield: 41.1 %

Procedure:
CDI (972 mg, 5.99 mmol) was added to a solution of diflunisal (1.50 g, 5.99 mmol) in DMF (30 mL). The reaction mixture was stirred at 50° C. for 2 h and isopropyl alcohol (1.15 mL, 14.97 mmol) was dropwise added. The reaction mixture was stirred at 50° C. for 3 h and allowed to reach r.t. It was poured into H2O (50 mL) and extracted with Et2O (2×60 mL). The organic layer was washed with NaHCO3 (20 mL, saturated aqueous solution), dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (15% EtOAc/hexanes) to furnish 720 mg of isopropyl 2′,4′-difluoro-4-hydroxybiphenyl-3-carboxylate (white solid, yield: 41%).
Reaction SMILES: [C:1]([OH:9])(=[O:8])/[C:2](=[C:4](\[CH:6]=O)/[Br:5])/Br.S(O)(O)(=O)=O.[CH3:15][S:16][C:17](=[NH:19])[NH2:18].C(N(CC)CC)C.C>O>[Br:5][C:4]1[C:2]([C:1]([OH:9])=[O:8])=[N:18][C:17]([S:16][CH3:15])=[N:19][CH:6]=1
Reactant: O=C/C(Br)=C(/Br)C(=O)O
Reactant: CSC(=N)N
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCN(CC)CC
Product: CSc1ncc(Br)c(C(=O)O)n1
Reaction time: 24 h
Yield: 59.1 %

Procedure:
Mucobromic acid (58.05 g, 0.225 mol) was added to a stirred solution of 2-methyl-2-thio-pseudourea sulfate (62.66 g, 0.225 mol) in water (500 mL) at r.t. The suspension was cooled to 10° C. (ice bath) and triethylamine (94.1 mL, 0.675 mol) was added dropwise over 4 h. The reaction mixture was then left to stand at r.t. for 24 h. Activated carbon (Darco G-60) was added to the now dark red/brown solution and after stirring for 10 min the charcoal was filtered off. The filtrate was acidified with concentrated hydrochloric acid (50 mL) and the yellow precipitate was filtered off, washed with water (2×80 mL) and diethyl ether (2×100 mL), and then placed in a vacuum oven at 50° C. for 2 days to yield 5-bromo-2-(methylthio)pyrimidine-4-carboxylic acid (33.13 g, 59%) as a yellow amorphous solid. 1H NMR δ (d6-DMSO, 400 MHz) 2.75 (s, 3H), 9.20 (s, 1H).
Reaction SMILES: I[C:2]([F:11])([F:10])[C:3]([F:9])([F:8])[C:4]([F:7])([F:6])I.I[C:13]1[CH:14]=[C:15]([C:21]#[N:22])[C:16](=[CH:19][CH:20]=1)[C:17]#[N:18].CS(C)=O>[Cu].O>[C:21]([C:15]1[CH:14]=[C:13]([C:2]([F:11])([F:10])[C:3]([F:9])([F:8])[C:4]([F:7])([F:6])[C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([C:21]#[N:22])[CH:14]=2)[CH:20]=[CH:19][C:16]=1[C:17]#[N:18])#[N:22]
Reactant: N#Cc1ccc(I)cc1C#N
Reactant: FC(F)(I)C(F)(F)C(F)(F)I
Agent: [Cu]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccc(C(F)(F)C(F)(F)C(F)(F)c2ccc(C#N)c(C#N)c2)cc1C#N
Yield: 54.4 %

Procedure:
1,3-Diiodoperfluoropropane (2.0 g, 5 mmol), 1.8 g (30 meq) of activated copper, 2.5 g (10 mmol) of 4-iodophthalonitrile and 6 ml of dry dimethyl sulfoxide were purged for 15 minutes with argon and the mixture was then heated at 115°-120° C. for 4 hours. After cooling, the content was poured into 100 ml of water and extracted with four 50 ml portions of ether. The combined ethereal extract was washed with water, charcoaled, dried over anhydrous sodium sulfate and concentrated at reduced pressure to afford 1.1 g (52%) of product, m.p 133°-135° C.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CN=C1.[CH3:14][O:15][C:16]([C:18]1[O:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([CH2:40][CH3:41])([C:32]3[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([CH3:39])[CH:33]=3)[CH2:30][CH3:31])=[CH:25][C:24]=2[CH3:42])=[CH:21][CH:22]=1)=[O:17].C(OCC)C>CN(C)C=O>[CH3:14][O:15][C:16]([C:18]1[O:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([C:32]3[CH:37]=[CH:36][C:35]([O:38][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[C:34]([CH3:39])[CH:33]=3)([CH2:30][CH3:31])[CH2:40][CH3:41])=[CH:25][C:24]=2[CH3:42])=[CH:21][CH:22]=1)=[O:17]
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(-c2ccc(C(=O)OC)o2)c(C)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCC(CC)(c1ccc(O[Si](C)(C)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(C(=O)OC)o2)c(C)c1
Temperature: 25 °C
Reaction time: 0.2 h
Yield: 86 %

Procedure:
t-Butyldimethylsilyl chloride (42.24 mg, 0.28 mmol) and imidazole (47.7 mg, 0.701 mmol) were added to a solution of 5-{4-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-2-methyl-phenyl}-furan-2-carboxylic acid methyl ester (Example 19-(1); 55 mg, 0.14 mmol) in N,N-dimethylformamide (0.2 mL) at room temperature, and the mixture was stirred at room temperature for 0.2 hour. Diethyl ether was added to the reaction solution. The organic layer was washed with distilled water and brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (n-hexane/ethyl acetate=95/5 to ethyl acetate only) to give the title compound (61 mg, 86%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.C([Li])CCC.C([O:18][B:19](OCC)[O:20]CC)C.Cl>O1CCCC1.CCCCCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([B:19]([OH:20])[OH:18])=[CH:7][C:6]=2[CH:10]=1
Reactant: CCOB(OCC)OCC
Reactant: Fc1ccc2occc2c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1cc2cc(F)ccc2o1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
In a nitrogen atmosphere, to a solution of 2.0 g of 5-fluorobenzofuran in 150 ml tetrahydrofuran was added 18.5 ml of a 1.59 M solution of n-butyllithium in n-hexane at −78° C., and the mixture was stirred at the same temperature for 10 minutes and at 0° C. for further 10 minutes. At −78° C., 3.7 ml of triethoxyborane was added, and the mixture was stirred for 2 hours while elevating to 0° C. 30 ml of 1 N hydrochloric acid was added, stirred at room temperature for 1 hour, and then the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=1:3 to 1:1), to give 525 mg of the title compound as colorless crystals.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:14](=O)[CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([N+:17]([O-])=O)[C:3]1=[O:20].[Cl-].[NH4+]>C(O)C.O.[Fe]>[CH3:15][C:14]1[NH:17][C:4]2[C:3](=[O:20])[N:2]([CH3:1])[CH:7]=[CH:6][C:5]=2[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C(C(C)=O)c1ccn(C)c(=O)c1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(C)[nH]c2c(=O)n(C)ccc12
Yield: 72.8 %

Procedure:
To a solution of ethyl 2-(1-methyl-3-nitro-2-oxo-1,2-dihydropyridin-4-yl)-3-oxobutanoate (2.5 g, 8.8 mmol) in ethanol (50 mL) was added ammonium chloride (0.5 g, 9 mmol) in water (5 mL) at room temperature. The mixture was stirred and heated to reflux. Then iron powder (0.5 g, 8.9 mmol) was added in one portion. The mixture was stirred at reflux for 2 hours. Once starting material was consumed, the resultant mixture was filtered when it was hot, and the filtrate was concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to give ethyl 2,6-dimethyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylate (1.5 g, 75%) as a brown solid. LRMS (M+H+) m/z: calcd 234.1. found 234. 1H NMR (400 MHz, d6-DMSO): h 12.54 (s, 1H), 7.30 (d, J=5.1 Hz, 1H), 6.78 (d, J=5.1 Hz, 1H), 4.24 (q, J=5.1 Hz, 2H), 3.51 (s, 3H), 2.56 (s, 3H), 1.32 (t, 0.1=5.1 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH2:11][CH:12]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:8][C:7]=2[CH:25]=1)#[N:2].C(OC([C@H](CC)C(N)O)=O)(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:70]([O:74][C:75]([NH:77][C@H:78]([CH2:81][CH3:82])[CH2:79]O)=[O:76])([CH3:73])([CH3:72])[CH3:71]>O1CCCC1>[C:70]([O:74][C:75]([NH:77][C@H:78]([CH2:81][CH3:82])[CH2:79][O:24][C:21]1[CH:20]=[CH:19][C:18]([CH:12]([CH2:11][C:9]2[O:10][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:25][C:7]=3[CH:8]=2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:23][CH:22]=1)=[O:76])([CH3:73])([CH3:72])[CH3:71]
Reactant: CC[C@H](CO)NC(=O)OC(C)(C)C
Reactant: CCOC(=O)C(Cc1cc2cc(C#N)ccc2o1)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: CC[C@@H](C(=O)OC(C)(C)C)C(N)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1cc2cc(C#N)ccc2o1)c1ccc(OC[C@@H](CC)NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 39.7 %

Procedure:
In 300 ml of tetrahydrofuran were dissolved 1.1 g of ethyl 3-(5-cyano-2-benzofuranyl)-2-(4-hydroxyphenyl)propionate, 1.24 g of (2R)-2-tert-butoxycarbonyl-amino-1-butanol and 1.72 g of triphenylphosphine. The thus prepared solution was mixed with 1.14 g of diethyl azodicarboxylate and stirred at room temperature for 18 hours. The resulting solution was further mixed with 0.83 g of (2R)-2-tert-butoxycarbonylamino-1-butanol, 1.2 g of triphenylphosphine and 0.76 g of diethyl azodicarboxylate, and the mixture was stirred at room temperature for 18 hours. After concentrating the thus prepared reaction solution to dryness, the resulting residue was purified by subjecting it to silica gel column chromatography using a toluene/ethyl acetate mixture as a developing solvent, thereby obtaining 660 mg of ethyl 2-[4-[((2R)-2-tert-butoxycarbonylamino-1-butyl)oxy]phenyl]-3-(5-cyano-2-benzofuranyl)propionate in a colorless and oily form.
Reaction SMILES: [H-].[Na+].[OH:3][C@H:4]1[CH2:8][CH2:7][NH:6][C:5]1=[O:9].Cl[C:11]1[N:16]=[CH:15][N:14]=[C:13]2[N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[N:18]=[CH:19][C:12]=12>C1COCC1.CN(C=O)C>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[N:17]1[C:13]2=[N:14][CH:15]=[N:16][C:11]([O:3][C@H:4]3[CH2:8][CH2:7][NH:6][C:5]3=[O:9])=[C:12]2[CH:19]=[N:18]1
Reactant: Clc1ccccc1-n1ncc2c(Cl)ncnc21
Reactant: O=C1NCC[C@@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C1NCC[C@@H]1Oc1ncnc2c1cnn2-c1ccccc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 24.8 %

Procedure:
Sodium hydride (60% in oil) (0.435 g, 10.88 mmol) was added to (S)-3-hydroxypyrrolidin-2-one (CAS no. 34368-52-0) (1 g, 9.89 mmol) in THF (50 mL) at 0° C. under nitrogen. The resulting suspension was stirred at 0° C. for 10 minutes. A solution of 4-chloro-1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate B15) (4.01 g, 15.13 mmol) in DMF (25 mL) was added and the resulting mixture was stirred at r.t. for 16 hours. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were dried (MgSO4) and evaporated (3.8 g). The crude product was purified by flash silica chromatography, eluting with 0-50% MeOH in ethyl acetate to afford the product (0.810 g, 24.8%). 1H NMR (400 MHz, CDCl3) δ 2.30-2.42 (1H, m), 2.81-2.91 (1H, m), 3.45-3.64 (2H, m), 6.05 (1H, t), 6.44 (1H, s), 7.42-7.51 (2H, m), 7.51-7.56 (1H, m), 7.57-7.66 (1H, m), 8.33 (1H, s), 8.60 (1H, s); m/z (ES+) (M+H)+=330.27; HPLC tR=1.61 min.
Reaction SMILES: Cl.[NH:2]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:4][C:3]1=[O:17].Cl[C:19]1[N:24]=[CH:23][N:22]=[C:21]([O:25][C:26]2[CH:27]=[C:28]([C:36](F)(F)F)[C:29]3[N:33]=[C:32]([CH3:34])[NH:31][C:30]=3[CH:35]=2)[CH:20]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:34][C:32]1[NH:31][C:30]2[CH:35]=[C:26]([O:25][C:21]3[N:22]=[CH:23][N:24]=[C:19]([N:14]4[CH2:13][CH2:12][C:5]5([O:4][C:3](=[O:17])[NH:2][C:7]6[N:8]=[CH:9][CH:10]=[CH:11][C:6]5=6)[CH2:16][CH2:15]4)[CH:20]=3)[CH:27]=[C:28]([CH3:36])[C:29]=2[N:33]=1
Reactant: O=C1Nc2ncccc2C2(CCNCC2)O1
Reactant: Cc1nc2c(C(F)(F)F)cc(Oc3cc(Cl)ncn3)cc2[nH]1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc2c(C)cc(Oc3cc(N4CCC5(CC4)OC(=O)Nc4ncccc45)ncn3)cc2[nH]1

Procedure:
128 mg (0.500 mmol) spiro[piperidin-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one hydrochloride, 167 mg (0.500 mmol) 6-(6-chloro-pyrimidin-4-yloxy)-2-methyl-4-trifluoromethyl-1H-benzimidazole and 0.261 mL (1.50 mmol) DIPEA in 1.5 mL DMF were stirred for 10 h at RT. The reaction mixture was purified by preparative HPLC-MS. The fractions containing product were combined and freeze-dried.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:15])[C:5]([N+:12]([O-])=O)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(O)(=O)C>CO.[Pd]>[NH2:12][C:5]1[C:4]([OH:15])=[CH:3][C:2]([F:1])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(F)cc(O)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cc(F)cc(O)c1N
Reaction time: 1.5 h
Yield: 80.9 %

Procedure:
To a solution of methyl 5-fluoro-3-hydroxy-2-nitrobenzoate (1.15 g, 5.34 mmol) in a mixture of CH3OH and glacial acetic acid (3:1, 40 mL) was added 10 wt % palladium on activated charcoal (0.20 g, 17 wt %). The suspension was placed in a Parr hydrogenation apparatus under a H2 atmosphere at 50 psi for 1.5 h. The suspension was filtered through diatomaceous earth eluting with CH2Cl2/CH3OH (9:1, 100 mL). Purification by column chromatography (silica gel, 5 to 100% EtOAc in hexanes) afforded methyl 2-amino-5-fluoro-3-hydroxybenzoate (0.80 g, 83%) as a white solid. 1H NMR and MS consistent.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C:7](=[O:9])[CH3:8])=[CH:3][CH:2]=1.[Br-:11].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl.CO>[Br:11][CH2:8][C:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=1)=[O:9]
Reactant: CC(=O)c1ccc(C)cc1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(C(=O)CBr)cc1
Yield: 83.5 %

Procedure:
To a solution of 1-p-tolyl-ethanone (0.5 g, 4.16 mmol) in dichloromethane-methanol (50 ml-20 mL) was added tetrabutylammonium tribromide (2.2 g, 4.58 mmol) at room temperature. The mixture was stirred until the orange color faded. The solvent was then distilled under reduced pressure and the resulting precipitate was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated in vacuo to give a residue which was purified by flash column chromatography to yield the desired product 2-bromo-1-p-tolyl-1-ethanone (0.74 g, 84%). 1H NMR (300 MHz, DMSO-d6) δ 2.39 (s, 3H), 4.89 (s, 2H), 7.37 (d, 2H), 7.89 (d, 2H); ESI-MS (MK): 213 and 215.