Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.N1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.O1C=C[C:14]([CH:17]=[O:18])=C1.C([Li])(CC)C.Cl[Si:25]([CH2:30][CH3:31])([CH2:28][CH3:29])[CH2:26][CH3:27].IC>C1COCC1.C1CCCCC1>[CH3:7][C:8]1[O:9][C:10]([Si:25]([CH2:30][CH3:31])([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:11][C:14]=1[CH:17]=[O:18]
Reactant: C1COCCN1
Reactant: O=Cc1ccoc1
Reactant: CC[Si](Cl)(CC)CC
Agent: [Li]C(C)CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Solvent: CI
Product: CC[Si](CC)(CC)c1cc(C=O)c(C)o1
Reaction time: 0.33 h

Procedure:
n-Butyl lithium (a 1.6 M solution in THF; 19.0 ml, 30.4 mmol) was added to a solution of morpholine (2.67 ml, 30.4 mmol) in THF (20 ml) at -78 degrees C. under argon. After 20 minutes, 3-furaldehyde (1.8 ml, 28.9 mmol) was added, followed by s-butyl-lithium (a 1.3 M solution in cyclohexane; 23.4 ml, 30.4 mmol) after another 20 minutes. Stirring was continued for 2 hours and chlorotriethylsilane (5.1 ml, 30.4 mmol) was added. After 2 hours at -78 degrees C., s Buli (23.4 ml, 30.4 mmol) was added, followed by iodomethane (5.4 ml, 86.9 mmol) after another 2 hours. The mixture was stirred at room temperature for 15 hours and quenched with ice cold dilute hydrochloric acid. Extraction with ethyl ether and evaporation of the dried (magnesium sulfate) extracts gave an oil, which was purified by flash chromatography on silica using 10% diethyl ether/hexane to give the titled aldehyde.
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.[F:13][C:14]1[C:19]2[CH:20]=[CH:21][O:22][C:18]=2[C:17]([NH2:23])=[C:16]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=2[F:32])[C:15]=1[F:33].C(OCC)(=O)C>C(Cl)Cl.CCCCCC>[F:33][C:15]1[C:16]2[N:24]([C:25]3[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=3[F:32])[C:6](=[O:7])[NH:23][C:17]=2[C:18]2[O:22][CH:21]=[CH:20][C:19]=2[C:14]=1[F:13]
Reactant: Nc1c(Nc2ccc(I)cc2F)c(F)c(F)c2ccoc12
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=c1[nH]c2c3occc3c(F)c(F)c2n1-c1ccc(I)cc1F
Temperature: 30 °C
Reaction time: 14 h
Yield: 70.5 %

Procedure:
CDI (0.144 g, 0.891 mmol) was added to a solution of 4,5-difluoro-N6-(2-fluoro-4-iodo-phenyl)-benzofuran-6,7-diamine (I-31a: 0.240 g, 0.5940 mmol) in dry DCM (5 mL). The reaction mass was stirred 12-16 hours at 20-40° C. The reaction was monitored by TLC (30% ethyl acetate in hexane). The reaction mass was concentrated under reduced pressure and the concentrate was extracted with ethyl acetate. The organic layer was washed with water, brine solution, dried over sodium sulphate and concentrated under reduced pressure to afford the crude compound. Purification by column chromatography on silica gel (30% ethyl acetate in hexane) afforded 0.180 g of the product (70% yield). 1H NMR (DMSO-d6, 300 MHz): δ 12.15 (bs, 1H), 8.12 (d, 1H), 7.95 (dd, 1H), 7.79 (d, 1H), 7.50 (t, 1H), 7.21 (d, 1H).
Reaction SMILES: [CH2:1]([C@:4]1([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:9][CH2:8][N:7]([C@H:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH3:11])[C:6](=[O:16])[NH:5]1)[CH:2]=[CH2:3].C1C[O:27]CC1>>[CH3:13][C:12]([CH3:14])([CH3:15])[C@@H:10]([N:7]1[CH2:8][CH2:9][C@@:4]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)([CH2:1][CH2:2][CH2:3][OH:27])[NH:5][C:6]1=[O:16])[CH3:11]
Reactant: C1CCOC1
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)C(C)(C)C)C(=O)N1
Product: C[C@H](N1CC[C@](CCCO)(c2ccc(F)cc2)NC1=O)C(C)(C)C
Reaction time: 2 h
Yield: 12 %

Procedure:
To a solution of (R)-4-allyl-1-((S)-3,3-dimethylbutan-2-yl)-4-(4-fluorophenyl)tetrahydropyrimidin-2(1H)-one (100 mg, 0.31 mmol) in THF (3 mL) was added BH3 THF (1 mL, 1 mol/L) at 0° C. under nitrogen atmosphere. The formed mixture was stirred for 2 h. The reaction was quenched with water. Aqueous NaOH solution (3 mol/L, 0.2 mL) and H2O2 (30%, 0.2 mL) were added and the resulting mixture was stirred for 1.5 h. The mixture was extracted with ethyl acetate and the combined organic phase was concentrated to give the crude product, which was purified by preparative TLC to give (R)-1-((S)-3,3-dimethylbutan-2-yl)-4-(4-fluorophenyl)-4-(3-hydroxypropyl)tetrahydropyrimidin-2(1H)-one (12 mg, 12%). 1H NMR (CDCl3): 0.73 (s, 3H), 1.04 (d, 3H), 1.29 (m, 1H), 1.48 (m, 1H), 1.81-2.07 (m, 4H), 2.46 (s, 1H), 2.57 (m, 1H), 3.07 (m, 1H), 3.58 (m, 1H), 4.46 (m, 1H), 5.93 (s, 1H), 6.98-7.03 (m, 2H), 7.29 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][C:5]=1[O:11][CH3:12])[CH3:2].C([O:15][CH:16]=[C:17]([C:23](OCC)=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19])C>>[CH2:1]([O:3][C:4]1[CH:10]=[C:9]2[C:7](=[CH:6][C:5]=1[O:11][CH3:12])[NH:8][CH:23]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:16]2=[O:15])[CH3:2]
Reactant: CCOc1ccc(N)cc1OC
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)c1c[nH]c2cc(OC)c(OCC)cc2c1=O
Yield: 55.2 %

Procedure:
4-Ethoxy-3-methoxyaniline (2.6 g) and diethyl ethoxymethylenemalonate (3.4 g) were reacted in the same manner as in Experimental Example 1 to obtain 6-ethoxy-3-ethoxycarbonyl-7-methoxy-4(1H)-quinolone (2.5 g). The compound (2.3 g) was ethylated with potassium carbonate (3.3 g) and ethyl iodide (6.1 g) in the same manner as in Experimental Example 9 to obtain 6-ethoxy-3-ethoxycarbonyl-1-ethyl-7-methoxy-4(1H)-quinolone (1.8 g). This compound (1.4 g) was hydrolyzed in the same manner as in Experimental Example 9 to obtain a carboxylic acid (1.2 g), which was then decarboxylated in the same manner as in Experimental Example 9 to obtain 6-ethoxy-1-ethyl-7-methoxy-4(1H)-quinolone (compound 49, 210 mg).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH:22]2[C@:17]([CH3:24])([CH2:18][CH2:19][C:20](=[O:23])[CH2:21]2)[C@@H:16]2[C@H:7]([C@H:8]3[C@@:12]([CH2:14][CH2:15]2)([CH3:13])[C:11](=[O:25])[CH2:10][CH2:9]3)[CH2:6]1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([O:4][C@@H:5]1[CH:22]2[C@:17]([CH3:24])([CH2:18][CH2:19][C@H:20]([OH:23])[CH2:21]2)[C@@H:16]2[C@H:7]([C@H:8]3[C@@:12]([CH2:14][CH2:15]2)([CH3:13])[C@@H:11]([OH:25])[CH2:10][CH2:9]3)[CH2:6]1)(=[O:3])[CH3:2].[C:1]([O:4][C@@H:5]1[CH:22]2[C@:17]([CH3:24])([CH2:18][CH2:19][C@@H:20]([OH:23])[CH2:21]2)[C@@H:16]2[C@H:7]([C@H:8]3[C@@:12]([CH2:14][CH2:15]2)([CH3:13])[C@@H:11]([OH:25])[CH2:10][CH2:9]3)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)O[C@H]1C[C@H]2[C@@H]3CC[C@H](O)[C@@]3(C)CC[C@@H]2[C@@]2(C)CC[C@@H](O)CC12
Product: CC(=O)O[C@H]1C[C@H]2[C@@H]3CC[C@H](O)[C@@]3(C)CC[C@@H]2[C@@]2(C)CC[C@H](O)CC12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 188.1 %

Procedure:
To a stirred solution of 6α-acetoxyandrostane-3,17-dione (5.57 g) in MeOH (188 mL), at 0° C. under N2, NaBH4 (615 mg) was added in portions over 15 min. After stirring for 1.5 h at room temperature, the mixture was quenched by careful addition of H2O (200 mL). MeOH was evaporated and the concentrated solution was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4 and evaporated to dryness. The mixture was purified by flash chromatography (SiO2, cyclohexane/Et2O/acetone 60/20/20) to give 6α-acetoxyandrostane-3β,17β-diol and 6α-acetoxyandrostane-3α,17β-diol (90/10 mixture, 5.30 g, 95%). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 4.55 (m, 1H), 4.49 (bb, 1H), 4.43 (bb, 1H), 3.41 (m, 1H), 3.28 (m, 1H), 1.97 (s, 3H), 1.88-0.82 (m, 19H), 0.79 (s, 3H), 0.64 (m, 1H), 0.61 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[NH:6][N:7]=[N:8][C:4]=2[CH:3]=1.C1C=[C:15]2[C:17](C(O)(O)C(=O)C2=CC=1)=[O:18].[C:24](OC(=O)C)(=[O:26])[CH3:25]>>[C:17]([N:6]1[C:5]2[CH:9]=[CH:10][C:2]([NH:1][C:24](=[O:26])[CH3:25])=[CH:3][C:4]=2[N:8]=[N:7]1)(=[O:18])[CH3:15]
Reactant: Nc1ccc2[nH]nnc2c1
Reactant: CC(=O)OC(C)=O
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Product: CC(=O)Nc1ccc2c(c1)nnn2C(C)=O

Procedure:
A solution of 5-amino-1H-benzotriazole (1.07 g, 8 mmol) in acetic anhydride (50 ml, excess) was stirred at 90° C. for two hours, by which time TLC (A) and ninhydrin development indicated conversion of starting materials. Excess acetic anhydride and acetic acid were removed in vacuo to afford [18] as an off white solid. Rf (A) 0.48; m/z (FAB) 219.08632 [(M+H)+ calc. for C10H11N4O2 219.08820].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:13]([OH:15])=O)[N:7]2[CH3:12].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[F:40][C:41]1[C:42]([B:50]2[O:54][C:53]([CH3:56])([CH3:55])[C:52]([CH3:58])([CH3:57])[O:51]2)=[CH:43][C:44]([O:48][CH3:49])=[C:45]([CH:47]=1)[NH2:46]>ClCCl.N1C=CC=CC=1>[F:40][C:41]1[C:42]([B:50]2[O:54][C:53]([CH3:56])([CH3:55])[C:52]([CH3:58])([CH3:57])[O:51]2)=[CH:43][C:44]([O:48][CH3:49])=[C:45]([NH:46][C:13]([C:6]2[N:7]([CH3:12])[C:8]3[C:4]([CH:5]=2)=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][CH:9]=3)=[O:15])[CH:47]=1
Reactant: COc1cccc2c1cc(C(=O)O)n2C
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)c(F)cc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(B2OC(C)(C)C(C)(C)O2)c(F)cc1NC(=O)c1cc2c(OC)cccc2n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
4-Methoxy-1-methyl-1H-indole-2-carboxylic acid (0.225 mmol, 46.1 mg) and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.247 mmol, 94 mg) were added to a solution of 5-fluoro-2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.225 mmol, 60 mg) in dichloromethane (2.5 mL) and pyridine (0.5 mL) at 0° C. After stirring the reaction mixture overnight at room temperature it was concentrated in vacuo. Water was added to the residue and extracted with dichloromethane. The organic extracts were washed with water. The combined organic layers were dried (sodium sulfate) and concentrated in vacuo. The residue was purified by column chromatography (silica gel, heptanes/ethyl acetate) to give impure N-(5-fluoro-2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-methoxy-1-methyl-1H-indole-2-carboxamide (45 mg). The latter compound and 1-bromo-8-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazine (35 mg) were reacted using the procedures described in example 4 step 4c and purification using column chromatography (silica gel, heptanes/ethyl acetate) gave N-(5-fluoro-2-methoxy-4-(8-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-4-methoxy-1-methyl-1H-indole-2-carboxamide (9.7 mg)
Reaction SMILES: C([O:4][C@H:5]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:28]2[C:27](=[O:33])[C@@H:26]([O:34]C(=O)C)[C@@:25]2([CH3:38])[C@H:11]3[CH2:12][C@@H:13]3[O:18][C@@:17]4([O:24][CH2:23][C@H:21]([CH3:22])[CH2:20][CH2:19]4)[C@@H:15]([CH3:16])[C@@H:14]32)[CH2:6]1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>O.CO.C1COCC1>[CH3:16][C@@H:15]1[C@:17]2([O:24][CH2:23][C@H:21]([CH3:22])[CH2:20][CH2:19]2)[O:18][C@H:13]2[CH2:12][C@@H:11]3[C@@:25]([CH3:38])([C@@H:14]12)[C@H:26]([OH:34])[C:27](=[O:33])[C@H:28]1[C@H:10]3[CH2:9][CH2:8][C@@H:7]2[C@:29]1([CH3:32])[CH2:30][CH2:31][C@H:5]([OH:4])[CH2:6]2
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2C(=O)[C@@H](OC(C)=O)[C@]2(C)[C@@H]4[C@H](C[C@@H]32)O[C@]2(CC[C@@H](C)CO2)[C@H]4C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O)CC[C@]5(C)[C@H]4C(=O)[C@@H](O)[C@]3(C)[C@H]1[C@@H]2C

Procedure:
(3β,5α,12β,25R)-3,12-di(acetoxy)spirostan-11-one (purchased from Steraloids, Inc., or see preparation G13) was saponified with potassium carbonate in water, methanol and THF to provide the title compound.
Reaction SMILES: [CH3:1][C:2]12[O:9][CH2:8][C:5]([CH2:10][OH:11])([CH2:6][O:7]1)[CH2:4][O:3]2.[H-].[Na+].Cl[C:15]1[CH:20]=[CH:19][N+:18]([O-:21])=[C:17]([CH3:22])[C:16]=1[CH3:23]>CS(C)=O>[CH3:22][C:17]1[C:16]([CH3:23])=[C:15]([O:11][CH2:10][C:5]23[CH2:4][O:3][C:2]([CH3:1])([O:7][CH2:6]2)[O:9][CH2:8]3)[CH:20]=[CH:19][N+:18]=1[O-:21]
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Reactant: CC12OCC(CO)(CO1)CO2
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1c(OCC23COC(C)(OC2)OC3)cc[n+]([O-])c1C
Temperature: 60 °C
Reaction time: 3 h
Yield: 104.8 %

Procedure:
To a dimethylsulfoxide solution (30 ml) of the (1-methyl-2,6,7-trioxabicyclo[2.2.2]oct-4-yl)methanol (4.5 g, 28.1 mmol) obtained in the step (24a), sodium hydride, in oil (1.29 g, 29.5 mmol as the content was regarded as 55%) was added at room temperature. To the mixture, 4-chloro-2,3-dimethylpyridine 1-oxide (3.99 g, 25.3 mmol) was added, which was stirred at 60° C. for 3 hours. After cooled to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/methanol) to obtain the title compound (7.46 g, yield: 81%) as a yellow oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[OH-].[Na+].Br[CH2:19][CH2:20][Cl:21].C(OCC)(=O)C.ClCCl>CS(C)=O>[Cl:21][CH2:20][CH2:19][N:13]1[CH2:14][CH2:15][N:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][CH3:2])[CH2:11][CH2:12]1
Reactant: ClCCBr
Reactant: COc1ccccc1N1CCNCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccccc1N1CCN(CCCl)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.6 %

Procedure:
A mixture of 1-(2-methoxyphenyl)piperazine HCl (52.5 mmol) and powdered sodium hydroxide (105 mmol) in DMSO (40 mL), was stirred at ambient temperature. After 0.5 h, 1-bromo-2-chloroethane (78.8 mmol) was added to the solution and left to stir for 4 h. The reaction was monitored by TLC (ethyl acetate: dichloromethane 1:4), upon completion, the mixture was poured into 200 mL of ice water and the product was extracted with dichloromethane twice, dried with sodium sulfate, and solvent was removed under vacuum. Flash chromatography (ethyl acetate: dichloromethane, 1:5 yielded an oil of the title compound (7.30 g).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[OH:13][C:14]([CH3:53])([CH3:52])[CH:15]([CH3:51])[O:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]3[N:48]=[CH:49][CH:50]=[C:24]23)[CH2:19][CH2:18]1>C(OCC)(=O)C>[OH:13][C:14]([CH3:52])([CH3:53])[CH:15]([CH3:51])[O:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[C:43]4[NH:3][C:4](=[O:7])[O:5][N:44]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]3[N:48]=[CH:49][CH:50]=[C:24]23)[CH2:19][CH2:18]1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OC(C)C(C)(C)O)CC2)c2ccnn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OC(C)C(C)(C)O)CC2)c2ccnn12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.68 g), sodium hydrogen carbonate (1.0 g) and dimethyl sulfoxide (5 mL) was stirred at 50° C. for 30 min, 4′-({4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.45 g) was added, and the mixture was stirred at 90° C. for 20 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (5 mL). N,N′-Carbonyldiimidazole (0.16 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.15 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and with saturated aqueous sodium hydrogen carbonate solution 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 to give the title compound as a pale-yellow amorphous solid (0.37 g, 73%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:4]=1[NH2:5].COC1C=CC=[C:17]([NH2:21])C=1N.[H][H].N#CBr>[Pd].CO.C(#N)C.O>[CH3:1][O:2][C:3]1[C:4]2[N:5]=[C:17]([NH2:21])[NH:10][C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc(N)c1N
Reactant: COc1cccc([N+](=O)[O-])c1N
Reactant: [H][H]
Agent: [Pd]
Agent: N#CBr
Solvent: O
Solvent: CC#N
Solvent: CO
Product: COc1cccc2[nH]c(N)nc12

Procedure:
The material was prepared by the catalytic reduction of 2-methoxy-6-nitroaniline to 3-methoxybenzene-1,2-diamine using a hydrogen atmosphere at 40 psi and 10% palladium on carbon (50% w/w water) in methanol. The resulting crude diamine was subsequently reacted with cyanogen bromide in an acetonitrile-water mixture according to previous procedure and used without further purification. 1H-NMR (400 MHz, CDCl3), δ 12.40 (bs, 1H), 7.26 (d, 1H), 7.15 (t, 1H), 6.77 (d, 1H), 6.59 (bs, 2H), 3.73 (s, 3H). MS (EI): 164 (MH+).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[C:23]([O:27][C:28]([NH:30][C@@H:31]([CH2:35][CH2:36][CH3:37])[C:32]([OH:34])=O)=[O:29])([CH3:26])([CH3:25])[CH3:24].[NH:38]1[CH2:43][CH2:42][CH:41]([OH:44])[CH2:40][CH2:39]1>C(Cl)Cl>[OH:44][CH:41]1[CH2:42][CH2:43][N:38]([C:32](=[O:34])[C@@H:31]([NH:30][C:28](=[O:29])[O:27][C:23]([CH3:24])([CH3:25])[CH3:26])[CH2:35][CH2:36][CH3:37])[CH2:39][CH2:40]1
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: OC1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC(O)CC1
Reaction time: 3 h
Yield: 106 %

Procedure:
TBTU (7.09 g, 22.09 mmol) was added to a solution of (S)-2-(tert-butoxycarbonylamino)pentanoic acid (4 g, 18.41 mmol), which is commercially available, and piperidin-4-ol (2.235 g, 22.09 mmol) in DCM (50 mL). The reaction was stirred for 3 h and was then quenched by addition of NaHCO3 (aq., 8%, 25 mL). The aqueous phase was extracted with DCM. The organic phases were combined, dried (MgSO4), filtered and evaporated. The residue was added H3PO4 (aq) (1 M, 25 mL) and the aqueous phase was extracted with Et2O. The organic phases were pooled, dried (MgSO4), filtered and evaporated to give the title product (5.86 g, 106%) as a yellow oil. The obtained crude product was used in the next step without characterization.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:34])[N:10]([CH2:15][CH:16]([OH:33])[CH:17]([NH:25]C(OC(C)(C)C)=O)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:11][CH:12]([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N(CC)C(C)C)(C)C.[O:45]1[CH:49]2[O:50][CH2:51][CH2:52][CH:48]2[CH:47]([O:53][C:54](=[O:63])ON2C(=O)CCC2=O)[CH2:46]1>O1CCOCC1>[CH2:1]([O:8][C:9](=[O:34])[N:10]([CH2:15][CH:16]([OH:33])[CH:17]([NH:25][C:54]([O:53][CH:47]1[CH:48]2[CH:49]([O:50][CH2:51][CH2:52]2)[O:45][CH2:46]1)=[O:63])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:11][CH:12]([CH3:13])[CH3:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OC1COC2OCCC12)ON1C(=O)CCC1=O
Reactant: CC(C)CN(CC(O)C(Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)CN(CC(O)C(Cc1ccccc1)NC(=O)OC1COC2OCCC12)C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 73.4 %

Procedure:
(3-tert-Butoxycarbonylamino-2-hydroxy-4-phenyl-butyl)-isobutyl-carbamic acid benzyl ester 16 (7.54 g, 15 mmol) and 35 ml of 4M HCl in dioxane were stirred 30 min under an argon atmosphere. The mixture was concentrated in vacuo, and co-evaporated twice with dichloromethane. The residue was dissolved in dichloromethane (50ml) and N,N-diisopropylethylamine (6.1 ml, 35 mmol), and carbonic acid 2,5-dioxo-pyrrolidin-1-yl ester hexahydro-furo[2,3-b]furan-3-yl ester 17 (4.88g, 18 mmol) was added. The reaction mixture was stirred overnight, and then concentrated in vacuo. The residue was diluted with dichloromethane, and sequentially washed with brine, 10% KHSO4, brine, saturated NaHCO3, and brine, then dried over MgSO4, and concentrated in vacuo. The oily residue was purified by flash chromatography using 70:30 ethyl acetate hexane as eluant, to give [3-(Hexahydro-furo[2,3-b]furan-3-yloxycarbonylamino)-2-hydroxy-4-phenyl-butyl]-isobutyl-carbamic acid benzyl ester 18 (5.8 g, 73%) as a white solid. TLC: Rf 0.56 (7:3 ethyl acetate: hexane). MS 527 (MH)+.
Reaction SMILES: C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:15]1[CH:32]=[CH:31][C:18]([O:19][CH2:20][C@H:21]([OH:30])[CH2:22][CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:17][CH:16]=1.[F:33][C:34]([F:45])([F:44])[C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1>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.C(O)C>[F:33][C:34]([F:45])([F:44])[C:35]1[CH:40]=[C:39]([C:15]2[CH:32]=[CH:31][C:18]([O:19][CH2:20][C@H:21]([OH:30])[CH2:22][CH2:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[CH:17][CH:16]=2)[CH:38]=[CH:37][CH:36]=1
Reactant: O[C@H](CCc1cccnc1)COc1ccc(Br)cc1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O[C@H](CCc1cccnc1)COc1ccc(-c2cccc(C(F)(F)F)c2)cc1
Yield: 59.9 %

Procedure:
Prepared according to the method described in Example 33a) from toluene (5 ml), aqueous sodium carbonate (2 M, 1 ml), (2R)-1-(4-bromophenoxy)-4-(3-pyridyl)-2-butanol (0.25 g), ethanol (1 ml), 3-trifluoromethylbenzeneboronic acid (0.161 g) and tetrakis(triphenylphosphine)palladium(0) (22 mg) with heating at reflux for 6 hours. The residue obtained after work-up was purified by column chromatography over silica eluting with ethyl acetate to give (2R)-1-(3'-trifluoromethylbiphenyl-4-yloxy)-4-(3-pyridyl)-2-butanol as a colourless oil (0.180 g). Conversion to the oxalate salt upon treatment with excess saturated ethereal oxalic acid gave the title compound as a hygroscopic gum. (0.150 g)
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:10](C(O)=O)=[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.N#N.Cl>N1C2C(=CC=CC=2)C=CC=1.O>[OH:1][C:2]1[C:3]2[CH:10]=[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=C(O)c1c(-c2cccc([N+](=O)[O-])c2)oc2ncnc(O)c12
Agent: Cl
Agent: N#N
Solvent: O
Solvent: c1ccc2ncccc2c1
Product: O=[N+]([O-])c1cccc(-c2cc3c(O)ncnc3o2)c1
Reaction time: 2 h

Procedure:
18.4 g of 4-hydroxy-6-(3-nitrophenyl)furo[2,3-d]pyrimidine-5-carboxylic acid are placed in ca. 200 ml of quinoline, and heated for 20 min to 200-220° C. under a constant stream of N2. Then, 0.7 g of Cu2O are added. After 2 hours, an additional 0.4 g of Cu2O is added. 1 hour later, another spatula tip of Cu2O is added and the temperature lowered. The next day, the reaction mixture is mixed with 0.5 litres of 2.5 M HCl, diluted with H2O, stirred, left to stand for 8 h and filtered by suction. The residue is washed with conc. ammonia and with a lot of H2O. The basic filtrate is acidified with conc. HCl, filtered by suction and washed with a lot of H2O. The crude product from the two residues is used directly without further working up m.p.: >300° C. IR: 3091 w, 2853w, 1670ss, 1593w, 1527s, 1496w, 1475w, 1373w, 1348s, 1297w, 1202m, 938m, 900m, 783w, 740w, 703w, 622w.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[CH:16][C:9]=23)[C:5]([C:17]2[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=2)=[N:4]1)[CH3:2].[CH:24]1([N:29]=[C:30]=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([NH:29][C:30]([NH:21][C:20]2[CH:22]=[CH:23][C:17]([C:5]3[C:6]([C:8]4[CH:13]=[CH:12][N:11]=[C:10]5[NH:14][CH:15]=[CH:16][C:9]=45)=[CH:7][N:3]([CH2:1][CH3:2])[N:4]=3)=[CH:18][CH:19]=2)=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(N)cc2)n1
Reactant: O=C=NC1CCCC1
Product: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(NC(=O)NC3CCCC3)cc2)n1

Procedure:
Following the procedure described in Example 47a with 4-[1-ethyl-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]aniline and cyclopentyl isocyanate provided the title compound. ESMS [M+H]+: 415.2