Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[C:4]1=[O:19])[CH3:2].CS([C:24]1[N:25](COCC[Si](C)(C)C)[C:26]2[C:27]([N:32]=1)=[N:28][CH:29]=[CH:30][CH:31]=2)(=O)=O.[H-].[Na+]>CN(C=O)C.CO>[CH2:1]([N:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:13]=[CH:14][C:15]([O:18][C:24]3[NH:32][C:27]4=[N:28][CH:29]=[CH:30][CH:31]=[C:26]4[N:25]=3)=[CH:16][CH:17]=2)[C:4]1=[O:19])[CH3:2]
Reactant: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2ncccc21
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2ncccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCn1c(=O)n(-c2ccc(Oc3nc4cccnc4[nH]3)cc2)c2ncccc21
Temperature: 200 °C
Yield: 14.7 %

Procedure:
The mixture of 1-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (281 mg), 2-(methylsulfonyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazo[4,5-b]pyridine (240 mg) and NaH (35.2 mg) in DMF (dry) (3 mL) was heated at 200° C. for 3 h under microwave irradiation. The reaction mixture was diluted with MeOH, and concentrated in vacuo. The residue was diluted with 6N HCl. The mixture was neutralized with aq. NaHCO3 at 0° C. and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0%-100% EtOAc in hexane) to give 1-ethyl-3-[4-(3H-imidazo[4,5-b]pyridin-2-yloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (40 mg) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:24]#[C:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:8][C:9]=1[N:10]1[CH:15]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:14][CH2:13][C@H:12](Br)[C:11]1=[O:23])=[O:4].[N-:30]=[N+:31]=[N-:32].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:24]#[C:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:8][C:9]=1[N:10]1[CH:15]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:14][CH2:13][C@H:12]([N:30]=[N+:31]=[N-:32])[C:11]1=[O:23])=[O:4]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N1C(=O)[C@@H](Br)CCC1C1CCCCC1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N1C(=O)[C@@H](N=[N+]=[N-])CCC1C1CCCCC1
Temperature: 65 °C
Reaction time: 18 h
Yield: 59.3 %

Procedure:
To the solution of 3-((S)-3-bromo-6-cyclohexyl-2-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (78 mg, 0.16 mmol, 1 equiv.) in DMF (1.0 mL) was added NaN3 (12 mg, 0.19 mmol, 1.2 equiv) and the resulting mixture was stirred at 65° C. for 18 hours. The solvent was then removed under vacuum. The residue was purified by silica gel column chromatography (EtOAc/Heptane, 10%˜60%) to give product 42 mg (yield 56%). MS: 442 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C:12](=[O:21])[CH2:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1.[CH3:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28]>>[CH2:19]([O:21][C:12]1([O:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22])[CH2:11][CH2:10][C@H:9]2[C@H:8]3[C@H:17]([CH2:16][CH2:15][C@:13]12[CH3:14])[C:18]1[CH:19]=[CH:20][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH2:6][CH2:7]3)[CH2:20][CH2:3][CH2:4][CH2:5][CH3:18]
Reactant: CCCCCCO
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Product: CCCCCCOC1(OCCCCCC)CC[C@H]2[C@@H]3CCc4cc(OC)ccc4[C@H]3CC[C@@]21C

Procedure:
5 g of 3-methoxy-estra-1,3,5(10)-trien-17-one is reacted according to example 1a. N-hexanol is used as alcohol. The reaction mixture was used in the next step without a preceding working up.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([OH:8])=O)=[O:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH:38]1[CH2:43][CH2:42][CH:41]([C:44]2[CH:51]=[CH:50][C:47]([C:48]#[N:49])=[CH:46][CH:45]=2)[CH2:40][CH2:39]1.CCN(C(C)C)C(C)C>CN(C)C=O.CCOC(C)=O>[CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([N:38]1[CH2:43][CH2:42][CH:41]([C:44]2[CH:51]=[CH:50][C:47]([C:48]#[N:49])=[CH:46][CH:45]=2)[CH2:40][CH2:39]1)=[O:8])=[O:2]
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Reactant: Cc1ccc(C(=O)O)cc1C=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)cc1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
A mixture of 3-formyl-4-methylbenzoic acid (compound 39.1, 660 mg, 4.02 mmol, 1.00 equiv), HBTU (2 g, 5.28 mmol, 1.30 equiv) in N,N-dimethylformamide (20 mL) was stiffed at room temperature. After 1 h, 4-(piperidin-4-yl)benzonitrile hydrochloride (1.5, 890 mg, 4.01 mmol, 1.00 equiv) and DIEA (1.03 g, 7.98 mmol, 2.00 equiv) were added. The resulting mixture was stirred for 5 h at room temperature and then overnight at 60° C. in. After cooling to ambient temperature, the reaction mixture was diluted with 100 mL of EtOAc and washed with 2×50 mL of NH4Cl (aq., sat.) followed by 2×50 mL of sodium bicarbonate (aq., sat.). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 1 g (75%) of the title compound as a brown oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([CH:12]=O)[CH2:6][C:5]2([CH3:15])[CH3:14].[CH2:16]([Mg]Br)[CH3:17].C(OCC)(=O)C>C(OCC)C.CCCCCC>[CH:12]1([N:7]2[CH2:6][C:5]([CH3:15])([CH3:14])[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([OH:1])[CH:3]=3)[CH2:8]2)[CH2:17][CH2:16]1
Reactant: CC1(C)CN(C=O)Cc2ccc(O)cc21
Reactant: CC[Mg]Br
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCOCC
Product: CC1(C)CN(C2CC2)Cc2ccc(O)cc21
Temperature: 55 °C
Yield: 63 %

Procedure:
A stirred, cooled (0° C.)solution of 6-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline-2-carbaldehyde (Intermediate 20, 2.3 g, 11.21 mmol) in anhydrous tetrahydrofuiran (40 mL) under argon was treated with titanium tetra-iso-propoxide (8.28 mL, 28 mmol) followed by 3M solution of ethyl magnesium bromide in diethyl ether (18.7 mL) and the reaction mixture was then heated at 55° C. overnight. It was then cooled in an ice-bath, quenched with saturated aqueous ammonium chloride solution and extracted with diethyl ether (×2). The combined organic phase was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford a yellow oily solid. Flash column chromatography over silica gel (230-400 mesh) using 10-20% ethyl acetate in hexane as the eluent afforded the title compound as a pale yellow solid (1.55 g, 63%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:16][CH2:15][CH:14]([N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13][CH:12]=1.I.CS[C:29]([C:31]1[S:32][CH:33]=[CH:34][CH:35]=1)=[NH:30]>C(O)C>[CH3:25][N:17]([CH:14]1[CH2:15][CH2:16][CH:11]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:29]([C:31]4[S:32][CH:33]=[CH:34][CH:35]=4)=[NH:30])[CH:3]=3)[NH:7][CH:6]=2)[CH2:12][CH2:13]1)[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23]
Reactant: CN(C(=O)OC(C)(C)C)C1CC=C(c2c[nH]c3ccc(N)cc23)CC1
Reactant: CSC(=N)c1cccs1
Agent: I
Solvent: CCO
Product: CN(C(=O)OC(C)(C)C)C1CCC(c2c[nH]c3ccc(NC(=N)c4cccs4)cc23)CC1
Reaction time: 24 h
Yield: 73.3 %

Procedure:
A solution of compound 82 (0.44 g, 1.281 mmol) in dry ethanol (20 mL) was treated with thiophene-2-carboximidothioic acid methyl ester hydroiodide (0.73 g, 2.562 mmol) at room temperature and stirred for 24 h. The solvent was evaporated and product was precipitated with ether (100 mL). The solid was dissolved into sat. NaHCO3 sol.: CH2Cl2 (50 mL, 1:1). The org. layer was separated and aqueous layer was extracted with CH2Cl2 (2×25 mL). The combined CH2Cl2 layer was washed with brine (20 mL) and dried (Na2SO4). The solvent was evaporated and crude was purified by column chromatography (2M NH3 in methanol: CH2Cl2, 5:95) to obtain compound 83 (0.425 g, 73%) as a foam in 1:2 ration of diastereomers. 1H NMR (DMSO-d6) δ 1.38-1.56 (m, 11H), 1.64-1.82 (m, 4H), 2.06-2.18 (m, 2H), 2.62-2.70 (m, 4H), 3.80-3.90 (m, 1H), 6.27 (brs, 1H), 6.62-6.66 (m, 1H), 6.95-7.11 (m, 3H), 7.22-7.29 (m, 1H), 7.59 (d, 1H, J=5.1 Hz), 7.71 (d, 1H, J=3.6 Hz), 10.59, 10.63 (2s, 1H); ESI-MS m/z (%): 453 (MH+, 100).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[C:8]([O:14][CH3:15])(=[O:13])[CH2:9][C:10]([CH3:12])=[O:11].C1C=CC=CC=1.N1CCCCC1>C(O)(=O)C>[C:10]([C:9](=[CH:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[C:8]([O:14][CH3:15])=[O:13])(=[O:11])[CH3:12]
Reactant: O=Cc1cccs1
Reactant: COC(=O)CC(C)=O
Solvent: c1ccccc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: COC(=O)C(=Cc1cccs1)C(C)=O
Yield: 94.8 %

Procedure:
A mixture of 112 g of 2-thiophenecarbaldehyde, 116 g of methyl acetoacetate, 770 ml of benzene, 4 ml of acetic acid and 3 ml of piperidine is heated under reflux for 2.5 hours under the condition of azeotropic dehydration. The benzene is evaporated under reduced pressure and the residual solvent is distilled off to give 199 g of methyl 2-acetyl-3-(2-thienyl)acrylate, boiling at 130°-160° C./0.2 mmHg.
Reaction SMILES: [N:1]1([CH2:5][C@@H:6]([NH2:10])[CH:7]([CH3:9])[CH3:8])[CH2:4][CH2:3][CH2:2]1.[CH:11](=O)[CH3:12].[Na].O>C(Cl)Cl>[N:1]1([CH2:5][C@@H:6]([NH:10][CH2:11][CH3:12])[CH:7]([CH3:9])[CH3:8])[CH2:4][CH2:3][CH2:2]1
Reactant: CC=O
Reactant: CC(C)[C@H](N)CN1CCC1
Agent: [Na]
Solvent: O
Solvent: ClCCl
Product: CCN[C@H](CN1CCC1)C(C)C
Yield: 19.9 %

Procedure:
(S)-1-(Azetidin-1-yl)-3-methylbutan-2-amine (Compound U) (0.420 g, 2.95 mmol) and acetaldehyde (0.166 mL, 2.95 mmol) was mixed in DCM (10 mL). Sodium triacetoxyhydroborate (0.813 g, 3.84 mmol) was added in small portions and the resultant mixture was stirred at rt for 5 h. Water was added and the pH was adjusted to pH9. The water phase was extracted with DCM (4×50 mL). The combined organic layers were combined and washed with brine, passed through phase separator and evaporated under reduced pressure to give the title compound (0.1 g, 20%). The obtained crude product was used without further purification. LCMS (M+H)+: 171.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=1[C:13]([N:15]([CH3:17])[CH3:16])=[O:14].C(N(C(C)C)CC)(C)C>C(O)(C)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=2[C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CN(C)C(=O)c1ccccc1N
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Temperature: 0 °C
Reaction time: 18 h
Yield: 84.7 %

Procedure:
A round-bottomed flask was charged with 2,4,5-trichloropyrimidine (1.0 g, 3.4 mmol), 2-amino-N,N-dimethylbenzamide (587 mg, 3.5 mmol), di-isopropyl-ethylamine (712 μL, 4.08 mmol) and 15 mL of isopropanol. The flask was fitted with a reflux condenser and the reaction was heated to reflux and stirred for 18 h. A white solid appeared in the reaction mixture. The reaction was cooled to 0° C. and filtered and solid was washed with ether to afford 2-[(2,5-dichloro-4-pyrimidinyl)amino]-N,N-dimethylbenzamide (896 mg, 94%):
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6](=[O:11])[O:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[H-].[Na+].[CH2:16](I)[CH:17]=[CH2:18]>CN(C=O)C.O>[F:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6](=[O:11])[O:7][C:8](=[O:10])[N:9]([CH2:18][CH:17]=[CH2:16])[C:4]=2[CH:3]=1
Reactant: C=CCI
Reactant: O=c1[nH]c2cc(F)ccc2c(=O)o1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCn1c(=O)oc(=O)c2ccc(F)cc21
Reaction time: 2 h
Yield: 73.9 %

Procedure:
To a solution of 7-fluoro-2H-3,1-benzoxazine-2,4(1H)-dione (5.01 g, 27.7 mmol) in DMF (100 ml) at 0° C. was added sodium hydride (1.11 g, 27.7 mmol, 60% in paraffin) over 15 min. Allyl iodide (2.6 ml, 27.7 mmol) was added and the solution stirred for 2 h, then poured onto ice (100 g) in water (200 ml). The precipitate was collected, washed with water, then hexane and dried under vacuum at 40° C. to yield the title compound (4.53 g, 74%) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([OH:12])=O)=[CH:4][CH:3]=1.[C:13](Cl)(=[O:17])[C:14](Cl)=O.C[N:20]([CH:22]=[O:23])C>C1COCC1>[CH2:8]([C@@H:14]1[CH2:13][O:17][C:22](=[O:23])[N:20]1[C:10](=[O:12])/[CH:9]=[CH:8]/[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: CN(C)C=O
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)/C=C/c1ccc(Cl)cc1
Solvent: C1CCOC1
Product: O=C(/C=C/c1ccc(Cl)cc1)N1C(=O)OC[C@H]1Cc1ccccc1
Reaction time: 1 h
Yield: 71 %

Procedure:
To a mixed solution of (2E)-3-(4-chlorophenyl)prop-2-enoic acid (30.0 g) in THF (350 mL) and DMF (0.90 mL) was slowly added oxalyl chloride (21.6 mL) at 5° C., and the mixture was stirred for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in THF (150 mL). This THF solution was added to a suspension of (R)-4-benzyloxazolidin-2-one (31.0 g), triethylamine (114 mL) and lithium chloride (34.8 g) in THF (350 mL) at 5° C., and the mixture was stirred at room temperature for 14 hr. The reaction mixture was concentrated under reduced pressure, and water and ethyl acetate were added to the residue. The organic layer was washed with 10% aqueous citric acid solution and saturated brine, dried and concentrated under reduced pressure to give (4R)-4-benzyl-3-[(2E)-3-(4-chlorophenyl)prop-2-enoyl]-1,3-oxazolidin-2-one (40.0 g, 71%) as a white powder.
Reaction SMILES: [H-].[Na+].CS(C)=O.[Cl:7][C:8]1[S:12][C:11]([C:13]([NH:15][CH2:16][C@@H:17]2[O:21][C:20](=[O:22])[N:19]([C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:36])[CH2:31][CH2:32][CH2:33][CH2:34]Cl)=[CH:25][CH:24]=3)[CH2:18]2)=[O:14])=[CH:10][CH:9]=1.O>C(Cl)Cl>[Cl:7][C:8]1[S:12][C:11]([C:13]([NH:15][CH2:16][C@@H:17]2[O:21][C:20](=[O:22])[N:19]([C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][C:30]4=[O:36])=[CH:25][CH:24]=3)[CH2:18]2)=[O:14])=[CH:10][CH:9]=1
Reactant: O=C(CCCCCl)Nc1ccc(N2C[C@H](CNC(=O)c3ccc(Cl)s3)OC2=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=C(NC[C@H]1CN(c2ccc(N3CCCCC3=O)cc2)C(=O)O1)c1ccc(Cl)s1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
30 mg of 60 percent NaH in liquid paraffin are added under inert conditions to 5 ml of DMSO, and the mixture is heated at 75° C. for 30 min until gas evolution ceases. Then a solution of 290 mg (0.617 mmol) of 5-chloro-N-[((5S)-3-{4-[(5-chloropentanoyl)amino]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamide (from Example 161) in 5 ml of methylene chloride is added dropwise, and the mixture is stirred at room temperature overnight. The reaction is stopped and the mixture is added to 100 ml of water and extracted with ethyl acetate. The evaporated organic phase is chromatographed on an RP-8 column and eluted with acetonitrile/water. 20 mg (7.5% of theory) of the target compound are obtained.
Reaction SMILES: [OH-].[Li+:2].[OH:3][CH2:4][CH:5]([C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1)[C:6]([O:8]C)=[O:7].O1CCCC1>O.CO>[OH:3][CH2:4][CH:5]([C:10]1[CH:11]=[C:12]([C:20]([F:21])([F:23])[F:22])[CH:13]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:15]=1)[C:6]([O-:8])=[O:7].[Li+:2]
Reactant: COC(=O)C(CO)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C([O-])C(CO)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 176.5 %

Procedure:
Lithium hydroxide (168 mg, 4 mmol) in water (2 mL) was added to a solution of (RS)-methyl α-(hydroxymethyl)-3,5-bis(trifluoromethyl)benzeneacetate (Description 7, 500 mg, 1.6 mmol) in methanol (4 mL). Methanol (2 mL) and tetrahydrofuran (2 mL) were added and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and the residue was dried azeotropically by evaporating toluene (×2) to to give the crude title compound as a colorless gum (870 mg), which was used without further purification. 1H NMR (400 MHz, CD3OD) δ 3.73–3.79 (1H, m), 3.85–3.92 (1H, m), 4.02–4.06 (1H, m), 7.80 (1H, s) and 7.98 (2H, s).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[Si:27]([O:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39]O)=[CH:37][CH:36]=1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>O1CCCC1>[C:30]([Si:27]([O:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][I:25])=[CH:37][CH:36]=1)([CH3:29])[CH3:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CO)cc1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CI)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
Triphenyl phosphine (1.32 g, 5.03 mmol), imidazole (370 mg, 5.47 mmol) and iodine (1.16 g, 4.61 mmol) were added to an ice-cooled solution of 4-(tert-butyldimethylsilyloxy)benzyl alcohol [(1 g, 4.19 mmol), Tet. Lett. (2004), 45, 9617] in tetrahydrofuran (50 mL) and the mixture was stirred at 0° C. for 10 minutes and room temperature for 30 minutes. The reaction mixture was then concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was separated, dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluting with pentane, afforded the title compound in 41% yield, 600 mg.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:41][CH:42]([CH3:44])[CH3:43])[CH2:14][C@@H:15]([OH:40])[C@@H:16]([NH:28][C:29](=[O:39])[O:30][C@@H:31]3[C@H:38]4[C@H:34]([O:35][CH2:36][CH2:37]4)[O:33][CH2:32]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][OH:27])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.C(N(CC)CC)C.[C:52]1([CH3:62])[CH:57]=[CH:56][C:55]([S:58](Cl)(=[O:60])=[O:59])=[CH:54][CH:53]=1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:62][C:52]1[CH:57]=[CH:56][C:55]([S:58]([O:27][CH2:26][CH2:25][O:24][C:21]2[CH:22]=[CH:23][C:18]([CH2:17][C@H:16]([NH:28][C:29]([O:30][C@@H:31]3[C@H:38]4[C@H:34]([O:35][CH2:36][CH2:37]4)[O:33][CH2:32]3)=[O:39])[C@H:15]([OH:40])[CH2:14][N:13]([S:10]([C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)(=[O:12])=[O:11])[CH2:41][CH:42]([CH3:44])[CH3:43])=[CH:19][CH:20]=2)(=[O:60])=[O:59])=[CH:54][CH:53]=1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCO)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCOc2ccc(C[C@H](NC(=O)O[C@H]3CO[C@H]4OCC[C@H]43)[C@H](O)CN(CC(C)C)S(=O)(=O)c3ccc4c(c3)OCO4)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-2-hydroxy-1-[4-(2-hydroxyethoxy)benzyl]propylcarbamate (0.11 g, 0.18 mmol), triethyl amine (0.055 mL, 40 mg, 0.39 mmol), and 4-dimethylaminopyridine (2 mg), in dichloromethane at 0° C. was added p-toluenesulfonyl chloride (38 mg, 0.2 mmol) and the mixture was stirred at ambient temperature for 4 h. Solvent was evaporated and the residue was purified by chromatography (silica gel, dichloromethane/methanol, 98:2) to provide the title compound as a solid foam (0.105 g) 1H NMR (DMSO-d6): δ 0.78 (3H, d), 0.82 (3H, d), 1.2 (1H, dd), 1.37 (1H, quintuplet), 1.9-2.0 (1H, m), 2.3 (1H, dd), 2.38 (3H, s), 2.6-2.8 (2H, m), 2.9 (1H, d), 2.97 (1H, dd), 3.2-3.3 (1H, m), 3.4-3.5 (1H, m), 3.5-3.6 (4H, m), 3.7 (1H, t), 3.8 (1H, dd), 4.0 (2H, d), 4.3 (2H, t), 4.8 (1H, dt), 5.0 (1H, d), 5.5 (1H, d), 6.18 (2H, s), 6.7 (2H, d), 7.0-7.1 (3H, m), 7.2 (1H, d), 7.22 (1H, s), 7.29 (1H, d), 7.4 (2H, d), 7.8 (2H, d); MS: 791 (MH+)
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[N-:11]=[N+:12]=[N-:13].[Na+]>CN(C)C=O.O>[N:11]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[N+:12]=[N-:13]
Reactant: CCOC(=O)CCCCBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCN=[N+]=[N-]
Yield: 95 %

Procedure:
Ethyl 5-bromovalerate (2.1 g; 10 mmol; Aldrich) was added to a stirred suspension of sodium azide (1.3 g, 20 mmol; Fisher) in 5 ml dimethylformamide and 5 ml water, and the reaction mixture was heated 12 h at 80° Cs. The reaction was partitioned between diethyl ether (100 ml) and water (100 ml), and the resulting organic layer was washed with water (100 ml) and brine (100 ml), dried over sodium sulfate, and dried in vacuo. Yield: 1.6 g (9.3 mmol, 95% yield).
Reaction SMILES: C(N1C2C(=CC=CC=2)C(C(C2C=NC=C[C:19]=2[C:20]([OH:22])=[O:21])=O)=C1C)C.[CH2:24]([N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([C:35]([C:37]2[CH:42]=[CH:41][N:40]=[CH:39][C:38]=2[C:43]([OH:45])=[O:44])=[O:36])=[C:27]1[CH3:46])[CH3:25].[C:47]1([NH:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>N1C=CC=CC=1>[C:35]([O:22][C:20](=[O:21])[CH3:19])(=[O:36])[CH3:28].[CH2:24]([N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([C:35]2([N:53]([C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)[C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=3)[C:37]3[CH:42]=[CH:41][N:40]=[CH:39][C:38]=3[C:43](=[O:45])[O:44]2)=[C:27]1[CH3:46])[CH3:25]
Reactant: CCn1c(C)c(C(=O)c2ccncc2C(=O)O)c2ccccc21
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: CCn1c(C)c(C(=O)c2cnccc2C(=O)O)c2ccccc21
Solvent: c1ccncc1
Product: CC(=O)OC(C)=O
Product: CCn1c(C)c(C2(N(c3ccccc3)c3ccccc3)OC(=O)c3cnccc32)c2ccccc21

Procedure:
Following a procedure similar to that described in Example 3 but employing 1.6 g. of an isomer mixture comprising 3-[(1-ethyl-2-methyl-3-indolyl)carbonyl]-4-pyridinecarboxylic acid and 4-[(1-ethyl-2-methyl-3-indolyl)carbonyl]-3-pyridinecarboxylic acid, 0.9 g. of diphenylamine, 0.5 ml. of pyridine and 6 ml. of acetic anhydride there was obtained 1-(1-ethyl-2-methyl-3-indolyl)-1-(diphenylamino)furo[3,4-c]pyridine-3(1H)-one as a viscous oil. A toluene solution of the product contacted with acidic clay or phenolic resin developed an orange image.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].FC(F)(F)C(O)=O.[CH2:22]([C:24]1[S:28][CH:27]=[C:26]([C:29]([N:31]2[CH2:36][C:35]3([CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)[O:34][CH2:33][CH2:32]2)=[O:30])[CH:25]=1)[CH3:23].[Si]([O:49][CH2:50][CH2:51][C:52]1[CH:53]=[CH:54][C:55]([F:60])=[C:56]([CH:59]=1)[CH:57]=O)(C(C)(C)C)(C)C.C(O)(=O)C>CN1C(=O)CCC1>[CH2:22]([C:24]1[S:28][CH:27]=[C:26]([C:29]([N:31]2[CH2:36][C:35]3([CH2:41][CH2:40][N:39]([CH2:57][C:56]4[CH:59]=[C:52]([CH2:51][CH2:50][OH:49])[CH:53]=[CH:54][C:55]=4[F:60])[CH2:38][CH2:37]3)[O:34][CH2:33][CH2:32]2)=[O:30])[CH:25]=1)[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccc(F)c(C=O)c1
Reactant: CCc1cc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Product: CCc1cc(C(=O)N2CCOC3(CCN(Cc4cc(CCO)ccc4F)CC3)C2)cs1
Temperature: 20 °C
Reaction time: 18 h

Procedure:
Sodium triacetoxyborohydride (0.225 g) was added to a stirred solution at 0° C. of (5-ethylthiophen-3-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate (example 99, step a) (0.289 g) and 5-(2-(tert-butyldimethylsilyloxy)ethyl)-2-fluorobenzaldehyde (example 100, step b) (0.2 g) and acetic acid (0.041 ml) in NMP (20 mL). The reaction mixture was then stirred at 20° C. for 18 hours. Further sodium triacetoxyborohydride (0.150 g) was added and stirring continued for 4 hours. The mixture was partitioned between ethyl acetate and saturated sodium bicarbonate solution, the organic layer was washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The resultant gum was dissolved in THF (20 mL) and treated with TBAF (1M in THF, 1.4 ml). The solution was allowed to stand at 20° C. for 8 hours. The solvent was evaporated under reduced pressure and the crude product was purified by flash silica chromatography using 2% methanol in dichloromethane with 1% triethylamine as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.18 g.