Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH2:2]1[CH:4]([C:5]([NH2:7])=[NH:6])[CH2:3]1.Cl.O=[C:10]1[CH2:15][CH2:14][CH2:13][S:12][CH:11]1[C:16](OCC)=[O:17].C(O)(=O)C>CO>[CH:4]1([C:5]2[N:6]=[C:16]([OH:17])[C:11]3[S:12][CH2:13][CH2:14][CH2:15][C:10]=3[N:7]=2)[CH2:3][CH2:2]1
Reactant: N=C(N)C1CC1
Reactant: CCOC(=O)C1SCCCC1=O
Agent: Cl
Agent: [Na]
Solvent: CC(=O)O
Solvent: CO
Product: Oc1nc(C2CC2)nc2c1SCCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.5 %

Procedure:
Sodium metal (3.94 g, 0.17 g atom) was dissolved in methanol (150 ml) and cyclopropylcarboxamidine hydrochloride (21.0 g, 0.174 mol) was added followed after 1/4 hour stirring by the addition of ethyl 3-oxotetrahydrothiopyran-2-carboxylate (27.2 g, 0.145 mol). The reaction mixture was stirred at 25° C. for 18 hours then treated with ice water (200 ml) and neutralized with acetic acid to give 24.6 g of the title compound which melted at 249°-250° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[C:6]([CH3:12])[CH:7]=[CH:8][C:9]=2[CH3:11])[NH:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14].N1C=CC=CC=1.[C:23](Cl)(=[O:25])[CH3:24].O>C1COCC1>[C:23]([NH:1][C:2]1[C:10]2[C:5](=[C:6]([CH3:12])[CH:7]=[CH:8][C:9]=2[CH3:11])[NH:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14])(=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1[nH]c2c(C)ccc(C)c2c1N
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1[nH]c2c(C)ccc(C)c2c1NC(C)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 27.9 %

Procedure:
A mixture of 0.6 g (2.75 mmol) of methyl 3-amino-4,7-dimethylindole-2-carboxylate, 0.22 ml (3.3 mmol) of pyridine and 15 ml of anhydrous THF was cooled to 0° C. 10 ml of a solution of 0.24 ml (3.3 mmol) of acetyl chloride in anhydrous THF was added dropwise over a period of 30 minutes. After completion of the addition, the reaction mixture was stirred for 30 minutes. The reaction mixture was poured into 200 ml of water and extracted with 30 ml of ethyl acetate three times. The ethyl acetate layers were combined, washed with 100 ml of water once, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to provide 200 mg of white crystals. Yield: 28%
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH2:25][CH2:26][C:27]([OH:29])=O)[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]>C1C=CC=CC=1>[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[C:27](=[O:29])[CH2:26][CH2:25]2
Reactant: COc1ccc(CCC(=O)O)cc1OC
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: c1ccccc1
Product: COc1cc2c(cc1OC)C(=O)CC2
Temperature: 0 °C
Yield: 46.6 %

Procedure:
Phosphorus pentoxide (500 g, 3.5 mol) is added portionwise to a mechanically stirred solution of 3-(3,4-dimethoxyphenyl)propionic acid (100 g, 0.67 mol) in benzene (2500 ml) and the mixture is refluxed for 8 hr. The reaction is slowly poured into ice-water, and the benzene layer is separated and washed with 10% sodium hydroxide and water, dried and evaporated to give 5,6-dimethoxyindan-1-one (60 g), mp 100° C., described by W. H. Perkin and R. Robinson, J. Chem. Soc., 1073 (1907).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:14]#[C:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[NH:8][N:7]=[CH:6]2.O=P(Cl)(Cl)[Cl:27]>C(Cl)Cl>[Cl:27][C:9]1[C:10]2[C:5](=[C:4]([C:14]#[C:15][CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[N:7][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(=O)[nH]ncc2c1C#CCCCc1ccccc1
Solvent: ClCCl
Product: COc1ccc2c(Cl)nncc2c1C#CCCCc1ccccc1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A suspension of 6-methoxy-5-(5-phenyl-pent-1-ynyl)-2H-phthalazin-1-one (1.26 g, 3.96 mmoles), prepared as described in example 64, and POCl3 (30 ml) was heated at 80° C. under stirring up to dissolution. After 30 minutes the solution was brought to dryness, the residue dissolved in CH2Cl2, washed to alkalinity with a diluted solution of K2CO3, then with water, anhydrified over Na2SO4 and brought to dryness to give 1.33 g of the title compound (quantitative yield). The compound was used as such in the subsequent step.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:31]([CH3:33])[CH3:32])[C:6]2[O:10][C:9]([C:11]3[CH:29]=[CH:28][C:14]([C:15]([NH:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([CH2:25][CH:26]=O)[CH2:21][CH2:20]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:30]=1)#[N:2].[F:34][C:35]([F:49])([F:48])[C:36]1[CH:37]=[C:38]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[CH2:39][NH2:40].C([BH3-])#N.[Na+]>CO.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>[F:34][C:35]([F:48])([F:49])[C:36]1[CH:37]=[C:38]([CH:41]=[C:42]([C:44]([F:47])([F:45])[F:46])[CH:43]=1)[CH2:39][NH:40][CH2:26][CH2:25][C@H:22]1[CH2:23][CH2:24][C@H:19]([CH2:18][NH:17][C:15](=[O:16])[C:14]2[CH:28]=[CH:29][C:11]([C:9]3[O:10][C:6]4[C:5]([CH:31]([CH3:32])[CH3:33])=[CH:4][C:3]([C:1]#[N:2])=[CH:30][C:7]=4[N:8]=3)=[CH:12][CH:13]=2)[CH2:20][CH2:21]1
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NC[C@H]4CC[C@H](CC=O)CC4)cc3)oc12
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NC[C@H]4CC[C@H](CCNCc5cc(C(F)(F)F)cc(C(F)(F)F)c5)CC4)cc3)oc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)-N-{[trans-4-(2-oxoethyl)cyclohexyl]methyl}benzamide (25 mg, 0.056 mmol) in methanol (2 ml) were added 3,5-bis(trifluoromethyl)benzylamine (20 mg, 0.082 mmol) and sodium cyanoborohydride (10 mg, 0.159 mmol). The mixture was stirred overnight at room temperature, at which point LC/MS analysis showed a new peak at the desired molecular weight. The reaction mixture was then diluted with 10 ml of saturated sodium bicarbonate solution and 10 ml of ethyl acetate. The phases were separated and the aqueous phase was extracted with 2×10 ml of ethyl acetate. The combined organics were washed with 10 ml of brine, dried (sodium sulfate), and concentrated. The residue was purified by flash chromatography on a Biotage Horizon, 25S column, eluting with 1 column volume of 100% dichloromethane followed by a gradient of 0 to 100% ethyl acetate in dichloromethane over 10 column volumes to provide the title compound (11.9 mg, 0.018 mmol, 31.5% yield). Mass spectrum (ESI) 671.5 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.33 (d, J=8.5 Hz, 2H); 7.96 (d, J=8.5 Hz, 2H), 7.93 (d, J=1.5 Hz, 1H); 7.83 (s, 2H), 7.75 (s, 1H), 7.51 (s, 1H), 6.35 (br t, J=5.5 Hz, 1H), 5.30 (s, 2H), 3.85 (s, 2H), 3.48 (septet, J=6.5 Hz, 1H), 3.35 (t, J=6.5 Hz, 2H), 2.65 (t, J=6.5 Hz, 2H), 1.80 (m, 4H), 1.60 (m, 1H), 1.46 (d, J=7.0 Hz, 6H), 1.40-1.52 (m, 1H), 0.90-1.15 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][N:3]=1.[F:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][C:11]=1[O:17][CH3:18].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+].OP([O-])(O)=O.[K+]>C1(C)C=CC=CC=1.ClCCl.CC#N>[Cl:1][C:2]1[CH:7]=[C:6]([NH:14][C:13]2[CH:15]=[CH:16][C:10]([F:9])=[C:11]([O:17][CH3:18])[CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1cc(N)ccc1F
Reactant: Clc1cc(I)ccn1
Agent: CC(C)(C)[O-]
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC#N
Solvent: ClCCl
Product: COc1cc(Nc2ccnc(Cl)c2)ccc1F

Procedure:
2-Chloro-4-iodopyridine (340.4 mg, 1.42 mmol) was dissolved in anhydrous toluene (15 mL), after which 4-fluoro-3-methoxyaniline (241.4 mg, 1.7 mmol), tris(dibenzylidineacetone)dipalladium(0) (26.5 mg, 0.028 mmol), 1,3-bis(diphenylphosphino)propane (23 mg, 0.06 mmol), and sodium-tert-butoxide (191.9 mg, 2.0 mmol) were added to the solution. This reaction mixture was stirred at reflux for 12-18 hours, after which the reaction was diluted in dichloromethane and filtered through Celite™. The Celite™ was washed with dichloromethane, and the resulting solution was concentrated to afford the product. This solid was collected and dried for 12-18 hours under vacuum. Purification (Biotage Horizon HPFC chromatography system, SiO2, 90:9:1 dichloromethane:methanol:ammonium hydroxide) yielded a light brown solid (18, 169 mg, 47%); HPLC: Inertsil ODS-3V C18, 30:70[KH2PO4 (0.01M, pH 3.2): CH3CN], 264 nm, Rt 5.2 min, 93.6% purity.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([CH:17]([NH:21][CH2:22][CH:23]=[CH2:24])[CH2:18][CH2:19][OH:20])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27].CCN(CC)CC>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([CH:17]([NH:21][CH2:22][CH:23]=[CH2:24])[CH2:18][CH2:19][O:20][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCNC(CCO)[C@@H]1CCCN(C(=O)OCc2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCNC(CCOS(C)(=O)=O)[C@@H]1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of (R)-3-(1-allylamino-3-hydroxypropyl)piperidine-1-carboxylic acid benzyl ester (0.264 g, 0.794 mmol) in DCM (15 mL) cooled at 0° C. was added successively methanesulfonyl chloride (68 μL, 0.873 mmol) and Et3N (0.133 mL, 0.953 mmol). The mixture was stirred at RT for 1.5 h, and then diluted with DCM, washed with a saturated solution of NaHCO3, followed by water, then dried (Na2SO4) and concentrated in vacuo affording the title compound as a colourless gum (quantitative). LCMS (Method B): RT 2.14 min [M+H]+ 411.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:28]4[CH:33]=[CH:32][C:31]([S:34][CH3:35])=[CH:30][CH:29]=4)[C@@H:19]([NH:21][S:22]([CH:25]4[CH2:27][CH2:26]4)(=[O:24])=[O:23])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:44])C=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:28]4[CH:29]=[CH:30][C:31]([S:34]([CH3:35])=[O:44])=[CH:32][CH:33]=4)[C@@H:19]([NH:21][S:22]([CH:25]4[CH2:26][CH2:27]4)(=[O:24])=[O:23])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NS(=O)(=O)C2CC2)cc1
Solvent: ClCCl
Product: C[C@H](NS(=O)(=O)C1CC1)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccc(S(C)=O)cc1
Reaction time: 0.5 h

Procedure:
N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-methylsulfanylphenyl)propan-2-yl]cyclopropanesulfonamide (29, 20.5 mg, 0.04 mmol) was dissolved in DCM (2 mL) and cooled in an ice bath. 3-Chloroperbenzoic acid (70-75%) (10 mg, 0.04 mmol) dissolved in DCM (0.1 mL) was added. The reaction was stirred for 30 min, quenched by addition of 10% Na2SO3 solution (0.5 mL). Purification by HPLC and freeze drying of fractions with product gave the title compound as a colourless solid. Yield 17 mg (80%).
Reaction SMILES: CC(C)([O-])C.[Li+].[OH:7][C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[C:12]([OH:17])[CH:11]=[CH:10][C:9]=1[C:18](=[O:20])[CH3:19].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O)C>CN(C=O)C>[CH2:21]([O:17][C:12]1[CH:11]=[CH:10][C:9]([C:18](=[O:20])[CH3:19])=[C:8]([OH:7])[C:13]=1[N+:14]([O-:16])=[O:15])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1ccc(O)c([N+](=O)[O-])c1O
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(=O)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Lithium tert-butoxide (4.06 g) was added to a stirred solution of 1-(2,4-dihydroxy-3-nitrophenyl)ethanone (example 11, step a) (10 g) in DMF (100 mL), under nitrogen, whilst maintaining the internal temperature below 30° C. After stirring for a further 10 minutes at ambient temperature, benzyl bromide (6.03 mL) was added and the mixture stirred for a further 20 h. Further benzyl bromide (3 mL) was added and the mixture stirred for 24 h. The reaction was quenched with water (300 mL), 1M aqueous sodium hydroxide (50 mL) was added and the mixture was washed with diethyl ether (2×300 mL), filtering through Celite to aid separation. The basic solution was cooled in ice/water, acidified with ice cold 2M hydrochloric acid (200 mL) and the resulting precipitate filtered off, washed with water and dried to afford a light brown solid. The solid was slurried with ethanol (100 mL) for 1 h and the solid filtered off, washed with cold ethanol (20 mL), and dried under vacuum at 40° C. to afford the subtitled compound as a light brown solid. Yield 6.8 g.
Reaction SMILES: [CH2:1]([C:5]1[N:13]2[C:8]([C:9]([CH2:31][C:32]([O:34]C(C)(C)C)=[O:33])=[CH:10][CH2:11][CH:12]2[C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:30][N:29]=[N:28][N:27]=3)=[CH:16][CH:15]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[CH2:1]([C:5]1[N:13]2[C:8]([C:9]([CH2:31][C:32]([OH:34])=[O:33])=[CH:10][CH2:11][CH:12]2[C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:27][N:28]=[N:29][N:30]=3)=[CH:16][CH:15]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc2n1C(c1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CC=C2CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CCCCc1ccc2n1C(c1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CC=C2CC(=O)O
Temperature: 25 °C

Procedure:
To a solution of biphenyl indolizinyl tert-butyl ester (0.039 mmol, the title compound of Example 1926) in 0.5 mL of chloroform is added 0.25 mL of TFA, and the progress of the reaction is monitored by 1H NMR. The resulting solution is stirred at room temperature until the reaction is complete. The mixture is quenched with methanol and concentrated in vacuo. The residue is purified to give the title compound of Example 1927.
Reaction SMILES: [C:1]([C:3]1[N:7]([CH3:8])[N:6]=[N:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)#[CH:2].Br[C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][N:18]=1.C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:24][O:23][C:21](=[O:22])[C:20]1[CH:25]=[CH:26][C:17]([C:2]#[C:1][C:3]2[N:7]([CH3:8])[N:6]=[N:5][C:4]=2[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:18][CH:19]=1
Reactant: C#Cc1c(-c2ccc(F)cc2)nnn1C
Reactant: COC(=O)c1ccc(Br)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C#Cc2c(-c3ccc(F)cc3)nnn2C)nc1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 79.1 %

Procedure:
A mixture of 5-ethynyl-4-(4-fluoro-phenyl)-1-methyl-1H-[1,2,3]triazole (101 mg, 0.5 mmol), methyl 6-bromonicotinate (130 mg, 0.6 mmol), triethylamine (174 μL, 1.25 mmol) and PdCl2(PPh3)2 (11 mg, 0.3 mol %) in DMF (1 mL) was evaporated and flushed with Ar five times. Then CuI (2 mg, 0.2 mol %) was added and the reaction mixture was stirred at 90° C. for 30 min and DMF (1 mL) was added. The mixture was then poured into sodium hydroxide solution (1 M) and extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 50% ethyl acetate in heptane) afforded the title compound (133 mg, 79%) as a light yellow solid. MS: m/e=337.1 [M]+.
Reaction SMILES: [C:1]([C:4]1[CH:25]=[CH:24][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[C:14]=2[C:15]#[N:16])=[C:6]([CH2:26][CH2:27][C:28]([F:31])([F:30])[F:29])[C:5]=1[OH:32])(=[O:3])[CH3:2].C1CCCCC=1>C(O)C>[NH2:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:13]([O:12][CH2:11][CH2:10][CH2:9][O:8][C:7]2[CH:24]=[CH:25][C:4]([C:1](=[O:3])[CH3:2])=[C:5]([OH:32])[C:6]=2[CH2:26][CH2:27][C:28]([F:29])([F:30])[F:31])[C:14]=1[C:15]#[N:16]
Reactant: CC(=O)c1ccc(OCCCOc2cccc([N+](=O)[O-])c2C#N)c(CCC(F)(F)F)c1O
Solvent: CCO
Solvent: C1=CCCCC1
Product: CC(=O)c1ccc(OCCCOc2cccc(N)c2C#N)c(CCC(F)(F)F)c1O
Temperature: 25 °C

Procedure:
2.5 g of 10% Pd-on-charcoal are added to a solution of 10 g of 2-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-6-nitro-benzonitrile and 10 g of cyclohexene in 500 ml of ethanol and the mixture is refluxed for 30 minutes. After cooling to room temperature, it is filtered and freed from the solvent. Ether is added to the residue and the crystals which have separated out are filtered off. 2-Amino-6-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-benzonitrile is obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][C@H:18]([C:39]([O:41]C(C)(C)C)=[O:40])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][C:30](=[O:38])[NH:31][C:32]2[NH:33][CH2:34][CH2:35][CH2:36][N:37]=2)=[CH:22][CH:21]=1.C1(C)C=CC=CC=1>ClCCl>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][C@H:18]([C:39]([OH:41])=[O:40])[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][CH2:29][C:30](=[O:38])[NH:31][C:32]2[NH:33][CH2:34][CH2:35][CH2:36][N:37]=2)=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCC(=O)NC2=NCCCN2)cc1)Nc1nc2ccccc2s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C(CCCOc1ccc(C[C@H](Nc2nc3ccccc3s2)C(=O)O)cc1)NC1=NCCCN1
Reaction time: 2 h
Yield: 89.3 %

Procedure:
2 ml of trifluoroacetic acid is added to 25 mg of ester 7-3 in 5 ml of dichloromethane, agitation is carried out for 2 hours at ambient temperature then 10 ml of toluene is added. After evaporating under reduced pressure, taking up in dichloromethane and crystallizing by adding an Et2O/pentane mixture. 20 mg of 7-4 is obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH2:2]1.O[C@H:16]1[O:24][C@H:23]([CH2:25][OH:26])[C@@H:21]([OH:22])[C@H:19]([OH:20])[C@H:17]1[OH:18]>CO>[OH:18][C@@H:17]1[C@@H:19]([OH:20])[C@H:21]([OH:22])[C@@H:23]([CH2:25][OH:26])[O:24][C@H:16]1[N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH2:2]1
Reactant: COC(=O)CC1CNc2ccccc21
Reactant: OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@@H]1O
Solvent: CO
Product: COC(=O)CC1CN([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c2ccccc21
Temperature: 70 °C
Reaction time: 60 h
Yield: 87.7 %

Procedure:
To a solution of indoline 75 (8.5 g, 44.2 mmol) in MeOH (150 mL) was added α-D-glucose (27 g, 146 mmol) at room temperature. The mixture was stirred at 70° C. for 60 h, cooled to room temperature and concentrated in vacuo to remove solvent. The residue was purified by silica column chromatography to provide the titled compound 76 (13.7 g, 88%). MH+354.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9](F)=[CH:8][C:3]=1[NH:4][C:5](=[O:7])[CH3:6].[NH2:16][C:17]1[CH:29]=[CH:28][C:20]([O:21][CH:22]([CH3:27])[C:23]([O:25][CH3:26])=[O:24])=[CH:19][CH:18]=1.O>O1CCOCC1.C(OCC)C>[C:5]([NH:4][C:3]1[C:2]([F:1])=[CH:11][C:10]([N+:12]([O-:14])=[O:13])=[C:9]([CH:8]=1)[NH:16][C:17]1[CH:18]=[CH:19][C:20]([O:21][CH:22]([CH3:27])[C:23]([O:25][CH3:26])=[O:24])=[CH:28][CH:29]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)Nc1cc(F)c([N+](=O)[O-])cc1F
Reactant: COC(=O)C(C)Oc1ccc(N)cc1
Solvent: CCOCC
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)C(C)Oc1ccc(Nc2cc(NC(C)=O)c(F)cc2[N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
A mixture of 2',5'-difluoro-4'-nitroacetanilide (7.35 g, 0.034 mol) and methyl 2-(4-aminophenoxy)propionate (16.6 g, 0.085 mol) in dioxane is refluxed for 2 days, cooled to room temperature and poured into water. The resultant aqueous mixture is extracted with ethyl acetate and the organic extracts are combined, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a dark red gum. The gum is dissolved in hot diethyl ether and, after stirring briefly, an orange solid forms. The solid is collected via filtration and dried to give the title product as an orange solid, mp 126.5°-128.4° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][O:17][CH3:18])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].C([O:29][C:30](=O)[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[CH:45]=[CH:44][N:43]=[C:42]([CH3:46])[CH:41]=2)[CH:35]=1)=[O:33])(C)(C)C>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][O:17][CH3:18])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:30](=[O:29])[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[CH:45]=[CH:44][N:43]=[C:42]([CH3:46])[CH:41]=2)[CH:35]=1)=[O:33])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Product: COCCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C)c3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from [2-amino-5-(2-methoxy-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J32) (263 mg, 0.75 mmol) and 3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K12) (234 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow solid (351 mg, 80%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([O:10]C)=[CH:5][C:4]=1[CH2:12][CH2:13][C:14]([OH:16])=[O:15].Br>>[OH:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([OH:10])=[CH:5][C:4]=1[CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: COc1cc(CCC(=O)O)c(OC)cc1C
Agent: Br
Product: Cc1cc(O)c(CCC(=O)O)cc1O

Procedure:
0.18 mol (40 g) of 3-(2',5'-dimethoxy-4'-methylphenyl)-propionic acid is heated under reflux in 300 ml of 48% strength hydrobromic acid. After cooling, the acid obtained precipitates. It is filtered off, dried and recrystallised from a mixture of ethanol, chloroform and petroleum ether. After drying, it melts at 181° C.
Reaction SMILES: [O:1]1[CH:5]=[C:4]([C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=2)[N:3]=[CH:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[I:24]I.C(=O)(O)[O-].[Na+].S([O-])([O-])=O.[Na+].[Na+]>O1CCCC1>[I:24][C:2]1[O:1][CH:5]=[C:4]([C:6]2[CH:7]=[CH:8][C:9]([C:10]#[N:11])=[CH:12][CH:13]=2)[N:3]=1
Reactant: N#Cc1ccc(-c2cocn2)cc1
Reactant: II
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2coc(I)n2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 68.4 %

Procedure:
4-(1,3-Oxazol-4-yl)benzonitrile (130 mg, 0.76 mmol), prepared in the previous step, was dissolved in tetrahydrofuran (10 mL) and cooled to −78° C. Sodium bis(trimethylsilyl)amide (1M solution in tetrahydrofuran) (0.84 mL, 0.84 mmol) was added dropwise and the mixture was stirred for 30 min. A solution of iodine (0.23 g, 0.91 mmol) in tetrahydrofuran (5 mL) was added dropwise and the mixture was stirred at −78° C. for 1 h. The mixture was poured into a 1:1 mixture of aqueous sodium bicarbonate and sodium sulfite and extracted with methylene chloride. The organics were combined, washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated. Flash chromatography (10% acetone in hexane) afforded 4-(2-iodo-1,3-oxazol-4-yl)benzonitrile (154 mg, 69%) as a white solid. HRMS: calcd for C10H51N2O, 295.94466; found (EI, M+), 295.9436; Analytical HPLC: purity 99.3% at 274 nm, 8.9 min; 99.5% at 210-370 nm, 8.9 min; the Xterra® RP18 column, 3.5%, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9](/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:8][C@@H:7]([N:17]2[CH:24]=[C:23]([CH2:25][CH3:26])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[CH2:6]1)(=[O:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:8][C@@H:7]([N:17]2[CH:24]=[C:23]([CH2:25][CH3:26])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)/C=C/[C@H]1O[C@@H](n2cc(CC)c(=O)[nH]c2=O)C[C@@H]1OC(C)=O
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC[C@H]1O[C@@H](n2cc(CC)c(=O)[nH]c2=O)C[C@@H]1OC(C)=O
Yield: 79 %

Procedure:
A solution of 7.3 g of trans-3'-O-acetyl-2',5'-dideoxy-5'-(ethoxycarbonylmethylene)-5-ethyluridine in 150 ml of ethanol was hydrogenated over 0.5 g of 10% palladium-on-carbon catalyst for 6 hours. The catalyst was removed by filtration and the filtrate was evaporated to dryness. The residue was recrystallized from ethanol to give 5.8 g of 3'-O-acetyl-2',5'-dideoxy-5'-(ethoxycarbonylmethyl)-5-ethyluridine in the form of a white solid of melting point 137°-138° C.