Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[NH:17][C:16]2=[O:24])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:25]1(B(O)O)[CH2:27][CH2:26]1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[N:17]([CH:25]3[CH2:27][CH2:26]3)[C:16]2=[O:24])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2cccnc2n1-c1ccc(OCc2ccccc2)cc1
Reactant: OB(O)C1CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=c1n(-c2ccc(OCc3ccccc3)cc2)c2ncccc2n1C1CC1
Temperature: 140 °C
Yield: 35.5 %

Procedure:
The mixture of 3-[4-(benzyloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (300 mg), cyclopropylboronic acid (731 mg), TEA (1976 μl), pyridine (1835 μl), copper(II) acetate (1030 mg) and THF (4727 μl) was heated at 140° C. for 30 min under microwave irradiation. The solid was removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0%-30% EtOAc in hexane) to give 3-[4-(benzyloxy)phenyl]-1-cyclopropyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (120 mg) as white crystals.
Reaction SMILES: [F:1][CH:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=O)[CH2:3]1.[OH-].[K+].[Cl:12][C:13]1[C:18]([O:19][CH:20]([CH3:22])[CH3:21])=[CH:17][C:16]([N:23]=[C:24]=[S:25])=[C:15]([F:26])[CH:14]=1.C1(N=C=NC2CCCCC2)CCCCC1>CO.O.C(#N)C>[Cl:12][C:13]1[C:18]([O:19][CH:20]([CH3:21])[CH3:22])=[CH:17][C:16]([N:23]=[C:24]2[N:5]3[CH2:6][CH:2]([F:1])[CH2:3][CH:4]3[C:7](=[O:9])[S:25]2)=[C:15]([F:26])[CH:14]=1
Reactant: O=C(O)[C@@H]1CC(F)CN1
Reactant: CC(C)Oc1cc(N=C=S)c(F)cc1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CC#N
Solvent: O
Product: CC(C)Oc1cc(N=C2SC(=O)C3CC(F)CN23)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
A mixture of 1.31 g (0.01 mol) 4-fluoroproline, 30 mL 2N KOH in methanol and 10 mL water is prepared before 2.46 g (0.01 mol) 4-chloro-2-fluoro-5-isopropoxy-phenylisothiocyanate dissolved in 250 mL methanol is added dropwise. The reaction mixture is stirred overnight at room temperature, the aqueous phase adjusted to pH 2 and the resultant product (3.77 g, See Formula X) is filtered. The compound thus obtained is dissolved in 50 mL acetonitrile before 2.59 g (0.01 mol) dicyclohexylcarbodiimide is added at room temperature. The reaction mixture is stirred for 3 h and the crude product is purified by silica gel chromatography to give 3.24 g (85% yield) of the desired product.
Reaction SMILES: C([Li])CCC.[CH2:6]([N:8]([CH2:11][C:12]#[CH:13])[CH2:9][CH3:10])[CH3:7].[Cl:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[CH3:20].Cl>CCCCCC.O1CCCC1>[Cl:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])([CH3:20])[C:13]#[C:12][CH2:11][N:8]([CH2:9][CH3:10])[CH2:6][CH3:7]
Reactant: CC(=O)CCCCCl
Reactant: C#CCN(CC)CC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCN(CC)CC#CC(C)(O)CCCCCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
12.37 ml (19.8 mmol) of a 1.6 M solution of n-butyllithium in n-hexane were slowly added dropwise to a solution of 2.0 g (18 mmol) of N,N-diethyl-2-propynylamine (Example 1C1)) in 50 ml of tetrahydrofuran at -78° C. After one hour at -78° C., the mixture was warmed to room temperature, and 2.42 g (18 mmol) of 1-chloro-5-hexanone were added. Stirring at room temperature for one hour was followed by adjustment to pH 7 with 2 N hydrochloric acid and partitioning between 5% strength sodium bicarbonate solution and dichloromethane. The organic phase was dried over magnesium sulfate, the solvent was removed under reduced pressure. Yield: 4.38 (99% of theory); oily product
Reaction SMILES: [Cl-].[NH4+].[CH3:3][NH:4][C:5](=[O:15])[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1>O.CO.C1COCC1.[Zn]>[NH2:12][C:9]1[CH:8]=[CH:7][C:6]([C:5]([NH:4][CH3:3])=[O:15])=[CH:11][CH:10]=1
Reactant: CNC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(N)cc1
Reaction time: 0.25 h
Yield: 86.5 %

Procedure:
Ammonium chloride (29.6 g, 55.4 mmol) in water (200 mL) and methanol (200 mL) was added to a solution of N-methyl-4-nitro-benzamide (10 g, 55.4 mmol) in THF (160 mL). Zinc powder (29 g, 44.4 mmol) was added portion wise and the mixture stirred for 15 minutes. The reaction mixture was filtered over celite, the filtrate was then concentrated and extracted with ethyl acetate. The organics were washed with brine solution, dried over Na2SO4 and concentrated to afford 7.2 g (86%) of 4-amino-N-methyl-benzamide. 1H NMR: (DMSO-d6): δ 7.9 (s, 1H), 7.6 (d, 2H), 6.5 (d, 2H), 5.6 (s, 2H), 2.7 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:22]([N:24]([CH2:38][CH3:39])[CH2:25][CH2:26][CH2:27][C:28]1[N:33]=[C:32]2[CH2:34][O:35][C:36](=O)[C:31]2=[CH:30][CH:29]=1)[CH3:23].C1(C2C(=CC=CC=2)CO1)=O.Cl.C([O-])(O)=O.[Na+]>C1COCC1>[CH2:38]([N:24]([CH2:22][CH3:23])[CH2:25][CH2:26][CH2:27][C:28]1[N:33]=[C:32]2[CH2:34][O:35][C:36](=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=4)[NH:7][C:6]3=[O:11])[C:31]2=[CH:30][CH:29]=1)[CH3:39]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: CCN(CC)CCCc1ccc2c(n1)COC2=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: CCN(CC)CCCc1ccc2c(n1)COC2=C1C(=O)Nc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 36.7 %

Procedure:
A solution of 5-Fluoro-1,3-dihydro-indol-2-one (100 mg) in anhydrous. THF (5 mL) at room temperature is treated with lithium bis(trimethylsilyl)amide (1.0 M solution in tetrahydrofuran, 1.33 mL, 6 equiv). The resulting mixture is stirred at room temperature for 10 min, then is added 2-(3-diethylamino-propyl)-7H-furo[3,4-b]pyridin-5-one (55 mg, 1 equiv) in one portion. The reaction mixture is stirred at room temperature until both TLC and HPLC indicated the disappearance of the phthalide. The reaction mixture is poured into 10% aqueous HCl solution (10 mL) with stirring. Then it is heated at 50° C. for 2 h and further stirred at room temperature for an overnight. The mixture is poured into 100 mL ice water, to which solid NaHCO3 is carefully added to adjust pH to 8. The aqueous layer is extracted with EtOAc (2×). Organic layer is combined, dried with anhydrous Na2SO4, filtered and concentrated. The residue obtained purified by chromatography (silica gel, MeOH-chloroform) to give the title compound as a yellow solid (31 mg, 37%).
Reaction SMILES: [S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[CH:3][CH:2]1[C:11]([OH:13])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O=S1(=O)C2C=CC=CC=2N=CC1C(O)=O>CN(C=O)C.C(OC(=O)C)C>[CH2:26]([NH:33][C:11]([CH:2]1[CH:3]=[N:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[S:1]1)=[O:13])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(O)C1C=Nc2ccccc2S1
Reactant: NCc1ccccc1
Agent: O=C(O)C1C=Nc2ccccc2S1(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NCc1ccccc1)C1C=Nc2ccccc2S1
Temperature: 80 °C
Yield: 34.4 %

Procedure:
A solution of 1,4-benzothiazine-2-carboxlic acid (70 mg, 0.36 mmol) and 1,1′-carbonyldiimidazole (70 mg, 0.43 mmole) in DMF ( 5 mL) is stirred at 80° C. for 30 mins. It is then treated with benzylamine (0.05 mL, 0.43 mmol) and heated at 80° C. for 1 h. The reaction mixture is cooled to room temperature, taken up with ethylacetate, and extracted with water (3×10 mL). The organic layer is dried over sodium sulfate and concentrated. The solid is filtered and washed with ethylacetate to give N-benzyl-1,4-benzothiazine-2-carboxamide (35 mg, 35% yield) as a white solid (compound 1), m.p. 160-162° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([N:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][N:23]2C(=O)C3=CC=CC=C3C2=O)[CH2:17][CH2:16]1)[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1.O.NN>>[NH2:23][CH2:22][CH2:21][N:18]1[CH2:17][CH2:16][N:15]([CH:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:8]2[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=2)[CH2:20][CH2:19]1
Reactant: O=C1c2ccccc2C(=O)N1CCN1CCN(C(c2ccc(F)cc2)c2ccccn2)CC1
Agent: NN
Solvent: O
Product: NCCN1CCN(C(c2ccc(F)cc2)c2ccccn2)CC1
Yield: 88 %

Procedure:
The title compound was prepared in a yield of 88% in a similar manner to that described in Preparation 15' by reacting 4-[α-(2-pyridyl)-4-fluorobenzyl]-1-(2-phthalimidoethyl)piperazine (prepared as described in Preparation 51') and hydrazine hydrate.
Reaction SMILES: COC([C:5]1[C:6]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[C:14]3[CH2:20][C@H:21]2[CH2:25][CH2:24][CH2:23][N:22]2[CH3:26])=[N:7][CH:8]=[CH:9][CH:10]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].[O:33]1CCC[CH2:34]1>>[OH:33][CH2:34][C:8]1[N:7]=[C:6]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[C:14]3[CH2:20][C@H:21]2[CH2:25][CH2:24][CH2:23][N:22]2[CH3:26])[CH:5]=[CH:10][CH:9]=1
Reactant: COC(=O)c1cccnc1-c1ccc2[nH]cc(C[C@H]3CCCN3C)c2c1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CN1CCC[C@@H]1Cc1c[nH]c2ccc(-c3cccc(CO)n3)cc12

Procedure:
A solution of 5-(3-MethoxycarbonyI-2-pyridyl)-3-(1-methylpyrrolidin-2(R)-ylmethyl)-1H-indole (393 mg, 1.073 mmol) (see Example 62) in tetrahydrofuran (2.5 ml) was added dropwise, with stirring, to a flask containing a solution of lithium aluminium hydride in tetrahydrofuran (35.9 mg of LiAIH4 in 10.0 ml THF) under a nitrogen atmosphere. The reaction was stirred for 24 hours whereupon the reaction mixture was quenched with aqueous sodium carbonate and the aqueous phase extracted with ethyl acetate. The combined organic layers were dried (Na2SO4) and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with dichloromethane/methanol/ammonium hydroxide (90:10:0.7), to afford, after combination and evaporation of the appropriate fractions, the title compound as a white foam (298 mg). Found: C,71.55; H,6.93; N,12.20. C20H22N3O.1/5CH2Cl2 requires: C,71.70; H,6.97; N,12.42%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:10])=[C:4]([NH:8][NH2:9])[CH:5]=[CH:6][CH:7]=1.[C:11]([O:16][CH2:17][CH3:18])(=[O:15])[C:12]([CH3:14])=O>>[CH2:17]([O:16][C:11](=[O:15])[C:12](=[N:9][NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[F:10])[CH3:14])[CH3:18]
Reactant: NNc1cccc(Cl)c1F
Reactant: CCOC(=O)C(C)=O
Product: CCOC(=O)C(C)=NNc1cccc(Cl)c1F

Procedure:
The title compound, EI-MS: m/e=258.1 (M+), was prepared in accordance with the general method of example 32d) from (3-Chloro-2-fluoro-phenyl)-hydrazine and ethyl pyruvate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:19]=1)(O)[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.C(O)(=O)C.O>ClCCl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:19]=1)=[CH2:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(O)(c1cccc(-c2ccccc2)n1)c1ccccc1OCc1ccccc1
Agent: Br
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: C=C(c1cccc(-c2ccccc2)n1)c1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.1 %

Procedure:
A mixture of 17.0 g (44.5 mmol) of 18, 220 mL of 40% HBr, and 440 mL of glacial acetic acid was refluxed for 10 hr, and then additionally stirred for 12 hr at room temperature. To the resulting mixture 2000 mL of water and 500 mL of dichloromethane were added. The organic layer was separated, and the aqueous layer was extracted with 2×200 mL of dichloromethane. The combined organic extract was washed with saturated aqueous NaHCO3, dried over K2CO3, and then evaporated to dryness. This procedure gave 15.7 g (97%) of 19 which was further used without an additional purification.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][C:23]=3[C:24]([F:27])([F:26])[F:25])[S:16][CH:17]=2)=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].[OH-].[Na+].Cl>C(O)C>[F:1][C:2]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][C:23]=3[C:24]([F:27])([F:25])[F:26])[S:16][CH:17]=2)=[CH:9][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)c1cc(-c2csc(-c3cnccc3C(F)(F)F)n2)ccc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc(-c2csc(-c3cnccc3C(F)(F)F)n2)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
Ethyl 2-fluoro-5-{2-[4-(trifluoromethyl)pyridin-3-yl]-1,3-thiazol-4-yl}benzoate (1.00 g) was suspended in a mixture of ethanol (20 ml)/1N NaOH (5 ml) and the mixture was stirred at room temperature for one hr. 1N Hydrochloric acid (5 ml) was added to the reaction mixture, and the precipitated crystals were collected by filtration and washed with water to give the title compound (0.86 g) as a pale-brown powder.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23](Br)[CH:22]=3)[C@H:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([NH:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH:22]=3)[C@H:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: Nc1ccccc1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](c2cccc(Br)c2)[C@H](c2ccccc2)C1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](c2cccc(Nc3ccccc3)c2)[C@H](c2ccccc2)C1

Procedure:
The title compound, MS: m/e=569.2 (M+), was prepared in accordance with the general method of example 10 from rac-cis-(3,5-bis-trifluoromethyl-phenyl)-[4-(3-bromo-phenyl)-3-phenyl-piperidin-1-yl]-methanone and aniline.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(#N)C>[I:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:23])=[O:22])=[CH:4][CH:3]=1
Reactant: Nc1ccc(I)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CC#N
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(I)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2.0 g of 4-iodoaniline (9.13 mmol) in 40 ml of acetonitrile there are added 1.48 ml of pyridine (18.26 mmol) and then, dropwise, a solution of 1.28 ml of benzenesulphonyl chloride (10 mmol) in 20 ml of acetonitrile. The reaction mixture is stirred overnight at ambient temperature and the acetonitrile is evaporated off under reduced pressure. The residue is taken up in 1N HCl and extracted with ethyl acetate. The organic phase is washed with brine, dried (MgSO4) and evaporated under reduced pressure. The oily residue obtained is triturated in isopropyl ether until the title product crystallises.
Reaction SMILES: C([C:5]1[CH:6]=[C:7]([CH:16]([C:19]2[CH:24]=[C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:22]([OH:29])=[C:21]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:20]=2)CCl)C=C(C(C)(C)C)C=1O)(C)(C)C.[C:34]([O-:37])(=O)[CH3:35].[Na+]>C(O)(=O)C>[C:30]([C:21]1[CH:20]=[C:19]([CH:16]=[CH:7][C:6]2[CH:5]=[C:35]([C:23]([CH3:25])([CH3:24])[CH3:22])[C:34]([OH:37])=[C:21]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:20]=2)[CH:24]=[C:23]([C:25]([CH3:27])([CH3:26])[CH3:28])[C:22]=1[OH:29])([CH3:32])([CH3:31])[CH3:33]
Reactant: CC(=O)[O-]
Reactant: CC(C)(C)c1cc(C(CCl)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(C=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Yield: 162.4 %

Procedure:
To a 100 milliliter round-bottomed flask equipped with a magnetic stirrer and a reflux condenser capped with a paraffin-sealed gas bubbler was added 9.45 grams (0.022 mole) of 1,1-bis(3,5-di-t-butyl-4-hydroxyphenyl)-2-chloroethane (from EXAMPLE 10 above), 20 milliliters of glacial acetic acid, and 2.0 grams (0.024 mole) of anhydrous sodium acetate. The mixture was stirred and heated to reflux for 4 hours. The resulting homogeneous solution was cooled to ambient temperatures to induce crystallization of the product. The precipitated solid material was collected by suction filtration, washed successively with acetic acid and water, and dried to yield 7.8 grams (90 percent) of 3,5,3',5'-tetra-t-butyl-4,4'-dihydroxystilbene, which identity was confirmed by nuclear magnetic resonance spectroscopy.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:17][O:16][C@H:15]([CH2:18]O)[C@H:14]1[CH2:13][S:12][C:11]([NH:20][C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[N:10]2.C(N(CC)CC)C.[F:36]C(F)(C(F)(F)F)C(F)(F)C(F)(F)S(F)(=O)=O>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:17][O:16][C@H:15]([CH2:18][F:36])[C@H:14]1[CH2:13][S:12][C:11]([NH:20][C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[N:10]2
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: O=C(NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@H](CO)[C@H]2CS1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@H](CF)[C@H]2CS1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 65.6 %

Procedure:
A solution of N-((4aS,5S,7aS)-7a-(2,4-difluorophenyl)-5-(hydroxymethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)benzamide (2.2 g, 5.44 mmol) in dry THF (40 mL) under nitrogen was cooled to 0° C. Triethylamine (4.55 mL, 32.6 mmol), triethylamine tri-hydrogen fluoride (1.77 mL, 10.9 mmol) and nonafluorobutanesulfonyl fluoride (1.95 mL, 10.9 mmol) were then added. The colourless solution was stirred at 0° C. for 10 minutes and then removed from the ice bath. After 120 minutes at RT, the reaction was quenched with saturated aqueous NaHCO3 (25 mL). The THF was removed in vacuo and then the mixture was partitioned between EtOAc and water. The layers were separated and the aqueous layer was further extracted with EtOAc (×2). The combined extracts were washed with brine (×1), then dried (Na2SO4), filtered and evaporated. The residue was treated with DCM (˜20 mL) to give a gelatinous precipitate. This mixture was filtered (washing with DCM). The filtrate was concentrated to ˜3 mL and loaded directly on to the column and purified by chromatography (normal phase, 50 g, Biotage SNAP cartridge KP-Sil, 50 mL per mm, gradient 5% to 35% n-hexane in EtOAc) to give the title compound (1.45 g). 1H NMR (400 MHz, MeOH-d4) δ ppm: 2.97 (br. d, J=13.00 Hz, 1 H) 3.10-3.28 (m, 2 H) 4.02 (br. s., 1 H) 4.45-4.61 (m, 3 H) 4.62-4.71 (m, 1 H) 6.98-7.12 (m, 2 H) 7.40-7.51 (m, 2 H) 7.51-7.62 (m, 2 H) 8.03 (br. s., 2 H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:12][O:13][CH:14]2[CH:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][O:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[O:38][CH3:39])=[CH:22][CH:21]=3)[CH2:18][CH2:17][N:16]([C:40]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:41])[CH2:15]2)=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH3:11].[H-].[Na+].Cl[CH2:53][C:54]#[N:55].[Cl-].[NH4+]>CN1C(=O)N(C)CCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:1][C:2]1[C:3]([CH2:12][O:13][CH:14]2[CH:19]([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][CH2:29][O:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[O:38][CH3:39])=[CH:24][CH:25]=3)[CH2:18][CH2:17][N:16]([C:40]([O:42][CH2:43][C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)=[O:41])[CH2:15]2)=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:53][C:54]#[N:55])[CH:8]=[C:7]2[CH3:11]
Reactant: N#CCCl
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2ccc3c(C)c[nH]c3c2Br)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [H-]
Solvent: CN1CCCN(C)C1=O
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2ccc3c(C)cn(CC#N)c3c2Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The solution of 3.38 g of benzyl 3-(7-bromo-3-methyl-1H-indol-6-ylmethoxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate (Example 21b) in 46 ml of DMPU is admixed with stirring at 0° C. with 0.367 g of sodium hydride dispersion (60%). The mixture is stirred at 0° C. over 30 minutes and then admixed with 0.323 ml of chloroacetonitrile and 0.172 g of tetrabutylammonium iodide. The reaction mixture is stirred at room temperature over 16 hours, poured onto 1M ammonium chloride solution and extracted with tert-butyl methyl ether (2×300 ml). The organic phases are washed successively with water (300 ml) and brine (300 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a white foam from the residue by means of flash chromatography (SiO2 60F). Rf=0.33 (1:1 EtOAc-heptane); Rt=6.10.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([N+:13]([O-])=O)[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:16][C:17]1[CH:18]=[C:19]([CH2:24][C:25]([NH:27][CH:28]([CH2:32][CH2:33][CH3:34])[C:29](O)=[O:30])=[O:26])[CH:20]=[C:21]([F:23])[CH:22]=1>>[CH2:1]([N:8]1[CH:12]=[C:11]([NH:13][C:29](=[O:30])[CH:28]([NH:27][C:25](=[O:26])[CH2:24][C:19]2[CH:20]=[C:21]([F:23])[CH:22]=[C:17]([F:16])[CH:18]=2)[CH2:32][CH2:33][CH3:34])[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: O=[N+]([O-])c1cn(Cc2ccccc2)cn1
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(Cc2ccccc2)cn1

Procedure:
1-Benzyl-4-nitro-1H-imidazole was reduced and coupled with 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid to afford the title compound; MS 470 m/z (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:18]3[NH:25][C:24]([C:26]4[CH:27]=[C:28]([CH:38]=[CH:39][CH:40]=4)[CH2:29][NH:30]C(=O)OC(C)(C)C)=[CH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1.Cl.[OH-].[Na+]>O1CCCC1>[NH2:30][CH2:29][C:28]1[CH:27]=[C:26]([C:24]2[NH:25][C:18]3[C:17]([NH:16][C:4]4[CH:5]=[CH:6][C:7]([O:8][C:9]5[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=5)=[C:2]([CH3:1])[CH:3]=4)=[N:22][CH:21]=[N:20][C:19]=3[CH:23]=2)[CH:40]=[CH:39][CH:38]=1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4cc(-c5cccc(CNC(=O)OC(C)(C)C)c5)[nH]c34)cc2C)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(Oc2ccc(Nc3ncnc4cc(-c5cccc(CN)c5)[nH]c34)cc2C)cn1
Temperature: 60 °C
Yield: 87.7 %

Procedure:
tert-Butyl 3-[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-6-yl]benzylcarbamate (230 mg) was suspended in tetrahydrofuran (2.3 mL), 2N hydrochloric acid (2.3 mL) was added, and the mixture was stirred with heating at 60° C. for 3 hrs. After cooling to room temperature, 1N aqueous sodium hydroxide solution (4.6 mL) was added, and the mixture was stirred at room temperature for 5 min. The solvent was removed by decantation, and the residue was dissolved in tetrahydrofuran (30 mL), dried over potassium carbonate, and concentrated under reduced pressure. The residue was triturated with diisopropyl ether, collected by filtration and dried under reduced pressure to give the title compound (164 mg).
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH2:34][OH:35])([CH2:32][OH:33])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[C:13]([C:28]([F:31])([F:30])[F:29])[CH:12]=1)(C)(C)C.[ClH:37].O1CCOCC1>C(Cl)Cl>[ClH:37].[NH2:7][C:8]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[C:13]([C:28]([F:29])([F:30])[F:31])[CH:12]=1)([CH2:32][OH:33])[CH2:34][OH:35]
Reactant: CC(C)(C)OC(=O)NC(CO)(CO)CCc1ccc(OCCCCC2CCCCC2)c(C(F)(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC(CO)(CO)CCc1ccc(OCCCCC2CCCCC2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Compound 3-8 (520 mg) was dissolved in methylene chloride (5 ml), hydrogen chloride-containing dioxane (4 mol/l 5 ml) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (410 mg) as a white powder.