Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@H:8]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([C:24]#[N:25])=[N:18][C:19]=3Cl)[O:7][C@@H:6]1[CH2:26][O:27][C:28](=[O:30])[CH3:29])(=[O:3])[CH3:2].[CH3:31][C:32]1[CH:33]=[C:34]([CH:38]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([CH3:47])[CH:42]=2)[CH2:39][NH2:40])[CH:35]=[CH:36][CH:37]=1>>[C:1]([O:4][C@H:5]1[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@H:8]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([C:24]#[N:25])=[N:18][C:19]=3[NH:40][CH2:39][CH:38]([C:34]2[CH:35]=[CH:36][CH:37]=[C:32]([CH3:31])[CH:33]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([CH3:47])[CH:42]=2)[O:7][C@@H:6]1[CH2:26][O:27][C:28](=[O:30])[CH3:29])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(C#N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Cc1cccc(C(CN)c2cccc(C)c2)c1
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NCC(c4cccc(C)c4)c4cccc(C)c4)nc(C#N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
The title compound was prepared from (2R,3R,4R,5R)-4-(acetyloxy)-2-[(acetyloxy)methyl]-5-(6-chloro-2-cyano-9H-purin-9-yl)tetrahydro-3-furanyl acetate (Preparation 45) and 2,2-bis(3-methylphenyl)ethanamine (J. Med. Chem., 1988, 31(7), 1282) using a similar procedure to that of Preparation 64.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[CH2:12]([O:14][CH:15]([O:18][CH2:19][CH3:20])[CH2:16]Cl)[CH3:13]>O>[CH2:12]([O:14][CH:15]([O:18][CH2:19][CH3:20])[CH2:16][O:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[CH:6][CH:7]=1)[CH3:13]
Reactant: COc1ccc(O)cc1
Reactant: CCOC(CCl)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCOC(COc1ccc(OC)cc1)OCC
Yield: 47.1 %

Procedure:
Potassium hydroxide pellets (22.4 g) and molten p-methoxyphenol (50 g) were heated with stirring to a temperature in the range from 90° to 100° C. until a clear solution was obtained. Chloroacetaldehyde diethylacetal (120 g) was added at such a rate to maintain the temperature in the range from 90° to 100° C. and after stirring for a further 15 minutes water was removed from the flask as an azeotrope with chloroacetaldehyde diethylacetal, the water and acetal were separated and the acetal was returned to the reaction mixture. Azeotropic distillation was continued until the temperature of the vapour reached 140°-150° C. and then the reaction mixture was heated under reflux for a further 6 hr. Water (200 ml) was added to the cooled mixture which was then extracted with chloroform (2×200 ml). The choroform extracts were washed with aqueous 2 N sodium hydroxide (100 ml) to remove unreacted phenols and the chloroform layer was dried over Na2SO4 and the solvent removed by distillation under reduced pressure. The crude product was distilled under reduced pressure to give, as a third fraction, p-methoxyphenoxyacetaldehyde diethyl acetal (45.6 g) of b.p. 180°-194° C. at 44 mm the product being characterised by p.m.r. spectroscopy.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[CH3:16][C:17]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:18]=1[OH:24].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:2]([O:24][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([CH3:23])[C:17]=1[CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: Cc1cccc(O)c1C
Reactant: CCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCCCCCCCCCCOc1cccc(C)c1C
Yield: 77.7 %

Procedure:
The product was generated via general protocol A using 1-bromotetradecane (45.0 mL, 147.9 mmol), 2,3-dimethylphenol (20.15 g, 163.3 mmol), K2CO3 (81.76 g, 591.6 mmol) and CH3CN (200 mL). Yielded 36.6 g (77.7%) of a brown liquid. 1H NMR (CDCl3, 400 MHz) δ: 7.03 (t, 3J=7.8 Hz, 1H, Ar—H), 6.76 (d, 3J=7.4 Hz, 1H, Ar—H), 6.70 (d, 3J=8.1 Hz, 1H, Ar—H), 3.93 (t, 3J=6.5, 2H, O—CH2), 2.27 (s, 3H, Ar—CH3), 2.16 (s, 3H, Ar—CH3), 1.79 (p, 3J=6.9, 2H, O—CH2—CH2), 1.48 (p, 3J=7.1, 2H, O—CH2—CH2—CH2), 1.27 (m, 22H), 0.88 (t, 3J=6.3, 3H, CH2—CH3). 13C NMR (CDCl3, 100 MHz) δ: 157.20, 137.86, 125.84, 125.33, 122.08, 108.98, 68.23, 32.07, 29.86, 29.83, 29.78, 29.61, 29.58, 29.54, 26.33, 22.88, 20.17, 14.24, 11.70.
Reaction SMILES: S(C)C.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([Mg]Br)=[CH:7][CH:6]=1.B(F)(F)F.CCOCC.[CH2:22]([CH:24]1[CH2:29][C:28](=[O:30])[CH:27]=[CH:26][N:25]1[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[CH3:23].[NH4+].[Cl-].[NH4+].[OH-]>C1COCC1>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH:26]2[CH2:27][C:28](=[O:30])[CH2:29][CH:24]([CH2:22][CH3:23])[N:25]2[C:31]([O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[O:32])=[CH:7][CH:6]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: CCC1CC(=O)C=CN1C(=O)OCc1ccccc1
Agent: FB(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CSC
Solvent: CCOCC
Product: CCC1CC(=O)CC(c2ccc(Cl)cc2)N1C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 33.3 %

Procedure:
CuBr.SMe2 (5.6 g, 27.2 mmol) was added to dry THF (64 mL). It was cooled to −78° C. 4-Chlorophenylmagnesium bromide (27.2 mL, 1 M in THF, 27.2 mmol) was added to the mixture slowly over 1 hr at −78° C. Then BF3.Et2O (3.44 mL, 27.2 mmol) was added and the mixture was stirred for 5 min. Then ketone 82 (4 g, 8.1 mmol) in THF (55 mL) was added slowly over 1 hr at −78° C. After 2 hr stirring at −78° C., an aqueous solution of NH4Cl/conc. NH4OH (1:1, 20%, 60 mL) was added. The mixture was warmed to rt and extracted with EtOAc (200 mL×3), The combined organic layers were washed with brine, dried and concentrated to a residue and purified by silica gel chromatography (0-40% EtOAc/hexanes) to afford pure 83 (1 g, 2.7 mmol, 33%) as a mixture of cis stereoisomers.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([OH:21])[C:14]([C:22]3[CH:26]=[CH:25][O:24][CH:23]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:27][N:28]([CH3:32])[CH2:29][CH2:30]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([O:21][CH2:30][CH2:29][N:28]([CH3:32])[CH3:27])[C:14]([C:22]3[CH:26]=[CH:25][O:24][CH:23]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN(C)CCO
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1OCCN(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
A mixture of methyl 6-(benzenesulphonylmethyl)-3-(furan-3-yl)-2-hydroxybenzoate (Intermediate 114, 0.08 g), N,N-dimethylethanolamine (0.024 g) and triphenylphosphine (0.085 g) in dry THF (1 ml) was stirred and cooled to 0° C. A solution of di-isopropyl azodicarboxylate (0.065 g) in dry THF (1 ml) was added dropwise. The resultant mixture was stirred at 0° C. for 10 minutes then at room temperature overnight. Further triphenylphosphine (0.028 g) and di-isopropyl azodicarboxylate (0.022 g) was added and the mixture was stirred at room temperature for 1.5 hours then left to stand at room temperature overnight. The mixture was added to a SCX-2 column and eluted with acetonitrile followed by 2M ammonia in methanol. After evaporation of the basic eluent, the residue was repurified using an SCX-2 column, eluting with methanol followed by 2M ammonia in methanol to give methyl 6-(benzenesulphonylmethyl)-2-(2-dimethylaminoethoxy)-3-(furan-3-yl)benzoate (0.07 g) as a gum.
Reaction SMILES: C[C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([CH3:13])=[O:12])=[CH:6][CH:5]=1)=[O:3].C(=[O:16])C.C(OC(=O)C)(=O)C.C(O)(=O)C>C(OCC)(=O)C.[Cr].[Co].O.O.O.O.C([O-])(=O)C.[Mn+2].C([O-])(=O)C>[C:11]([O:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]([OH:3])=[O:16])=[CH:5][CH:6]=1)(=[O:12])[CH3:13]
Reactant: CC=O
Reactant: CC(=O)Oc1ccc(C(C)=O)cc1
Agent: [Co]
Agent: [Cr]
Agent: [Mn+2]
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Oc1ccc(C(=O)O)cc1
Reaction time: 3 h

Procedure:
A 300 cc Hastelloy C autoclave was charged with 17.8 g (0.1 mol) of 4-acetoxy acetophenone (4-AAP), 0.25 g of manganese (II) acetate tetrahydrate, 1.0 g of acetaldehyde, 25 g of acetic anhydride, and 125 g of acetic acid. An oxygen/nitrogen mixture was sparged into the autoclave at 1000 cc/min such that 5% oxygen was maintained in the vent. A 10% acetaldehyde in acetic acid solution was fed at a rate of 3.0 cc/h. The reaction was run at 150° C. and 100 psig for 3 h. using a stirring speed of 1000 rpm whereupon the acetic acid and acetic anhydride were removed on a rotary evaporator to yield orange crystals. The crystals were dissolved in ca. 150 mL of ethyl acetate and the solution was extracted with 100 mL of water (3×). The organic phase was dried over anhydrous magnesium sulfate, filtered, and the solvent was removed on a rotary evaporator to yield 4-acetoxybenzoic acid (4-ABA) at a conversion of 92.7% based on 4-HAP and with 55.1% selectivity to 4-ABA.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[CH:7]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:8][S:9](=[O:24])(=[O:23])[CH2:10][CH2:11][NH:12]C(OCC1C=CC=CC=1)=O)([CH3:4])([CH3:3])[CH3:2]>C(O)=O.CO.[Pd]>[CH:6]([OH:33])=[O:5].[C:1]([O:5][C:6](=[O:33])[CH:7]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:8][S:9](=[O:23])(=[O:24])[CH2:10][CH2:11][NH2:12])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(CS(=O)(=O)CCNC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Product: CC(C)(C)OC(=O)NC(CS(=O)(=O)CCN)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 178.3 %

Procedure:
t-Butyl-6-benzyloxycarbonylamino-2-t-butoxycarbonylamino-4,4-dioxo-4-thiahexanoate 152 mg) dissolved in 5% formic acid/methanol (8 ml) was added dropwise to a stirred suspension of 10% Pd/C in 5% formic acid/methanol (2 ml) at 0° C. The reaction mixture was stirred at 0° C. for 1 h then at room temperature for 1-2 h. The reaction mixture was filtered through hyflo, and the catalyst washed with methanol (25 ml) and water (25 ml). The filtrate was concentrated to one quarter volume in vacuo and diluted with water (25 ml). This process was repeated twice then evaporated to dryness in vacuo. The residue was dissolved in water and lyophilised to give an off-white solid (111 mg).
Reaction SMILES: [F:1][C:2]1[N:6](COCC[Si](C)(C)C)[CH:5]=[N:4][C:3]=1[CH2:15][N:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1CCCCC1>O1CCCC1>[F:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:15][N:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1
Reactant: C[Si](C)(C)CCOCn1cnc(CN2CCCc3ccccc32)c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: Fc1[nH]cnc1CN1CCCc2ccccc21
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 48.6 %

Procedure:
To a stirred solution of 1-[5-fluoro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-ylmethyl]-1,2,3,4-tetrahydroquinoline (103 mg) at room temperature in tetrahydrofuran (THF) (5 ml) under an argon atmosphere was added tetra-n-butylammonium fluoride (TBAF) (1.1 ml; 1 M solution in THF). The mixture was heated to 60° C. and stirring at that temperature was continued for 20 minutes, then the mixture was adsorbed directly on silica gel. The crude product was isolated by column chromatography (silica gel; gradient: cyclohexane→ethyl acetate) to give 1-(5-fluoro-1H-imidazol-4-ylmethyl)-1,2,3,4-tetrahydro-quinoline (32 mg) as light yellow solid. (MS (ISP): 232.1 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH2:6].[NH2:7][C:8]1[C:21]2[C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:23])[C:12]=2[C:11]([NH2:24])=[C:10]2[C:25](=[O:29])N[C:27](=[O:28])[C:9]=12.N>>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:25](=[O:29])[C:10]2[C:9](=[C:8]([NH2:7])[C:21]3[C:20](=[O:22])[C:19]4[C:14]([C:13](=[O:23])[C:12]=3[C:11]=2[NH2:24])=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:27]1=[O:28]
Reactant: Nc1c2c(=O)[nH]c(=O)c2c(N)c2c(=O)c3ccccc3c(=O)c12
Reactant: COCCCN
Agent: N
Product: COCCCn1c(=O)c2c(N)c3c(=O)c4ccccc4c(=O)c3c(N)c2c1=O
Temperature: 40 °C
Yield: 130 %

Procedure:
225.2 g of 3-methoxypropylamine are charged to a 750 ml sulfonating flask and heated to 40° C. With stirring, 141.2 g of 1,4-diaminoanthraquinone-2,3-dicarboximide are added over 3 hours. The ensuing reaction is slightly exothermic, with evolution of NH3. The viscous suspension is stirred for another hour at 40°-45° C., then cooled to 20° C. and further stirred for one hour. The precipitated product is filtered with suction and washed with 300 ml of methanol and then with 300 ml of water, affording 226.6 g of N-(3-methoxypropyl)-1,4-diaminoanthraquinone-2,3-dicarboximide [dye of formula (3)]. After optional replenishment with fresh 3-methoxypropylamine, the mother liquor can be re-used for a new batch.
Reaction SMILES: [C:1]([O:15]C)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12]C)=O.[CH3:17][O:18][CH:19]([O:24][CH3:25])[CH2:20][CH2:21][CH2:22][NH2:23]>C[O-].C[O-].C([Sn+2]CCCC)CCC>[CH3:17][O:18][CH:19]([O:24][CH3:25])[CH2:20][CH2:21][CH2:22][NH:23][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([NH:23][CH2:22][CH2:21][CH2:20][CH:19]([O:24][CH3:25])[O:18][CH3:17])=[O:15]
Reactant: COC(=O)CCCCCCCCC(=O)OC
Reactant: COC(CCCN)OC
Agent: CCCC[Sn+2]CCCC
Agent: C[O-]
Product: COC(CCCNC(=O)CCCCCCCCC(=O)NCCCC(OC)OC)OC
Yield: 85.3 %

Procedure:
Dimethyl sebacate (25.00 g, 0.1085 mol) was aminated with 30.63g (0.230 mol) of 4,4-dimethoxybutylamine and 2.50 g (0.00847 mol) of dibutyl tin dimethoxide in 200 g of mixed xylenes according to the procedure used in Example 1. This procedure afforded 40.00 g (0.0925 mol, 85.2% isolated yield) of the desired N,N'-bis(4,4-dimethoxybutyl)sebacamide after recrystallization from mixed xylenes, mp 83.5-85.5° C.; IR (KBr) 1640 (C=O), 1540, 1190, 1135, 1040 cm-1 ; 1H NMR (CDCl3 ; 300 MHz)δ1.13 (br s, 8H, --CH2 --), 1.35-1.58 (m, 12H, --CH2 --), 2.00 (t, 4H, J=7.6 Hz, CO--CH2 --), 3.08 (m, 4H, --NH2CH2 --), 3.16 (s , 12H, --OCH3), 4.20 (t, 2H, J= 5.1 Hz, CH2CH--), 6.38 (t, 2H, J=5.4 Hz, --NH--CH2 --); 13C NMR (CDCl3 ; 75.5 MHz)δ24.3, 25.5, 28.8, 28.9, 29.7, 36.3, 38.8, 52.7, 104.0, 173.0; MS (70eV) m/z (rel. intensity) 353 (1.90), 305 (9.00), 236 (8.14), 128 (6.94), 100 (8.59), 85 (20.70), 84 (40.52), 75 (100.00); HRMS (FAB) 433.3278 (MH+).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH:12]=1)(=O)=O.[Cl:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][C:28]=1[Cl:29].C([O-])([O-])=O.[Na+].[Na+].[NH4+].[Cl-]>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.C1(C)C=CC=CC=1>[Cl:22][C:23]1[CH:24]=[C:25]([C:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH:12]=2)[CH:26]=[CH:27][C:28]=1[Cl:29]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
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: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(Cl)c(Cl)c2)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 80.7 %

Procedure:
To a mixture of 1,1-dimethylethyl 4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydro-1(2H)-pyridinecarboxylate (P52, 500 mg), 3,4-dichlorophenylboronic acid (330 mg) and Pd(PPh3)4 (50 mg) under nitrogen, toluene (6.5 mL), ethanol (5 mL) and Na2CO3 (2M, 5 mL) were added in sequence. The mixture was stirred at 80° C. for 2 hours then the reaction mixture was allowed to reach room temperature. Saturated NH4Cl (30 mL) was poured into the solution and the mixture was transferred in a separator funnel. The mixture was extracted with ethyl acetate (3×40 mL), the combined organic phases were dried on anhydrous Na2SO4 and the solvent evaporated obtaining a crude product that was purified by flash-chromatography (eluting with ethyl acetate/cycloexane 1:9) to give the title compound (400 mg).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:41])[N:10]([CH:12]([C:14](=[O:40])[NH:15][CH:16]([C:21]([N:23]1[CH2:27][CH2:26][CH:25]2[NH:28][CH2:29][CH:30]([O:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[C:34]([F:39])[CH:33]=3)[CH:24]12)=[O:22])[C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:51][S:52](Cl)(=[O:54])=[O:53]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:41])[N:10]([CH:12]([C:14](=[O:40])[NH:15][CH:16]([C:21]([N:23]1[CH2:27][CH2:26][CH:25]2[N:28]([S:52]([CH3:51])(=[O:54])=[O:53])[CH2:29][CH:30]([O:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[C:34]([F:39])[CH:33]=3)[CH:24]12)=[O:22])[C:17]([CH3:19])([CH3:18])[CH3:20])[CH3:13])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C(=O)NC(C(=O)N1CCC2NCC(Oc3ccc(F)c(F)c3)C21)C(C)(C)C)N(C)C(=O)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C(=O)NC(C(=O)N1CCC2C1C(Oc1ccc(F)c(F)c1)CN2S(C)(=O)=O)C(C)(C)C)N(C)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
A solution containing 35 (228 mg, 0.4 mmol), DIPEA (104 mg, 0.8 mmol) and DMAP (cat) in DCM (5 mL) was cooled to 0° C. Methanesulfonyl chloride (55 mg, 0.48 mmol) was added. After 1 h, the reaction mixture was warmed to ambient temperature, diluted with DCM, washed successively with saturated aqueous NaHCO3, 1N HCl, and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by RP-HPLC (2″ Dynamax® C18; 10-100% ACN/water containing 0.1% HOAc over 30 min; Flow: 40 mL/min) to afford compound 36 (190 mg) as a white solid. Mass spectrum, m/z [651.1] (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([NH2:15])=[O:14])[O:10][N:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:26]Br>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:26][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([C:13]([NH2:15])=[O:14])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(CBr)cc1F
Reactant: NC(=O)c1cc(-c2ccc(O)cc2)no1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2ccc(OCc3ccc(F)c(F)c3)cc2)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.7 %

Procedure:
3-(4-Hydroxy-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 2; 50 mg, 0.24 mmol), K2CO3 (37 mg, 0.27 mmol) and tetrabutylammonium iodide (9 mg, 0.024 mmol) were taken up in DMF (2.4 mL). 3,4-Difluorobenzyl bromide (56 mg, 0.27 mmol) was added and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was purified by high-throughput purification to give 3-[4-(3,4-difluoro-benzyloxy)-phenyl]-isoxazole-5-carboxylic acid amide (14 mg, 18%). HRMS Calcd. for C17H13F2N2O (M+H)+, 331.0889. Found: 331.0886.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([OH:16])[C:12]([O:14]C)=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Li+].[OH-]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([OH:16])[C:12]([OH:14])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)C(O)c1ccc(OC)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(C(O)C(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
6B (890 mg, 3.9 mmol) was dissolved in THF (6 mL). 1M LiOH (6 mL) was added, and the reaction was stirred at rt for 1 h. The solvent was removed under reduced pressure, and water (10 mL) was added. The solution was acidified with 1 N HCl, then extracted with ethyl acetate (3×20 mL). The organic layer was concentrated to provide 6C (830 mg, 100%). LC-MS: 235.11 (M+Na)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[C:9]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH:23]=[CH:22][CH:21]=[N:20]4)=[CH:15][C:14]=3[O:24][CH3:25])=[N:10][N:11]([CH3:12])[C:3]=12.C(=O)([O-])[O-].[K+].[K+]>O>[C:13]1([CH:9]=[CH:4][C:2]2[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]3[C:9]([C:13]4[CH:18]=[CH:17][C:16]([N:19]5[CH:23]=[CH:22][CH:21]=[N:20]5)=[CH:15][C:14]=4[O:24][CH3:25])=[N:10][N:11]([CH3:12])[C:3]=23)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1cc(-n2cccn2)ccc1-c1nn(C)c2c(Cl)cc(C)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1cc(-n2cccn2)ccc1-c1nn(C)c2c(C=Cc3ccccc3)cc(C)nc12
Yield: 167.3 %

Procedure:
Compound 5a (0.75 mL of the nominally 1.0 M solution, 0.75 mmol) was added via syringe to 7-chloro-3-[2-methoxy-4-(pyrazol-1-yl)phenyl]-1,5-dimethyl pyrazolo[4,3-b]pyridine (compound 4b, 200 mg, 0.57 mmol) under nitrogen and the mixture was evaporated to dryness. Dioxane (2 mL) and water (2 mL) were added, followed by potassium carbonate (157 mg, 1.14 mmol) and tetrakis (triphenylphosphine)palladium(0) (66 mg, 0.057 mmol). The mixture was stirred and heated to reflux for 6 hr and then was allowed to cool. Water (5 mL) was added and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, concentrated, and the residue was chromatographed on silica gel using 1:2 hexanes/ethyl acetate to afford 7-(2-phenyl-1-ethenyl)-3-[2-methoxy-4-(pyrazol-1-yl)phenyl]-1,5-dimethylpyrazolo[4,3-b]pyridine (compound 5b, 201 mg) as a yellow oil.
Reaction SMILES: CN=C(Cl)Cl.CC1NC=NC=1CSCCN.C1CCN2C(=NCCC2)CC1.[CH3:28][N:29]=[C:30](Cl)[NH:31][CH2:32][CH2:33][S:34][CH2:35][C:36]1[N:37]=[CH:38][NH:39][C:40]=1[CH3:41].[N:43]#[C:44][NH2:45]>C(Cl)Cl>[C:44]([N:45]=[C:30]([NH:31][CH2:32][CH2:33][S:34][CH2:35][C:36]1[N:37]=[CH:38][NH:39][C:40]=1[CH3:41])[NH:29][CH3:28])#[N:43]
Reactant: CN=C(Cl)NCCSCc1nc[nH]c1C
Reactant: N#CN
Agent: CN=C(Cl)Cl
Agent: Cc1[nH]cnc1CSCCN
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CNC(=NC#N)NCCSCc1nc[nH]c1C
Yield: 19 %

Procedure:
A solution of N-methyl-chloroformimidoyl chloride (1.12 g), 2-(5-methylimidazol-4-ylmethylthio)ethylamine (0.855 g) and DBU (0.988 g) in CH2Cl2 (16 ml was heated under reflux for 6 hrs. To the reaction mixture containing N'-methyl-N-[2-(5-methylimidazol-4-ylmethylthio)ethyl]chloroformamidine was added a solution of cyanamide (0.84 g) and DBU (3.04 g) in CH2Cl2 (16 ml). After refluxing for 15 hrs., the solvent was removed and the residue was chromatographed [SiO2, CH3CN-CH3OH (4:1)]. The crude product was purified by preparative chromatography [SiO2, CH3COOC2H5 --CH3OH-- 28% NH3 (aq) (10:1:1)] and then recrystallization from CH3CN to give N"-cyano-N-methyl-N'-[2-(5-methylimidazol-4-ylmethylthio)ethyl]guanidine (0.24 g). Yield 19.0%, m.p. 139°-141° C.
Reaction SMILES: P(Cl)(C(C)(C)C)C(C)(C)C.Cl[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>CCO.C(OCC)C.O>[C:18]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Clc1ccccn1
Reactant: OB(O)c1ccccc1
Agent: CC(C)(C)P(Cl)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: c1ccc(-c2ccccn2)cc1
Temperature: 25 °C

Procedure:
A 30 mL of reactor equipped with magnetic stir bar was charged with 23.7 mg (0.044 mmol) of (t-Bu)2PCl)2PdCl2, 0.50 g (4.4 mmol) of 2-chloropyridine, 0.65 g (5.33 mmol) of PhB(OH)2 and 0.92 g (6.67 mmol) of K2CO3 in 3 mL of EtOH (95%). The reaction mixture was refluxed for 5 hours. The reaction mixture was cooled to room temperature, transferred to a separatory funnel, and diluted with 100 mL of diethyl ether and 20 mL of H2O. The layers were separated, and organic layer was washed with H2O (50 mL), brine (30 mL), and dried over MgSO4, filtered, and solvents removed from the filtrate by rotary evaporation. The resulting residue was chromatographed on silicon gel. The eluate was concentrated by rotary evaporation followed by high vacuum to give 2-phenylpyridine. LC-MS Found: 156.2 (M++1).