Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:30][CH2:31][CH2:32][OH:33])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26](=[O:29])[NH:25][CH:24]=4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.N1C=CN=C1.[C:39]([Si:43](Cl)([CH3:45])[CH3:44])([CH3:42])([CH3:41])[CH3:40]>C(Cl)Cl>[Si:43]([O:33][CH2:32][CH2:31][CH2:30][C@@:8]1([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26](=[O:29])[NH:25][CH:24]=3)=[CH:19][CH:18]=2)[CH3:16])[CH2:10][CH2:9]1)([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:45])[CH3:44]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@@H](c1ccc(-c2ccc(=O)[nH]c2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C[C@@H](c1ccc(-c2ccc(=O)[nH]c2)cc1)N1CC[C@](CCCO[Si](C)(C)C(C)(C)C)(c2ccc(F)cc2)OC1=O
Reaction time: 8 h
Yield: 27.2 %

Procedure:
A mixture of (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one (100 mg, 0.78 mmol), imidazole (142.8 mg, 2.1 mmol), and tert-butylchlorodimethylsilane (350 mg, 2.34 mmol) in CH2Cl2 (20 mL) was stirred overnight. The mixture was washed with water and extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to give crude (R)-6-(3-(tert-butyldimethylsilyloxy)propyl)-6-(4-fluorophenyl)-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one (120 mg), which was used for the next step without further purification.
Reaction SMILES: [C:1]([O:8]CC)(=O)[C:2]([O:4][CH2:5][CH3:6])=[O:3].O.[NH2:12][NH2:13]>C(O)C>[NH:12]([C:1](=[O:8])[C:2]([O:4][CH2:5][CH3:6])=[O:3])[NH2:13]
Reactant: NN
Reactant: CCOC(=O)C(=O)OCC
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(=O)NN
Temperature: 80 °C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
To a round-bottom flask was added a solution of diethyl oxalate (10.0 g, 68.4 mmol, 1.00 equiv) in ethanol (100 mL). Hydrazine hydrate (2.75 g, 85.8 mmol, 1.00 equiv) was added and the resulting mixture was stirred for 3 h at 80° C. After cooling to ambient temperature, the solids were removed via filtration and the filtrate was concentrated in vacuo to yield 8.00 g (80%) of the title compound as a colorless oil.
Reaction SMILES: [ClH:1].Cl.Cl[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:18][C:17]3[C:16](=[O:19])[N:15]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([CH2:28][NH:29][CH3:30])=[CH:24][CH:23]=4)[CH:14]=[N:13][C:12]=3[CH:11]=2)=[CH:6][CH:5]=1.[CH3:31][N:32]([CH3:36])[C:33](Cl)=[O:34].C(N(CC)CC)C.O1CCCC1>C(OCC)(=O)C>[Cl:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:18][C:17]3[C:16](=[O:19])[N:15]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([CH2:28][N:29]([CH3:30])[C:33]([N:32]([CH3:36])[CH3:31])=[O:34])=[CH:24][CH:23]=4)[CH:14]=[N:13][C:12]=3[CH:11]=2)=[CH:6][CH:5]=1
Reactant: CNCc1ccc(CCn2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1
Reactant: CN(C)C(=O)Cl
Reactant: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)C(=O)N(C)Cc1ccc(CCn2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 70.3 %

Procedure:
A mixture of the compound (0.1 g) obtained in Example 4, dimethylcarbamoyl chloride (25 mg), triethylamine (76 mg) and tetrahydrofuran (2 ml) was stirred at 60° C. for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane (1:1, volume ratio) to give the title compound (70 mg) as a colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([C:23]#[N:24])=[C:16]2[N:15]=1.[OH:25]S(O)(=O)=O.O.CCCCCC>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([C:23]([NH2:24])=[O:25])=[C:16]2[N:15]=1
Reactant: N#Cc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Reactant: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Solvent: CCCCCC
Product: NC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
The product from Step B (3.00 g, 8.85 mmol) was added in small portions over 5 minutes to concentrated H2SO4 (30 mL) and the mixture was stirred at ambient temperature for 2 hours (homogeneous after 5 minutes). The solution was slowly added to chilled H2O (300 mL) with stirring and the mixture was extracted with EtOAc. The combined EtOAc portions were washed with H2O, 1M Na2CO3 and saturated NaCl. The EtOAc solution was dried over MgSO4/activated carbon, filtered through a packed Celite pad and concentrated to give a white foam. The foam was dissolved in minimal CH2Cl2 and hexane was added to induce formation of a white precipitate. The mixture was concentrated to provide the title compound as a flowing white solid after drying in vacuum (2.80 g, 92%). MS (apci) m/z=344.1 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([OH:9])[C:5]2[S:10][CH:11]=[CH:12][C:4]=2[CH2:3]1.[Cl:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17](O)=[CH:16][C:15]=1[CH3:22]>>[ClH:13].[Cl:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([O:9][CH:6]2[CH2:7][CH2:8][N:2]([CH3:1])[CH2:3][C:4]3[CH:12]=[CH:11][S:10][C:5]2=3)=[CH:16][C:15]=1[CH3:22]
Reactant: CN1CCC(O)c2sccc2C1
Reactant: Cc1cc(O)cc(C)c1Cl
Product: Cc1cc(OC2CCN(C)Cc3ccsc32)cc(C)c1Cl
Product: Cl

Procedure:
The same method as in Example 47 was conducted using 5-methyl-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-8-ol (Reference Example 25) instead of 6-methyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridin-4-ol (Reference Example 1) and was conducted using 4-chloro-3,5-dimethylphenol instead of 4-chloro-3-methylphenol to give the objective compound.
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][NH2:28]>>[CH3:19][S:16]([C:13]1[CH:14]=[CH:15][C:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:28][CH2:27][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=4)[N:20]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:11][CH:12]=1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(Cl)nc23)cc1
Reactant: NCc1ccccn1
Product: CS(=O)(=O)c1ccc(-c2cccn3nc(NCc4ccccn4)nc23)cc1

Procedure:
[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-pyridin-2-ylmethyl-amine was prepared from 2-chloro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (250 mg, 0.81 mmol) and C-pyridin-2-yl-methylamine (0.84 mL, 8.1 mmol) in a manner analogous to Example 406. Product isolated as a light yellow powder (207 mg, 67%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.68 (d, J=6.5 Hz, 1H), 8.51 (m, 1H), 8.38 (d, J=7.7 Hz, 2H), 8.04 (d, J=7.9 Hz, 2H), 7.87 (d, J=7.7 Hz, 1H), 7.73 (t, J=15.5, 7.9 Hz, 1H), 7.46-7.37 (m, 2H), 7.24 (m, 1H), 7.04 (t, J=14.2, 6.9 Hz, 1H), 4.59 (d, J=5.8 Hz, 2H), 3.28 (s, 3H). MS=380 (MH)+.
Reaction SMILES: [F:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=O)[CH2:8][CH2:7]2.[C:14](#[N:18])[CH2:15][C:16]#[N:17].C([O-])(=O)C.[NH4+].C(O)(=O)C>C1(C)C=CC=CC=1>[F:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[C:15]([C:14]#[N:18])[C:16]#[N:17])[CH2:8][CH2:7]2
Reactant: N#CCC#N
Reactant: COc1ccc2c(c1F)C(=O)CC2
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COc1ccc2c(c1F)C(=C(C#N)C#N)CC2
Temperature: 140 °C
Yield: 27.6 %

Procedure:
To a solution of 38.1 (740 mg, 4.13 mmol) and malononitrile (0.275 mL, 4.96 mmol) in toluene (10.0 mL), was added ammonium acetate (79.6 mg, 1.03 mmol) followed by acetic acid (0.284 mL, 4.96 mmol). The resulting mixture was heated at reflux at 140° C. with a Dean-Stark trap for 18 hours. The reaction was concentrated under reduced pressure, and the residue was purified by medium pressure chromatography to yield 38.2 (260 mg, 27% yield). MS ESI (neg.) m/e: 227.1 (M−H)−.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:20]=[C:19]2[C:12]([NH:13][CH:14]=[C:15]2[CH2:16][CH2:17][NH2:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][N:22]([CH3:36])[C:23]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O>[CH2:1]([O:8][C:9]1[CH:20]=[C:19]2[C:12](=[CH:11][CH:10]=1)[NH:13][CH:14]=[C:15]2[CH2:16][CH2:17][NH:18][CH:26]1[CH2:25][CH2:24][C:23]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)([N:22]([CH3:36])[CH3:21])[CH2:28][CH2:27]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: NCCc1c[nH]c2ccc(OCc3ccccc3)cc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCCl
Product: CN(C)C1(c2ccccc2)CCC(NCCc2c[nH]c3ccc(OCc4ccccc4)cc23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.3 %

Procedure:
5-Benzyloxytryptamine (440 mg, 1.65 mmol) were dissolved in 1,2-dichloroethane (14 ml) under argon (slightly cloudy solution). After addition of 4-dimethylamino-4-phenylcyclohexanone (359 mg, 1.65 mmol) and glacial acetic acid (189 μl, 3.3 mmol), the mixture was stirred for two hours at RT. Sodium triacetoxyborohydride (462 mg) was then added and the suspension was stirred for four days at RT. For working up, water (15 ml) was added to the reaction mixture. The phases were separated and the aqueous phase was washed with ether (20 ml) and then rendered strongly alkaline with sodium hydroxide solution. The aqueous phase was extracted with ether (2×10 ml) and ethyl acetate (4×10 ml), the combined extracts were dried over sodium sulfate and filtered and the filtrate was concentrated. The crude product obtained (686 mg) was recrystallized from a mixture of ethyl acetate/cyclohexane (35 ml/5 ml). 396 mg N′-[2-(5-benzyloxy-1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenyl-cyclohexane-1,4-diamine were obtained as a cis/trans mixture (m.p. 130-134° C.).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH2:32][CH3:33])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[NH2:77][CH:78]1[CH2:83][CH2:82][O:81][CH2:80][CH2:79]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:77][CH:78]5[CH2:83][CH2:82][O:81][CH2:80][CH2:79]5)=[O:27])=[CH:24][C:23]=4[O:31][CH2:32][CH3:33])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCOCC1
Reactant: CCOc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(C(=O)NC2CCOCC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.17 h
Yield: 82.2 %

Procedure:
To a mixture of 0.0651 g (0.141 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethoxy-benzoic acid (I-214) and 4 mL of dimethylformamide was added 0.0309 g (0.229 mmole) of 1-hydroxybenzotriazole, 0.0825 g (0.229 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.1113 g (0.862 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0213 g (0.211 mmole) of 4-aminotetrahydropyran was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.0631 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethoxy-N-(tetrahydro-pyran-4-yl)-benzamide (I-217).
Reaction SMILES: C(OC([N:8]([C:26]1[CH:30]=[C:29]([CH3:31])[N:28](C(OC(C)(C)C)=O)[N:27]=1)[C:9]1[C:18]2[C:13](=[CH:14][C:15](C(O)=O)=[CH:16][CH:17]=2)[C:12](=[O:22])[N:11]([CH:23]([CH3:25])[CH3:24])[N:10]=1)=O)(C)(C)C.[C:39]([O-:42])([O-])=[O:40].[K+].[K+].[CH3:45]I>C(Cl)Cl>[CH3:45][O:42][C:39]([C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[C:9]([NH:8][C:26]1[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=1)=[N:10][N:11]([CH:23]([CH3:25])[CH3:24])[C:12]2=[O:22])=[O:40]
Reactant: CI
Reactant: Cc1cc(N(C(=O)OC(C)(C)C)c2nn(C(C)C)c(=O)c3cc(C(=O)O)ccc23)nn1C(=O)OC(C)(C)C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)c1ccc2c(Nc3cc(C)[nH]n3)nn(C(C)C)c(=O)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-[tert-Butoxycarbonyl-(1-tert-butoxycarbonyl-5-methyl-1H-pyrazol-3-yl)-amino] -3-iso-propyl-4-oxo-3,4-dihydro-phthalazine-6-carboxylic acid (10 mg, 0.019 mmol) (Intermediate of Example M-1) was dissolved in DCM (1 ml). To this was added K2CO3 (3.1 mg, 0.028 mmol) followed by methyl iodide (3.3 mg, 0.028 mmol) and the reaction mixture was stirred at RT for 30 min. After this time the reaction mixture was partitioned between EtOAc (10 ml) and water (1:0 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated under vacuum.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:23])[CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:23])[CH:20]=[C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(F)cc(Br)c3O2)cc1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cc(F)cc(-c4ccccc4)c3O2)cc1
Yield: 81.6 %

Procedure:
Treatment of (±)-(7-bromo-5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (2.00 g, 4.98 mmol) with phenyl boronic acid (0.912 g, 7.48 mmol), dichlorobis(tri-o-tolylphosphine)palladium(II) (0.196 g, 0.249 mmol), and potassium carbonate (1.72 g, 12.46 mmol) generally according to the procedure described for Intermediate 37 gave 1.62 g (82%) of (±)-(5-fluoro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a yellow oil. Rf=0.54 (silica, ethyl acetate:hexanes 1:4); Anal. calcd. for C22H19FO4S-0.2 C4H8O2: C, 65.82; H, 4.99. Found: C, 65.77; H, 4.99.
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].C[O-].[Na+].CO.[CH:11]([C:15]1[C:16]([CH3:34])=[CH:17][C:18]([I:33])=[C:19]([CH:32]=1)[O:20][C:21](=[CH:24]NC1C=CC=CC=1)[C:22]#[N:23])=[CH:12][CH:13]=[CH2:14]>C(O)C>[CH:11]([C:15]1[C:16]([CH3:34])=[CH:17][C:18]([I:33])=[C:19]([CH:32]=1)[O:20][C:21]1[C:22]([NH2:23])=[N:4][C:3]([NH2:5])=[N:2][CH:24]=1)=[CH:12][CH:13]=[CH2:14]
Reactant: N=C(N)N
Reactant: C=CC=Cc1cc(OC(C#N)=CNc2ccccc2)c(I)cc1C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: C=CC=Cc1cc(Oc2cnc(N)nc2N)c(I)cc1C

Procedure:
To a suspension of guanidine hydrochloride (3.10 g, 32.5 mmol) in 10 mL ethanol was added a solution of 25% NaOMe in methanol (7.0 mL, 32.5 mmol). The resulting solution was added to the crude 2-(5-buta-1,3-dienyl-2-iodo-4-methyl-phenoxy)-3-phenylamino-acrylonitrile of step 4, and the mixture was heated to reflux under nitrogen for 16 hours. The reaction mixture was cooled, concentrated under reduced pressure, diluted with water, and extracted with methylene chloride. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on silica (10% MeOH/methylene chloride+0.1% NH4OH), and recrystallized from EtOAc to give 2.1 g of 5-(5-buta-1,3-dienyl-2-iodo-4-methyl-phenoxy)-pyrimidine-2,4-diamine, MP=195-197° C.
Reaction SMILES: C([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[N:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)#N.[N+:18](C1C=CC(N)=CC=1)([O-:20])=[O:19]>>[N+:18]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[N:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)([O-:20])=[O:19]
Reactant: N#Cc1ccc(N=Nc2ccc(O)cc2)cc1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Product: O=[N+]([O-])c1ccc(N=Nc2ccc(O)cc2)cc1

Procedure:
4-(4-Nitrophenylazo)phenol was prepared analogous with 4-(4-cyanophenylazo)phenol starting from 4-nitroaniline.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7](Cl)(=[O:9])=[O:8])[CH:2]=1.[Cl:11][C:12]1[C:13]([OH:41])=[C:14]([S:19]([N:22]([CH2:27][C:28]2[CH:33]=[C:32]([CH2:34][NH:35][CH2:36][CH:37]([CH3:39])[CH3:38])[CH:31]=[C:30]([Cl:40])[CH:29]=2)[CH2:23][CH:24]([CH3:26])[CH3:25])(=[O:21])=[O:20])[CH:15]=[C:16]([Cl:18])[CH:17]=1.CCN(CC)CC>C1COCC1>[Cl:40][C:30]1[CH:31]=[C:32]([CH:33]=[C:28]([CH2:27][N:22]([CH2:23][CH:24]([CH3:26])[CH3:25])[S:19]([C:14]2[CH:15]=[C:16]([Cl:18])[CH:17]=[C:12]([Cl:11])[C:13]=2[OH:41])(=[O:21])=[O:20])[CH:29]=1)[CH2:34][N:35]([CH2:36][CH:37]([CH3:39])[CH3:38])[S:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)(=[O:9])=[O:8]
Reactant: CC(C)CNCc1cc(Cl)cc(CN(CC(C)C)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1
Reactant: O=S(=O)(Cl)c1cccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)CN(Cc1cc(Cl)cc(CN(CC(C)C)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1)S(=O)(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.2 %

Procedure:
To a solution of pyridine-3-sulfonyl chloride (70 mg, 0.40 mmol) in THF (4 mL) were added 3,5-dichloro-N-(3-chloro-5-((isobutylamino)methyl)benzyl)-2-hydroxy-N-isobutylbenzenesulfonamide (100 mg, 0.20 mmol) and Et3N (0.14 mL, 0.98 mmol). The reaction mixture was stirred at rt for 3 h. The mixture was concentrated. To the residue was added 1 N NaOH/THF/MeOH. After 4 h, the mixture was concentrated and the residue was purified by preparative HPLC. Fractions containing the desired product were combined, concentrated, and lyophilized to give the desired product as a white solid (60 mg, 40%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:21][C@@H:20]2[C@:15]([CH3:23])([CH:16]=[CH:17][C:18](=[O:22])[NH:19]2)[C@@H:14]2[C@@H:3]1[C@H:4]1[C@:11]([CH3:24])([CH2:12][CH2:13]2)[C@@H:7]([C:8](=[O:10])[CH3:9])[CH2:6][CH2:5]1.[CH3:25][Mg]Br.[Cl-].[NH4+]>O1CCCC1.CCOCC>[CH3:1][C@H:2]1[CH2:21][C@@H:20]2[C@:15]([CH3:23])([CH:16]=[CH:17][C:18](=[O:22])[NH:19]2)[C@@H:14]2[C@@H:3]1[C@H:4]1[C@:11]([CH3:24])([CH2:12][CH2:13]2)[C@@H:7]([C:8]([CH3:25])([OH:10])[CH3:9])[CH2:6][CH2:5]1
Reactant: C[Mg]Br
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3[C@@H](C)C[C@H]4NC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@H]1C[C@H]2NC(=O)C=C[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(C)(C)O)CC[C@H]3[C@H]12
Temperature: 25 °C
Yield: 76.7 %

Procedure:
To a solution of 20 mg (0.06 mmol) 7β-methyl-5α-4-azapregn-1-ene-3,20-dione in 4 ml dry tetrahydrofuran at -40° C. under N2 was added 10 eq methylmagnesium bromide (0.6 mmol) in ether. The reaction was stirred and allowed to warm to RT over 18 hours. Aqueous ammonium chloride (5 ml) was added and the solvents were evaporated. The residue was partitioned between methylene chloride and water. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated. The product was purified via HPLC on a 19×300 mm 8 micron silica column using 5% isopropanol/hexane at 20 ml/min to yield 16 mg (0.046 mmol, 77% yield) of the title compound.
Reaction SMILES: [CH:1]1([C:4](=O)[CH2:5][NH:6][C:7]2[C:8]([CH3:16])=[CH:9][C:10]([F:15])=[C:11]([CH:14]=2)[C:12]#[N:13])[CH2:3][CH2:2]1.[S-:18][C:19]#[N:20].[K+]>C(O)(=O)C>[CH:1]1([C:4]2[N:20]=[C:19]([SH:18])[N:6]([C:7]3[C:8]([CH3:16])=[CH:9][C:10]([F:15])=[C:11]([CH:14]=3)[C:12]#[N:13])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: N#C[S-]
Reactant: Cc1cc(F)c(C#N)cc1NCC(=O)C1CC1
Agent: [K+]
Solvent: CC(=O)O
Product: Cc1cc(F)c(C#N)cc1-n1cc(C2CC2)nc1S
Temperature: 110 °C
Yield: 85.3 %

Procedure:
5-(2-Cyclopropyl-2-oxoethylamino)-2-fluoro-4-methylbenzonitrile (14.19 g, 61.2 mmol) was dissolved in glacial acetic acid (300 mL). Potassium thiocyanate (11.9 g, 122.4 mmol) was added as a solid with stirring. The reaction mixture was heated to 110° C. for 4 hours at which time the solvent was removed under reduced pressure. The residue was taken up in dichloromethane (200 mL) and washed with 200 mL water. The aqueous extract was extracted with (2×200 mL) additional dichloromethane, the organic extracts combined and dried over magnesium sulfate. The solvent was removed under reduced pressure and the oily residue was re-dissolved in EA (50 mL) and 150 mL hexanes was added. A dark layer formed and a stir bar was added to the flask. Vigorous stirring caused the product to precipitate as a peach colored solid. The product was collected by filtration, to yield 5-(4-cyclopropyl-2-mercapto-1H-imidazol-1-yl)-2-fluoro-4-methylbenzonitrile, (14.26 g, 52.23 mmol). Anal. LC/MS (m/z: 274, M+1)
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH2:6][NH2:7].C(N(CC)CC)C.[Cl:23][C:24]1[N:29]=[CH:28][C:27]([CH:30]=[CH:31][C:32](O)=[O:33])=[CH:26][CH:25]=1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>C1COCC1.CCOC(C)=O>[Cl:23][C:24]1[N:29]=[CH:28][C:27]([CH:30]=[CH:31][C:32]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:3]([F:2])[CH:4]=2)=[O:33])=[CH:26][CH:25]=1
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Reactant: O=C(O)C=Cc1ccc(Cl)nc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1ccc(CNC(=O)C=Cc2ccc(Cl)nc2)cc1F
Reaction time: 0.17 h
Yield: 95.9 %

Procedure:
3-Fluoro-4-methanesulfonylaminobenzylamine hydrochloride (51 mg, 0.201 mmol) was suspended in THF and treated with triethylamine (23 mg, 0.22 mmol) and then the resulting mixture was stirred for 10 mins. 3-(6-chloro-pyridin-3-yl)-acrylic acid (37 mg, 0.201 mmol) was added to the reaction mixture followed by DMTMM (61 mg, 0.22 mmol) after 10 mins. The resulting mixture was stirred overnight at ambient temperature and then diluted with EtOAc. The resulting solution was washed successively with water, sat'd NaHCO3 (×2), brine, and then dried over anhyd. Na2SO4, filtered and concentrated under reduced pressure. The crude residue was column-chromatographed to yield the title compound (74 mg, 96%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([O:10][CH2:11][CH2:12][O:13][CH3:14])[C:4]=1[O:15][CH2:16][CH2:17][O:18][CH3:19].[C-:20]#[N:21].[K+]>CN(C)C=O.C(OCC)(=O)C>[F:9][C:7]1[CH:6]=[C:5]([O:10][CH2:11][CH2:12][O:13][CH3:14])[C:4]([O:15][CH2:16][CH2:17][O:18][CH3:19])=[C:3]([CH2:2][C:20]#[N:21])[CH:8]=1
Reactant: [C-]#N
Reactant: COCCOc1cc(F)cc(CCl)c1OCCOC
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCOc1cc(F)cc(CC#N)c1OCCOC
Temperature: 60 °C
Yield: 83 %

Procedure:
1-(Chloromethyl)-5-fluoro-2,3-bis{[2-(methyloxy)ethyl]oxy}benzene (0.31 g, 1.06 mmol) was dissolved in N,N-dimethylformamide (2 mL) followed by the addition potassium cyanide (0.10 g, 1.7 mmol), and the resulting mixture was heated at 60° C. for 18 hours. After cooling to room temperature, it was diluted with ethyl acetate (50 mL), washed with water and brine (20 mL each), dried over sodium sulfate, filtered and concentrated to give an oily residue which was purified by flash chromatography (30% ethyl acetate-hexane) to provide (5-fluoro-2,3-bis{[2-(methyloxy)ethyl]oxy}phenyl)acetonitrile (0.25 g, 0.88 mmol, 85% yield). 1H NMR (400 MHz, CDCl3): 6.76-6.74 (d, d, 1H), 6.66-6.63 (d, d, 1H), 4.22-4.21 (m, 2H), 4.13-4.11 (m, 2H), 3.84 (s, 2H), 3.78-3.76 (m, 2H), 3.64-3.61 (m, 2H), 3.43 (s, 3H), 3.42 (s, 3H).