Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[CH:4][N:3]=1.[C:20]([CH:24]1[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]1)([CH3:23])([CH3:22])[CH3:21]>CCOC(C)=O.C([O-])(O)=O.[Na+]>[C:20]([C@H:24]1[CH2:25][CH2:26][C@H:27]([NH:30][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[CH:4][N:3]=2)[CH2:28][CH2:29]1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)C1CCC(N)CC1
Reactant: Clc1ncc(CCc2cccnc2)c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)[C@H]1CC[C@H](Nc2ncc(CCc3cccnc3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Under a N2 atmosphere, 300 mg (1.11 mmol) of 1-chloro-4-[2-(pyridin-3-yl)-ethyl]-isoquinoline (step 1.6) and 520 mg (3.3 mmol) 4-tert-butyl-cyclohexylamine (cis/trans mixture) are stirred at 120° C. After 2 days, a further 520 mg of 4-tert-butyl-cyclohexylamine are added, followed by 1 g after a total of 4 days. Stirring continues for 3 days at 150° C., then the reaction mixture is cooled to RT and diluted with EtOAc and NaHCO3 solution. The water phase is separated off and extracted twice with EtOAc. The organic phases are washed 3 times with water and brine, dried (Na2SO4) and concentrated by evaporation. Column chromatography (SiO2; toluene/EtOAc 3:1) and elution (toluene/EtOAc 3:1+1% Et3N) yields trans 1-(4-tert-butyl-cyclohexylamino)-4-[2-(pyridin-3-yl)-ethyl]-isoquinoline (crystallised from DIPE), followed by cis 1-(4-tert-butyl-cyclohexylamino)-4-[2-(pyridin-3-yl)-ethyl]-isoquinoline. trans derivative: m.p. 124-125° C.; 1H NMR (CDCl3) δ8.47 (m, 2H), 7.83 (d, 1H), 7.77 (m, 2H), 7.64 (t, 1H), 7.47 (m, 2H), 7.19 (m, 1H), 4.98 (d, HN), 4.05 (m, 1H), 3.14 (t, 2H), 2.98 (t, 2H), 2.27 (m, 2H), 1.86 (m, 2H), 1.25 (m, 4H), 1.07 (m, 1H), 0.90 (s, 9H). cis derivative: 1H NMR (CDCl3) δ8.47 (m, 2H), 7.85 (d, 1H), 7.77 (m, 2H), 7.66 (t, 1H), 7.50 (m, 2H), 7.20 (m, 1H), 5.40 (d, HN), 4.45 (m, 1H), 3.14 (t, 2H), 2.98 (t, 2H), 2.13 (m, 2H), 1.7 (m, 4H), 1.28 (m, 2H), 1.13 (m, 1H), 0.92 (s, 9H).
Reaction SMILES: O1CCCC1.Br[C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[N:11][CH:12]=1.C[O:15][B:16](OC)[O:17]C>CCCCCC>[Cl:13][C:10]1[N:11]=[CH:12][C:7]([B:16]([OH:17])[OH:15])=[CH:8][CH:9]=1
Reactant: COB(OC)OC
Reactant: Clc1ccc(Br)cn1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(Cl)nc1
Temperature: -78 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
In a flask replaced by nitrogen, tetrahydrofuran solution (80 g) containing 5-bromo-2-chloropyridine (9.6 g, 50.0 mmol) was charged, and cooled at −78° C., and then n-hexane solution of n-butyllthium (15% by weight, 24.6 g, 57.5 mmol) was added dropwise at −78° C. Next, at −78° C., trimethoxyborane (5.7 g, 55.0 mmol) was added dropwise. After 30 minutes from adding dropwise, cooling bath was removed off, and the reaction mixture was stirred at room temperature overnight. Then, 10% by weight of hydrochloric acid (50 g) was added under ice cooling condition, and the reaction mixture was stirred for 1.5 hours, and then neutralized by adding 40% by weight of sodium hydroxide aqueous solution (15 g). Ethyl acetate (50 g) was added to the reaction mixture, and the reaction mixture was stirred for 1.0 hour, and then left to stand to separate organic layer. Organic layer was dried with anhydrous magnesium sulfate, and then condensed under reduced pressure to obtain 6-chloro-3-pyridylboronic acid (6.9 g, 44.0 mmol).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[C:3]=1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[C:24]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>>[CH2:11]([C:3]1[C:4]([C:7]([F:10])([F:9])[F:8])=[N:5][O:6][C:2]=1[NH:1][S:30]([C:27]1[CH:26]=[CH:25][C:24]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:29][CH:28]=1)(=[O:32])=[O:31])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCCCCc1c(C(F)(F)F)noc1N
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Product: CCCCCCCCCCCCCc1c(C(F)(F)F)noc1NS(=O)(=O)c1ccc(-c2ccccc2)cc1
Yield: 81 %

Procedure:
N-(4-Tridecyl-3-trifluoromethyl-5-isoxazolyl)-4-biphenylsulfonamide was prepared, in the same manner as described in Example 194b, from 5-amino-4-tridecyl-3-trifluoromethyl-isoxazole and 4-biphenylsulfonyl chloride in 81% yield. Purification was achieved by recrystallization from methanol/water to give an off white solid, m.p. 115-116° C.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][C:11]([OH:15])([C:13]#[CH:14])[CH3:12]>[Pd].[Cu](I)I.C1(C(C2C=CC=CC=2)=C(P(C2CCCCC2)C2CCCCC2)C)C=CC=CC=1.C(NC(C)C)(C)C.CN(C)C=O>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([C:14]#[C:13][C:11]([CH3:12])([OH:15])[CH3:10])=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(Cl)cc1
Reactant: C#CC(C)(C)O
Agent: I[Cu]I
Agent: [Pd]
Agent: CC(=C(c1ccccc1)c1ccccc1)P(C1CCCCC1)C1CCCCC1
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: CC(C)(O)C#Cc1ccc(C#N)cc1
Temperature: 100 °C
Reaction time: 23 h
Yield: 84.2 %

Procedure:
Into a reactor were introduced 1.38 g (10.0 mmol) of 4-chlorobenzonitrile, 1.68 g (20.0 mmol) of 2-methyl-3 butyne-2-ol, 2.7 mg (0.015 mmol) of palladium, 1.4 mg (0.0075 mmol) of copper iodide, 17.6 mg (0.045 mmol) of the 1,1-diphenyl-2-(dicyclohexylphosphine)propene obtained in Example 2, 4.0 mL (0.055 mmol) of diisopropylamine, and 4.0 ml of N,N-dimethylformamide under a nitrogen atmosphere. The resultant reaction mixture was stirred at 100° C. for 23 hours and then cooled. Thereafter, the solvent was removed under pressure. The concentrate was purified by column clromatography to obtain 1.56 g (84%) of 4-(4-cyanophenyl)-2-methyl-3-butyne-2-ol as white crystals.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([CH2:19][OH:20])=[CH:16][CH:17]=3)[CH:12]=[C:11]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CN=C1.Cl[Si:33]([CH:40]([CH3:42])[CH3:41])([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35].O>CN(C)C=O>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([CH2:19][O:20][Si:33]([CH:40]([CH3:42])[CH3:41])([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35])=[CH:16][CH:17]=3)[CH:12]=[C:11]2[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: O=S(=O)(c1ccccc1)n1c(-c2ccccc2)cc2cc(CO)ccc21
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[Si](OCc1ccc2c(c1)cc(-c1ccccc1)n2S(=O)(=O)c1ccccc1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 1-benzenesulfonyl-5-hydroxymethyl-2-phenylindole (171 mg) in N,N-dimethylformamide (2.4 mL) were added imidazole (128 mg) and chlorotriisopropylsilane (0.150 mL) under cooling with ice, and the mixture was stirred at room temperature for 20 hours. Water was added to the reaction mixture and this resulting mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (221 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:45])[C@@H:4]([NH:32][S:33]([C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)(=[O:35])=[O:34])[CH2:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@@H:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)=[CH:16][CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:65]1([C@H:71](O)[CH2:72][CH3:73])[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3](=[O:45])[C@@H:4]([N:32]([S:33]([C:36]1[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=1)(=[O:35])=[O:34])[C@H:71]([C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[CH2:72][CH3:73])[CH2:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@@H:11]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)=[CH:18][CH:19]=3)[CH2:12][O:13][C:8]=2[CH:7]=1
Reactant: CC[C@@H](O)c1ccccc1
Reactant: COC(=O)[C@H](Cc1ccc2c(c1)OC[C@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC[C@@H](c1ccccc1)N([C@@H](Cc1ccc2c(c1)OC[C@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2)C(=O)OC)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
(S)-3-{(S)-2-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-2-(4-nitro-benzenesulfonylamino)-propionic acid methyl ester (1.6 g) was dissolved in 4 mL dry THF and 1247 mg triphenylphosphine and 650 μL (R)-(+)-1-phenyl-1-propanol were added. The mixture was stirred at 0° C. for 10 min, then 933 μL DIAD was added over 2 min. The reaction stirred at rt for 5 h, then was evaporated. The residue was purified by silica gel flash chromatography (9:1 to 8:2 hexanes/EtOAc) to give 1.8 g desired product after drying. 1H NMR (400 MHz, acetone-d6): 8.35 (m, 2H), 7.96 (m, 2H), 7.72 (d, 1H), 7.62 (d, 1H), 7.51-7.42 (m, 3H), 7.29 (m, 5H), 7.10 (m, 2H), 6.88-6.80 (m, 3H), 5.21 (s, 2H), 5.11 (m, 1H), 4.82 (m, 1H), 4.45 (m, 1H), 4.36 (m, 1H), 4.03 (m, 1H), 3.49 (m, 1H), 3.35 (s, 3H), 3.04 (m, 1H), 2.31 (m, 1H), 1.81 (m, 1H), 0.77 (t, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=1.[H-].[Na+].Br[CH2:15][CH2:16][OH:17]>CN(C=O)C.O>[OH:17][CH2:16][CH2:15][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: OCCBr
Reactant: COc1cc(O)ccc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OCCO)ccc1C=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-hydroxy-2-methoxybenzaldehyde (1.217 g, 8.00 mmol) in dry DMF (8.88 mL) was added to a stirred suspension of sodium hydride (60% dispersion in mineral oil) (0.267 mL, 8.00 mmol) in dry DMF (2.22 mL) via cannula at 0° C. under N2. The reaction mixture was stirred at 0° C. for 30 min and warmed to room temperature. 2-bromoethanol (0.851 mL, 12.00 mmol) was added dropwise and the reaction mixture was stirred at 50° C. overnight. The reaction was diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The combined extracts were washed with 1N aq. NaOH (50 mL), dried (MgSO4) and concentrated in vacuo to afford the crude product. This was purified by flash chromatography (Biotage Horizon, 40M, Si, ˜30 mL/min, 100% hexanes for 360 mL, gradient to 60% EtOAc in hexanes over 4536 mL) to afford 4-(2-hydroxyethoxy)-2-methoxybenzaidehyde, as a colorless solid. Rf=0.29 (50% EtOAc/hexanes). LCMS calc.=197.1; found=197.0 (M+H)+. 1H NMR (500 MHz, CHCl3): δ 10.16 (s, 1 H); 7.68 (d, J=8.7 Hz, 1 H); 6.46 (dd, J=8.7, 2.2 Hz, 1 H); 6.40 (d, J=2.2 Hz, 1 H); 4.09 (t, J=4,6 Hz, 2 H); 3.94 (t, J=4.4 Hz, 2 H); 3.79 (s, 3 H); 3.20 (s, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.[Br:9]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][Br:9]
Reactant: Cc1cccc(Br)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cccc(Br)c1
Reaction time: 15 h
Yield: 67.8 %

Procedure:
m-bromotoluene (25.33 g; 148.1 mmol), N-bromosuccinimide (26.36 g; 148.1 mmol), and benzoyl peroxide (0.3 g) were added to carbon tetrachloride (200 ml), and the mixture was heated under reflux for 3 hours. The white crystals that precipitated were filtered off, and the filtrate was concentrated under reduced pressure. The residue was taken up in n-hexane (200 ml), and the mixture was left to stand for 15 hours at room temperature. The white crystals that precipitated were filtered off, and the filtrate was concentrated, to thereby yield a yellow oily compound (25.1 g). The compound was analyzed by 1H-NMR and found to be a mixture of the target compound, the starting compound, and a dibromo compound (4.34:1.03:1.00). The yield based on the result of 1H-NMR analysis was 67.9%.
Reaction SMILES: [I:1][CH2:2][C:3]1[N:4]=C(C2C=CC(C)=CC=2)O[C:7]=1[C:8]1C=CC=C[CH:9]=1.CC(=NO)C(=O)CC.[CH:29]([C:32]1[CH:39]=[CH:38][C:35]([CH:36]=[O:37])=[CH:34][CH:33]=1)([CH3:31])[CH3:30]>>[CH2:8]([C:7]1[O:37][C:36]([C:35]2[CH:34]=[CH:33][C:32]([CH:29]([CH3:31])[CH3:30])=[CH:39][CH:38]=2)=[N:4][C:3]=1[CH2:2][I:1])[CH3:9]
Reactant: Cc1ccc(-c2nc(CI)c(-c3ccccc3)o2)cc1
Reactant: CC(C)c1ccc(C=O)cc1
Agent: CCC(=O)C(C)=NO
Product: CCc1oc(-c2ccc(C(C)C)cc2)nc1CI

Procedure:
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, pentane-2,3-dione-2-oxime and 4-isopropylbenzaldehyde gave 5-ethyl-4-iodomethyl-2-(4-isopropylphenyl)oxazole.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-])=O.O.[CH:15]([C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)([CH3:17])[CH3:16]>C1COCC1>[NH2:11][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[CH3:1])[C:6]([NH:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([CH:15]([CH3:17])[CH3:16])[CH:19]=1)=[O:7]
Reactant: Cc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Reactant: CC(C)c1cccc(N)c1
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C(=O)Nc2cccc(C(C)C)c2)cc1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-methyl-3-nitro-benzoyl chloride (2.00 g, 0.010 mol) in THF (30 mL), in a water bath-cooled 100 mL round bottom flask, was added 3-isopropyl-phenylamine (1.35 g, 0.010 mol) dropwise. The reaction was allowed to stir at room temperature for 1 hour before being concentrated. The mixture was taken up in EtOAc and washed with NaHCO3 (aq., conc.) and then brine. The solution was dried over MgSO4, filtered, and concentrated to yield the title compound as an orange oil that solidifies upon standing. MS m/z 299=[M+H]+. Calc'd for C17H18N2O3: 298.34.
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].I[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C(#N)C>[CH3:17][C:3]1([C:1]#[C:2][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)=[CH:23][CH:24]=2)[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reactant: Ic1ccc(-c2cccnc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#Cc1ccc(-c3cccnc3)cc1)O2
Reaction time: 3 h

Procedure:
A mixture of 1.15 g of rac-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol, 1.14 g (4 mmol) of 3-(4-iodophenyl)pyridine, 0.2 g of triphenylphosphine, 50 mg of cuprous iodide, 1.5 ml of triethylamine and 20 ml of acetonitrile was degassed with argon for 10 minutes. Palladium acetate, 75 mg, was then added and stirring was continued for 3 hours. The reaction mixture was partitioned between methylene chloride and water. The organic layer was dried and evaporated. The residue was crystallized from ethyl acetate and recrystallized from methanol/ethyl acetate to give colorless crystals with m.p. 190°-192° C.
Reaction SMILES: FC(F)(F)C1C=CC(CBr)=CC=1.[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1.[CH3:22][C:23]1[CH:27]=[C:26]([N:28]2[CH2:32][CH2:31][NH:30][C:29]2=[O:33])[S:25][C:24]=1[C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][N:30]2[CH2:31][CH2:32][N:28]([C:26]3[S:25][C:24]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:23]([CH3:22])[CH:27]=3)[C:29]2=[O:33])=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1sc(N2CCNC2=O)cc1C
Reactant: Fc1ccc(CBr)cc1
Agent: FC(F)(F)c1ccc(CBr)cc1
Product: CCOC(=O)c1sc(N2CCN(Cc3ccc(F)cc3)C2=O)cc1C
Yield: 95 %

Procedure:
Following the procedure as described in Example 13, making variations as required to replace 4-(trifluoromethyl)benzyl bromide with 4-fluorobenzyl bromide to react with ethyl 3-methyl-5-(2-oxoimidazolidin-1-yl)thiophene-2-carboxylate, the title compound was obtained as a colorless solid in 95% yield: 1H NMR (300 MHz, CDCl3) δ 7.31-7.25 (in, 2H), 7.04 (t, J=8.6 Hz, 2H), 6.15 (s, 1H), 4.44 (s, 2H), 4.28 (q, J=7.1 Hz, 2H), 3.84-3.76 (m, 2H), 3.48-3.40 (m, 2H), 2.49 (s, 3H), 1.34 (t, J=7.1 Hz, 3H): MS (ES+) m/z 363.2 (M+1).
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:11][C@@H:10]([C:12]([O:14][C@H:15]2[CH2:32][CH2:31][C@@:30]3([CH3:33])[C@@H:17]([CH2:18][CH2:19][C@:20]4([CH3:44])[C@@H:29]3[CH2:28][CH2:27][C@H:26]3[C@@:21]4([CH3:43])[CH2:22][CH2:23][C@@:24]4([C:40]([OH:42])=[O:41])[CH2:36][CH2:35][C@@H:34]([C:37]([CH3:39])=[CH2:38])[C@@H:25]43)[C:16]2([CH3:46])[CH3:45])=[O:13])[C:9]1([CH3:48])[CH3:47])=[O:7])(C)(C)C>Cl.O1CCOCC1.CCOC(C)=O>[C:6]([C@H:8]1[CH2:11][C@@H:10]([C:12]([O:14][C@H:15]2[CH2:32][CH2:31][C@@:30]3([CH3:33])[C@@H:17]([CH2:18][CH2:19][C@:20]4([CH3:44])[C@@H:29]3[CH2:28][CH2:27][C@H:26]3[C@@:21]4([CH3:43])[CH2:22][CH2:23][C@@:24]4([C:40]([OH:42])=[O:41])[CH2:36][CH2:35][C@@H:34]([C:37]([CH3:39])=[CH2:38])[C@@H:25]43)[C:16]2([CH3:46])[CH3:45])=[O:13])[C:9]1([CH3:48])[CH3:47])([OH:7])=[O:5]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)[C@@H]6C[C@H](C(=O)OC(C)(C)C)C6(C)C)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)[C@@H]6C[C@H](C(=O)O)C6(C)C)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 59 %

Procedure:
To a stirred solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-((1R,3S)-3-(tert-butoxycarbonyl)-2,2-dimethylcyclobutanecarbonyloxy)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (Example 3, about 0.160 g, 0.239 mmol) in 2M HCl in Dioxane (10 ml) was stirred at room temperature for about 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc and washed with water, the organic layer dried over Na2SO4 and concentrated under reduced pressure. The resulting crude was purified by Silica gel column chromatography (100-200 Mesh, Elution: 20% EtOAc in Hexane) to afford the title compound as a white solid. Wt: 0.086 g; Yield: 59.0%; 1H NMR (300 MHZ, CDCl3): δ 4.74 (s, 1H), 4.61 (s, 1H), 4.47-4.43 (m, 1H), 3.03-2.97 (m, 1H), 2.87-2.74 (m, 2H), 2.63-2.51 (m, 1H), 2.31-2.24 (m, 2H), 2.19-1.90 (m, 3H), 1.69 (s, 3H), 1.78-1.68 (m, 5H), 1.52-1.41 (m, 12H), 1.29-1.02 (m, 9H), 0.97 (s, 3H), 0.93 (s, 3H), 0.85 (s, 9H); Mass: [M+Na]+ 633 (100%); IR (KBr, cm−1): 3427, 2951, 1730, 1706, 1698, 1456, 1376, 1242, 1190, 1107, 1020, 885; M. Range: 282.5-289.3° C.; HPLC: 92.2% % at RT 8.76 minutes.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:16]([Si:20]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)Cl)([CH3:19])([CH3:18])[CH3:17]>ClCCl>[Si:20]([O:8][CH2:7][CH:4]1[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCC1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](OCC1CCNCC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.00 g (43.41 mmol) of 4-piperidinemethanol are dissolved in 400 ml of dichloromethane, and 9.1 ml (65.11 mmol) of triethylamine, 212 mg (1.74 mmol) of 4-N,N-dimethylaminopyridine and 16.9 ml (65.12 mmol) of tert-butyldiphenylchlorosilane are added in succession. The reaction mixture is stirred at RT for 8 h. After addition of 50 ml of dichloromethane the mixture is washed once with 20 ml of water and once with 20 ml of saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulfate. The crude product is used in the next reaction without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:15]=[CH:14][C:7]([CH:8]=[CH:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][C:5]=1[O:16][CH3:17])(O)=[O:2].Cl.CN.Cl.[CH2:22]([N:24]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O>[CH3:17][O:16][C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][C:4]=1[C:1](=[O:2])[NH:24][CH3:22])[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: CCN=C=NCCCN(C)C
Reactant: COC(=O)C=Cc1ccc(C(=O)O)c(OC)c1
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1ccc(C=CC(=O)OC)cc1OC
Reaction time: 18 h
Yield: 75.6 %

Procedure:
To a solution of methyl 4-carboxy-3-methoxycinnamate (400 mg) in N,N-dimethylformamide were added methylamine hydrochloride (126 mg), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (390 mg) and 1-hydroxybenzotriazole (320 mg) at ambient temperature, and the mixture was stirred for 18 hours at the same temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (chloroform methanol=40:1, v/v) to give methyl 3-methoxy-4-(methylcarbamoyl)cinnamate (319 mg).
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1.[Cl:16][C:17]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[C:19]([CH3:32])[N:18]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[Cl:16][C:17]1[CH:22]=[C:21]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:20]=[C:19]([CH3:32])[N:18]=1
Reactant: Nc1nnc(Br)c(-c2ccc(F)cc2)n1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(-c2nnc(N)nc2-c2ccc(F)cc2)cc(Cl)n1
Yield: 61 %

Procedure:
6-bromo-5-(4-fluorophenyl)-1,2,4-triazin-3-amine (1 molar eq.), 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-methylpyridine (1 molar eq.) and K2CO3 (1.5 molar eq.) are suspended in a mixture of 1,4-dioxane and water (2:1; 10 mL of solvent per gram of bromotriazine). The resulting mixture is degassed, treated with dichlorobis[di-tert-butyl(4-dimethylaminophenyl)phosphino]palladium(II) (2 mol %) and refluxed until full consumption of bromotriazine is observed by LCMS. The cooled reaction mixture is then diluted with water, extracted with DCM and passed through a phase separator. The organic phase is concentrated under reduced pressure and purified by gradient flash chromatography, eluting with mixtures of ethyl acetate and hexanes to afford 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine (61%).