Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH3:9])[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:12][O:13][CH2:14][CH2:15][O:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH:22]2[S:26][C:25](=[O:27])[NH:24][C:23]2=[O:28])=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[N:12][O:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:29][CH:30]=2)[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: NOCCOc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CC(=O)c1cccc(Cl)c1
Agent: Cl
Product: CC(=NOCCOc1ccc(CC2SC(=O)NC2=O)cc1)c1cccc(Cl)c1

Procedure:
Following a procedure similar to that described in Example 40(f), 0.18 ml of 3'-chloroacetophenone was reacted with 400 mg of 5-[4-(2-aminooxyethoxy)benzyl]-thiazolidine-2,4-dione hydrochloride [prepared as described in Example 40(e)]. The reaction mixture was then concentrated by evaporation under reduced pressure, and the resulting residue was extracted with ethyl acetate. The extract was washed with water and the solvent was removed by distillation under reduced pressure. The residue was mixed with a mixture of diethyl ether, diisopropyl ether and hexane, and stirred. The resulting precipitate was collected by filtration, to give 290 mg of the title compound, melting at 82-84° C.
Reaction SMILES: [C-:1]#[N:2].[Na+].[C:4]([O:8][C:9]([NH:11][C@@H:12]([CH3:19])[CH2:13]OS(C)(=O)=O)=[O:10])([CH3:7])([CH3:6])[CH3:5]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[C:4]([O:8][C:9](=[O:10])[NH:11][C@@H:12]([CH3:19])[CH2:13][C:1]#[N:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: [C-]#N
Reactant: C[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](CC#N)NC(=O)OC(C)(C)C
Temperature: 35 °C
Reaction time: 0.5 h

Procedure:
Sodium cyanide (48.92 g, 0.421 mol) was added to dimethylformamide (DMF) (420 mL) and the mixture was stirred at 35° C. for 30 minutes. Tetrabutylammonium bromide (5.22 g, 0.016 mol) was added and the reaction mixture was stirred for an additional 2 h at 35° C. Methanesulfonic acid 2-(S)-tert-butoxycarbonylamino-propyl ester (82.03 g, 0.324 mol) was added and the reaction mixture was stirred at 35° C. overnight. Add an additional 5.22 g of tetrabutylammonium bromide (0.016 mol) was added and stirred overnight at 35° C. The mixture was then partitioned between 1200 mL water and 1600 mL of ethyl acetate. The resulting organic and aqueous phases were separated and extracted sequentially 2 times with 800 mL of ethyl acetate. The combined extracts were washed 3 times with 500 mL of water and a saturated solution of sodium chloride in water. The organic layer was dried over magnesium sulfate, filtered and concentrated to afford a solid in 84% of (S)-(2-cyano-1-methyl-ethyl)-carbamic acid tert-butyl ester.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:8]=[C:9]([CH:12]=[O:13])[S:10][CH:11]=1.C[OH:15]>O.CC(C)=O.[O-2].[Cr+6].[O-2].[O-2]>[Br:6][C:7]1[CH:8]=[C:9]([C:12]([OH:15])=[O:13])[S:10][CH:11]=1
Reactant: CO
Reactant: O=Cc1cc(Br)cs1
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)c1cc(Br)cs1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
To a solution of chromium(VI)oxide (1.57 g, 15.70 mmol) in water (3 mL) was added dropwise concentrated sulfuric acid (1.3 mL, 23.55 mmol). The formed precipitate was re-dissolved by slow addition of the minimum required amount of water and the solution was cooled with an ice bath. This solution was then added dropwise to a solution of 4-bromo-2-thiophenecarboxaldehyde (2.0 g, 10.47 mmol) in acetone (20 mL) at about 5° C. The reaction mixture was stirred at about 5° C. for about 30 minutes and then at room temperature for about 2 hours. Methanol (30 mL) was added to the reaction mixture to destroy excess oxidant and the formed solids were collected by filtration. The filtrate was concentrated under vacuum and the residue was partitioned between diethyl ether and water. The organic extract was washed with water and brine, dried (MgSO4), filtered and concentrated under vacuum to provide the desired product. MS (DCI-NH3): m/z 206, 208 (M)+.
Reaction SMILES: [F:1][C:2]1([CH2:8][OH:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[H-].[Na+].F[C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][C:14]=1[S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24].Cl>O1CCCC1.ClCCl>[F:1][C:2]1([CH2:8][O:9][C:13]2[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][C:14]=2[S:23]([C:26]([F:27])([F:29])[F:28])(=[O:25])=[O:24])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: NS(=O)(=O)c1ccc(F)c(S(=O)(=O)C(F)(F)F)c1
Reactant: OCC1(F)CCOCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(OCC2(F)CCOCC2)c(S(=O)(=O)C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
To a solution of EXAMPLE 37C (0.500 g) in tetrahydrofuran (5 mL) was added sodium hydride (0.596 g). Additional tetrahydrofuran (25 mL) was added and the mixture stirred for 30 minutes, then 4-fluoro-3-(trifluoromethylsulfonyl)benzenesulfonamide (1.145 g) was added as a solution in tetrahydrofuran (5 mL). After stirring for 2 hours, the reaction mixture was partioned between 1N aqueous HCl (50 mL) and dichloromethane (200 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated. The resulting solid was chromatographed over silica gel (Reveleris 80 g) eluting with a gradient of 0.5% to 7.5% methanol/dichloromethane over 30 minutes (flow=40 mL/min) to provide the title compound.
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[C:18](Br)=[CH:19][CH:20]=[CH:21][C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:25]=1B(O)O.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>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>[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[C:18]([C:25]4[C:26]([CH3:30])=[CH:27][CH:28]=[CH:29][C:24]=4[CH3:23])=[CH:19][CH:20]=[CH:21][C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1cccc(C)c1B(O)O
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3c(Br)cccc3O2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC2Cc3c(cccc3-c3c(C)cccc3C)O2)cc1
Yield: 167.4 %

Procedure:
Treatment of (±)-(4-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.5 g, 3.32 mmol) with 2,6-dimethylphenylboronic acid (2.35 g, 15.66 mmol), tetrakis(triphenylphosphine)palladium(0) (0.452 g, 0.394 mmol), and barium hydroxide octahydrate (6.17 g, 19.57 mmol) generally according to the procedure described for Intermediate 50 provided 2.27 g (71%) of (±)-[4-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a colorless oil. Anal. calcd. for C24H24O4S: C, 70.56; H, 5.92. Found: C, 69.72; H, 5.87.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]2[S:18][CH:17]=[C:16]([C:19]#[CH:20])[C:11]=2[N:12]=[C:13](Cl)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][CH2:22][C@@H:23]([OH:25])[CH3:24].C(OCC)(=O)C>O1CCOCC1>[CH2:1]([NH:8][C:9]1[C:10]2[S:18][CH:17]=[C:16]([C:19]#[CH:20])[C:11]=2[N:12]=[C:13]([NH:21][CH2:22][C@@H:23]([OH:25])[CH3:24])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#Cc1csc2c(NCc3ccccc3)nc(Cl)nc12
Reactant: C[C@H](O)CN
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C#Cc1csc2c(NCc3ccccc3)nc(NC[C@H](C)O)nc12
Temperature: 120 °C
Reaction time: 24 h
Yield: 52.3 %

Procedure:
N-Benzyl-2-chloro-7-ethynylthieno[3,2-d]pyrimidin-4-amine (30 mg, 0.096 mmol) was dissolved in anhydrous dioxane (0.5 mL) and (S)-1-aminopropan-2-ol (23 μL, 0.288 mmol) was added. The reaction mixture was stirred at 120° C. for 24 hours. After adding ethyl acetate (3 mL), the reaction mixture was washed with brine. After drying with MgSO4 and concentrating by filtration, purification by silica gel chromatography (ethyl acetate/hexane:1/3→1/1) yielded the target compound of Example 44 (17 mg, 50% yield).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[C:6]([O:13][CH3:14])[CH:5]=[C:4]([O:15][CH3:16])[C:3]=1[C:17](=[O:32])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=1.[H-].[Na+].Br[CH2:36][C:37]([O:39][CH3:40])=[O:38]>CN(C)C=O>[CH3:14][O:13][C:6]1[CH:5]=[C:4]([O:15][CH3:16])[C:3]([C:17](=[O:32])[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=2)=[C:2]([O:1][CH2:36][C:37]([O:39][CH3:40])=[O:38])[C:7]=1[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: COCOc1ccc(CCC(=O)c2c(OC)cc(OC)c(CCC(C)C)c2O)cc1OC
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1ccc(CCC(=O)c2c(OC)cc(OC)c(CCC(C)C)c2OCC(=O)OC)cc1OC
Reaction time: 1 h

Procedure:
Then, 10 ml of dimethylformamide was dropped into a mixture of 2.0 g of 1-(2-hydroxy-4,6-dimethoxy-3-isopentylphenyl)-3-(3-methoxy-4-methoxymethoxyphenyl)-1-propanone and 0.2 g of sodium hydride, and the mixture was stirred for 60 minutes. Then, 0.5 ml of methyl α-bromoacetate was added to the mixture at 0° C., and the mixture was stirred for 45 minutes. After the reaction, the solvent was removed from the reaction liquid mixture by distillation, and the residue was dried under reduced pressure to obtain substantially quantitatively 1-(4,6-dimethoxy- 2-methoxycarbonylmethoxy-3-isopentylphenyl)-3-(3-methoxy-4-methoxymethoxyphenyl)-1-propanone in the form of a colorless transparent oil.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[CH3:13].[H-].[Na+].[Cl:16][CH2:17][CH2:18][CH2:19]I>CN(C=O)C>[Cl:16][CH2:17][CH2:18][CH2:19][N:9]1[C:10]2[C:5](=[CH:4][C:3]([CH3:13])=[C:2]([F:1])[CH:11]=2)[CH2:6][CH2:7][C:8]1=[O:12]
Reactant: ClCCCI
Reactant: Cc1cc2c(cc1F)NC(=O)CC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2c(cc1F)N(CCCCl)C(=O)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.3 %

Procedure:
A reaction flask was charged with 7-fluoro-6-methyl-3,4-dihydro-1H-quinolin-2-one (97KK40) (0.102 g, 0.57 mmol) in dry DMF (5 mL) under an argon atmosphere. Washed NaH (0.015 g, 0.63 mmol) was added and the mixture was stirred at rt for 1 h. Then 1-chloro-3-iodopropane (0.104 g, 0.51 mmol) dissolved in DMF (1 mL) was added followed by stirring at rt for 20 h. The reaction mixture was quenched with water, and the product extracted into Et2O. The combined organic layers were washed with aqueous 4% MgSO4, dried over Na2SO4, filtered, and concentrated. The product was purified by flash CC (SiO2; DCM/n-heptane 2:1, DCM, MeOH/DCM 1:10) to give the title compound (112KK01) (0.050 g, 38%). 1H NMR (CDCl3) δ 6.95-6.93 (m, 1H), 6.73 (d, J=11.5 Hz, 1H), 4.03-4.00 (m, 2H), 3.59 (t, J=6.5 Hz, CH2), 2.83-2.79 (m, 2H), 2.62-2.58 (m, 2H), 2.20 (d, J=1.8 Hz, CH3), 2.13-2.07 (m, 2H).
Reaction SMILES: [C:1]1([C:11]([N:13]2[C:17](=[O:18])[C:16]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:15]([CH2:31][C:32]([O:34]C(C)(C)C)=[O:33])[C:14]2=[O:39])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl>FC(F)(F)C(O)=O.ClCCl>[C:1]1([C:11]([N:13]2[C:17](=[O:18])[C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:15]([CH2:31][C:32]([OH:34])=[O:33])[C:14]2=[O:39])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)CN1C(=O)N(C(=O)c2cccc3ccccc23)C(=O)C1(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CN1C(=O)N(C(=O)c2cccc3ccccc23)C(=O)C1(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 2-(3-naphthylcarbonyl-2,4-dioxo-5,5-diphenylimidazolidinyl)acetate (300 mg) was dissolved in a 20% trifluoroacetic acid/dichloromethane solution (2 mL), and the solution was stirred at room temperature overnight. After a 1N aqueous hydrogen chloride solution was added, the solution was extracted three times using chloroform (50 mL). The resulting organic layer was washed with a saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was distilled off. Further, recrystallization from IPE afforded 231 mg of white crystals.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[OH:24])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].Cl[CH2:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]=1[O:37][CH2:38][CH2:39][O:40][CH3:41]>>[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]=2[O:37][CH2:38][CH2:39][O:40][CH3:41])=[CH:9][CH:10]=1)[CH:2]=[CH2:3]
Reactant: COCCOc1c(CCl)ccc2ccccc12
Reactant: C=CCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: C=CCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3ccccc3c2OCCOC)cc1

Procedure:
In an analogous manner to that described in Example 1(g), by alkylating tert-butyl (3RS,4RS)-4-(4-allyloxy-phenyl)-3-hydroxy-piperidine-1-carboxylate [Example 86(b)] with 2-chloromethyl-1-(2-methoxy-ethoxy)-naphthalene [Example 122(h)] there was obtained tert-butyl (3RS,4RS)-4-(4-allyloxy-phenyl)-3-[1-(2-methoxy-ethoxy)-naphthalen-2-ylmethoxy]-piperidine-1-carboxylate, from which by cleavage of the allyl group by means of bis-(triphenylphosphine)-palladium(II) diacetate analogously to Example 152(e) there was obtained tert-butyl (3RS,4RS)-4-(4-hydroxy-phenyl)-3-[1-(2-methoxy-ethoxy)-naphthalen-2-ylmethoxy]-piperidine-1-carboxylate. Subsequent alkylation with 3-phenyl-isoxazol-5-ylmethyl methanesulphonate analogously to Example 44(e) gave tert-butyl (3RS,4RS)-3-[1-(2-methoxy-ethoxy)-naphthalen-2-ylmethoxy]-4-[4-(3-phenyl-isoxazol-5-ylmethoxy)-phenyl]-piperidine-1-carboxylate as a colourless solid; MS: 665 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)[OH:19])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].N[C:30]([O:32][CH2:33][CH3:34])=O.CC(C)([O-])C.[Li+].C(C1OC1)Br>CC(N(C)C)=O>[CH2:34]([CH2:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)[OH:19])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1])[CH:33]1[O:32][CH2:30]1
Reactant: CCOC(N)=O
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: BrCC1CO1
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: CC(=O)N(C)C
Product: CC(CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)CCC1CO1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
A schematic diagram of the reactions used for covalent binding of cholesterol to the urethane hard segments by the reaction of bromobutylated Tecothane® with 2-hydroxy-3-β-cholesteryloxypropanethiol is presented in FIGS. 1 and 2. Glycidyl cholesterol (FIG. 1) was synthesized by dissolving cholesterol in DMAc under a flow of dry argon and adding 1 M lithium tert-butoxide in hexanes. After cooling to 5° C., freshly distilled epibromohydrin was added and the mixture was stirred at 3-5° C. for 2 hours and allowed to slowly come to room temperature (21-23° C.) where it was incubated for an additional hour. The reaction mixture was diluted with 0.5% aqueous KHCO3 and extracted with three administrations of n-heptane. The combined organic layers were dried over Na2SO4. After filtration from the desiccant, the solvent was removed in vacuo and the residue was purified by flash-chromatography on silica gel employing elution with hexane, hexane/toluene (1:1 mixture), and toluene. The fractions containing pure glycidyl cholesterol were pooled and dried in vacuo until crystallization occurred. Purity was confirmed with 1H NMR (data not shown).
Reaction SMILES: Cl.[CH3:2][C:3]1[NH:4][C:5]2[CH:11]=[C:10]([NH2:12])[CH:9]=[C:8]([CH3:13])[C:6]=2[N:7]=1.[Cl:14][C:15]1[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=1>C(O)CCC>[Cl:14][C:15]1[N:16]=[CH:17][N:18]=[C:19]([NH:12][C:10]2[CH:9]=[C:8]([CH3:13])[C:6]3[NH:7][C:3]([CH3:2])=[N:4][C:5]=3[CH:11]=2)[CH:20]=1
Reactant: Cc1nc2c(C)cc(N)cc2[nH]1
Reactant: Clc1cc(Cl)ncn1
Agent: Cl
Solvent: CCCCO
Product: Cc1nc2cc(Nc3cc(Cl)ncn3)cc(C)c2[nH]1
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere 3.00 g (15.2 mmol) 2,7-dimethyl-benzimidazol-5-ylamine-hydrochloride, 2.30 g (15.4 mmol) 4,6-dichloropyrimidine and 6.50 mL (47.0 mmol) TEA in 15 mL 1-butanol were stirred for 3 h at 100° C. After cooling to RT the reaction mixture was evaporated down, the residue was stirred in DCM and the precipitate formed was suction filtered and dried.
Reaction SMILES: CS(O[C@@H:6]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[CH:8]([C:9](=[O:26])[CH2:10][C@@H:11]3[C@@H:20]2[CH2:19][CH2:18][C@@:16]2([CH3:17])[C@H:12]3[CH2:13][CH2:14][C:15]2=[O:25])[CH2:7]1)(=O)=O.[K+].[C:28]([O-:31])(=[S:30])[CH3:29]>CN(C=O)C>[C:28]([S:30][C@H:6]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[CH:8]([C:9](=[O:26])[CH2:10][C@@H:11]3[C@@H:20]2[CH2:19][CH2:18][C@@:16]2([CH3:17])[C@H:12]3[CH2:13][CH2:14][C:15]2=[O:25])[CH2:7]1)(=[O:31])[CH3:29]
Reactant: C[C@]12CC[C@@H](OS(C)(=O)=O)CC1C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)S[C@H]1CC[C@@]2(C)C(C1)C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 70 °C
Yield: 55 %

Procedure:
To a solution of 3α-methanesulfonyloxyandrostane-6,17-dione (2.00 g) in dry DMF (25 mL), thioacetic acid potassium salt (1.20 g) was added. The mixture was heated to 70° C. for 3 h. After cooling, 5% NaH2PO4 was added and extracted with EtOAc (3×). The organic extracts were washed with brine, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography (SiO2, n-hexane/EtOAc 8/2) to give 3β-acetylthioandrostane-6,17-dione in 55% yield as a yellow solid. 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 4.50 (1H, m), 3.10 (3H, s), 2.50-0.90 (20H, m), 0.88 (3H, s), 0.77 (3H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:23]2[O:24][C:25]3[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][C:26]=3[C:27](=[O:30])[C:28]=2[OH:29])[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36](#[N:38])[CH3:37]>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:23]2[O:24][C:25]3[CH:34]=[CH:33][C:32]([NH:35][C:36](=[NH:38])[CH3:37])=[CH:31][C:26]=3[C:27](=[O:30])[C:28]=2[OH:29])[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc2oc(-c3ccc(OCc4ccccc4)c(OCc4ccccc4)c3)c(O)c(=O)c2c1
Reactant: CC#N
Product: CC(=N)Nc1ccc2oc(-c3ccc(OCc4ccccc4)c(OCc4ccccc4)c3)c(O)c(=O)c2c1
Temperature: 0 °C
Reaction time: 120 h
Yield: 92 %

Procedure:
2-(3,4-dibenzyloxyphenyl)-3-hydroxy-6-amino-4H-1-benzopyran-4-one (1.9 g; 3.78 mmol) was suspended in acetonitrile (40 mL) and cooled at 0° C. HCl was bubbled into the solution upon saturation. The reaction was then stirred for 5 days at r.t. Upon completion, H2O (20 mL) was added and the acetonitrile removed under vacuum. The precipitate was filtered off and dried to afford the titled compound as a bright yellow solid. Yield: 92%. TLC (9/1 Chloroform/Methanol) Rf: 0.2. 1H-NMR (d6-DMSO): 11.61 (br s, 1H); 9.62 (s, 1H); 8.65 (s, 1H); 8.01 (d, 1H), 7.90 (d, 2H); 7.78 (d, 1H); 7.35 (d, 2H); 7.65 (dt, 2H); 6.93 (d, 1H); 3.35 (s, 3H)
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:33]([C:36]1[CH:44]=[CH:43][C:39]([C:40](O)=[O:41])=[CH:38][CH:37]=1)([O-:35])=[O:34].N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[O:13]=[C:9]1[CH2:10][CH2:11][CH2:12][N:8]1[C@@H:5]1[CH2:4][CH2:3][C@H:2]([O:1][C:40](=[O:41])[C:39]2[CH:38]=[CH:37][C:36]([N+:33]([O-:35])=[O:34])=[CH:44][CH:43]=2)[CH2:7][CH2:6]1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C1CCCN1[C@H]1CC[C@H](O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(O[C@H]1CC[C@@H](N2CCCC2=O)CC1)c1ccc([N+](=O)[O-])cc1
Temperature: -5 °C
Yield: 62.1 %

Procedure:
Dissolve 1-(trans-4-hydroxy-cyclohexyl)-pyrrolidin-2-one (144 g, 0.79 mol) in dry tetrahydrofuran (5 L) and cool to −5° C. under nitrogen. Add triphenylphosphine (310 g, 1.185 mol) and 4-nitrobenzoic acid (198 g, 1.185 mol). Add diisopropyl azodicarboxylate (230 mL, 1.185 mol) drop-wise and stir at room temperature overnight. Add saturated aqueous sodium bicarbonate (1 L) and extract into dichloromethane (2×2.5 L) in a 20 L separating funnel. Dry the combined organic layers over magnesium sulfate, filter and concentrate. Purify over silica gel (iso-hexane/ethyl acetate 50-100% then 10% methanol in ethyl acetate) to afford 163 g (62%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][C:11](=[O:13])[CH3:12])=[CH:4][C:3]=1[N+:14]([O-])=O>C(O)C.C(O)(=O)C.[Pd]>[NH2:14][C:3]1[CH:4]=[C:5]([CH2:8][CH2:9][O:10][C:11](=[O:13])[CH3:12])[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: CC(=O)OCCc1ccc(N)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(=O)OCCc1ccc(N)c(N)c1
Reaction time: 2 h

Procedure:
Aryl nitrate 187 was dissolved in neat ethanol (25 mL) and 10% Pd/C (50 mg) was added, followed by 3 drops of glacial acetic acid. H2 gas was applied at 46 psi for 2 h with vigorous shaking, after which time TLC analysis indicated complete consumption of 187. The reaction mixture was filtered through a pad of Celite to remove the catalyst and the filtrate was concentrated under reduced pressure to give 188 as an oil. Column chromatography was employed with 10% MeOH/CH2Cl2 as eluant to give pure 188 as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH3:25][O:26][CH2:27][C:28]1([CH2:33][NH2:34])[CH2:32][CH2:31][CH2:30][CH2:29]1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:34][CH2:33][C:28]4([CH2:27][O:26][CH3:25])[CH2:32][CH2:31][CH2:30][CH2:29]4)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: COCC1(CN)CCCC1
Product: COCC1(CNC(=O)c2ccc(-n3ncc(-c4ccc(C#N)cc4C)c3O)nc2)CCCC1

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (1-(methoxymethyl)cyclopentyl)methanamine 1H NMR (400 MHz, DMSO-d6) δ ppm 1.26-1.38 (m, 2 H) 1.38-1.59 (m, 6 H) 2.37 (s, 3 H) 3.13 (s, 2 H) 3.21 (s, 3 H) 3.26 (d, J=6.32 Hz, 2 H) 7.59 (dd, J=7.83, 1.52 Hz, 1 H) 7.66 (s, 1 H) 7.73 (d, J=8.08 Hz, 1 H) 8.09 (s, 1 H) 8.33 (s, 2 H) 8.42 (t, J=6.06 Hz, 1 H) 8.82 (t, J=1.52 Hz, 1 H) 12.56-13.49 (m, 1 H). MS m/z [M+H]+ 446.2.
Reaction SMILES: [F:1][C:2]([S:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=O)([F:4])[F:3].[C@@H:14]1([NH2:24])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH2:15]1>>[C@@H:14]1([NH:24][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[C:6]([S:5][C:2]([F:4])([F:3])[F:1])[CH:7]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH2:15]1
Reactant: O=Cc1cccc(SC(F)(F)F)c1
Reactant: N[C@H]1CCCc2ccccc21
Product: FC(F)(F)Sc1cccc(CN[C@H]2CCCc3ccccc32)c1

Procedure:
3-[(Trifluoromethyl)sulfanyl]benzaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.