Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5](=[O:18])([O:15][CH2:16][CH3:17])[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[F:14]>S(=O)(=O)(O)O>[C:5](=[O:18])([O:15][CH2:16][CH3:17])[O:6][C:7]1[CH:12]=[C:11]([N+:1]([O-:4])=[O:2])[CH:10]=[C:9]([F:13])[C:8]=1[F:14]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)Oc1cccc(F)c1F
Agent: O=S(=O)(O)O
Product: CCOC(=O)Oc1cc([N+](=O)[O-])cc(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 6 %

Procedure:
Step M (2): A mixture of concentrated sulfuric acid and nitric acid (1:1 ratio, 60 mL total volume) was slowly and carefully added to a solution of 2,3-difluorophenyl ethyl carbonate (20 g, 98.9 mmol) in concentrated sulfuric acid (15 mL). The internal temperature was maintained at rt throughout the addition. After complete addition, the resulting mixture was stirred for 2 h. The mixture was poured onto ice and extracted with chloroform. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified using silica gel column chromatography (hexane) to afford 2,3-difluoro-5-nitrophenyl ethyl carbonate (1.5 g, 6% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[C:12]1([CH3:22])[CH:17]=[CH:16][CH:15]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:13]=1>CN(C1C=CN=CC=1)C>[CH3:22][C:12]1[CH:13]=[C:14]([S:18]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Reactant: Nc1cccc2cccnc12
Agent: CN(C)c1ccncc1
Product: Cc1cccc(S(=O)(=O)Nc2cccc3cccnc23)c1
Yield: 64.5 %

Procedure:
In the similar fashion using route 14 general procedure 27, 8-aminoquinoline (200 mg, 1.38 mmol), m-toluenesulfonyl chloride (260 mg, 1.3 mmol) and DMAP (cat.) gave the title compound (250 mg, 60%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH2:9][CH3:10])[C:5]([C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[O:12])=[C:4]([CH3:22])[CH:3]=1.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.CCN(C(C)C)C(C)C>CC#N.O.CCOC(C)=O>[CH2:9]([S:8][C:6]1[C:5]([C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[O:12])=[C:4]([CH3:22])[CH:3]=[C:2]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:7]=1)[CH3:10]
Reactant: C1COCCN1
Reactant: CCSc1nc(Cl)cc(C)c1C(=O)NCc1ccc(F)cc1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCSc1nc(N2CCOCC2)cc(C)c1C(=O)NCc1ccc(F)cc1
Temperature: 180 °C
Yield: 53.3 %

Procedure:
A solution of 254 mg (0.75 mmol) 6-chloro-2-ethylsulfanyl-N-[(4-fluorophenyl)-methyl]-4-methyl-pyridine-3-carboxylic acid amide (synthesized according to the methods described in sections a) and b) of example 2), 196 μl (2.25 mmol) morpholine and 392 μl (2.25 mmol) DIPEA in MeCN (2 ml) was heated in the microwave at 180° C. for 4 h. Subsequently the RM was diluted with water and EtOAc and the layers were separated. The organic layer was washed with water and brine, dried over MgSO4 and concentrated in vacuo. Crystallisation (hexane/EtOAc 1:1) of the residue yielded 154 mg (0.40 mmol, 53%) 2-ethylsulfanyl-N-[(4-fluorophenyl)-methyl]-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide (example 4). [M+H]+ 390.2.
Reaction SMILES: [C:1]([OH:6])(=O)[CH:2]([CH3:4])[OH:3].[CH2:7]([NH2:10])[CH2:8][NH2:9]>O>[CH2:7]([NH:10][C:1](=[O:6])[CH:2]([CH3:4])[OH:3])[CH2:8][NH:9][C:1](=[O:6])[CH:2]([CH3:4])[OH:3]
Reactant: NCCN
Reactant: CC(O)C(=O)O
Solvent: O
Product: CC(O)C(=O)NCCNC(=O)C(C)O
Temperature: 125 °C

Procedure:
Lactic acid (441 g; 4.90 moles) was placed in a reaction flask equipped with a distillation head. Under a nitrogen atmosphere, ethylene diamine (147 g; 2.45 moles) was slowly added with stirring to the reaction flask. During the course of the addition, the reaction mixture turned a deep orange and the temperature reached 140° C. The reaction mixture was then heated at 150° C. overnight with the water being removed by distillation. The reaction mixture was allowed to cool to 125° C. then it was poured into an aluminum pan and allowed to cool to ambient temperature. to provide 468 g of crude product. This material was recrystallized from methanol (1.9 L) to provide N,N'-1,2-ethanediylbislactamide, m.p. 188° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:17]=[N:18][C:19]([NH:22][NH2:23])=[CH:20][CH:21]=2)[CH:13]=[CH:12][O:11]3)=[CH:4][CH:3]=1.FC1C=CC(C2N=C3N(C=2)C=CO3)=CC=1.C1C(=O)N(I)C(=O)C1.FC1C=CC(B(O)O)=CN=1.NN.[CH3:59][C:60]1([CH3:67])[CH2:64][C:63](=O)[O:62][C:61]1=[O:66]>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:21]=[CH:20][C:19]4[N:18]([C:63]([CH2:64][C:60]([CH3:67])([CH3:59])[C:61]([OH:66])=[O:62])=[N:23][N:22]=4)[CH:17]=2)[CH:13]=[CH:12][O:11]3)=[CH:4][CH:3]=1
Reactant: CC1(C)CC(=O)OC1=O
Reactant: NNc1ccc(-c2c(-c3ccc(F)cc3)nc3occn23)cn1
Agent: Fc1ccc(-c2cn3ccoc3n2)cc1
Agent: NN
Agent: O=C1CCC(=O)N1I
Solvent: C1COCCO1
Product: CC(C)(Cc1nnc2ccc(-c3c(-c4ccc(F)cc4)nc4occn34)cn12)C(=O)O
Temperature: 100 °C
Yield: 81 %

Procedure:
In a 100 mL round-bottom flask 6-(4-fluorophenyl)-5-(6-hydrazinylpyridin-3-yl)imidazo[2,1-b]oxazole (0.20 g, 0.65 mmol; prepared using A from 6-(4-fluorophenyl)-imidazo[2,1-b]oxazole [prepared according to WO2004110990A2, Example 1, Steps 1-3] with NIS, C using 2-fluoropyridine-5-boronic acid [Asymchem], D using hydrazine) and 3,3-dimethyldihydrofuran-2,5-dione (0.091 g, 0.71 mmol) were dissolved in 1,4-dioxane (5 mL) and the mixture was heated to about 100° C. After about 2 h the reaction was cooled to ambient temperature and concentrated in vacuo. The crude material was dissolved in DCM and crystallized upon the addition of Et2O. The resulting solid was filtered and dried under vacuum to provide the title compound as a white solid (0.22 g, 81%): LC/MS (Table 1, Method a) Rt, =1.86 min; MS m/z: 420.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([CH3:16])[C:12]([NH2:15])=[N:13][CH:14]=2)=[CH:5][CH:4]=1.[CH3:18][C:19]1[O:23][C:22]([CH2:24][CH2:25][C:26](Cl)=[O:27])=[CH:21][CH:20]=1>N1C=CC=CC=1>[CH3:1][N:2]([CH3:17])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[C:11]([CH3:16])[C:12]([NH:15][C:26](=[O:27])[CH2:25][CH2:24][C:22]3[O:23][C:19]([CH3:18])=[CH:20][CH:21]=3)=[N:13][CH:14]=2)=[CH:7][CH:8]=1
Reactant: Cc1ccc(CCC(=O)Cl)o1
Reactant: Cc1cc(-c2ccc(N(C)C)cc2)cnc1N
Solvent: c1ccncc1
Product: Cc1ccc(CCC(=O)Nc2ncc(-c3ccc(N(C)C)cc3)cc2C)o1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 5-(4-(dimethylamino)phenyl)-3-methylpyridin-2-amine (120b, 2.27 g, 10.0 mmol) in pyridine (30 ml) was added with 3-(5-methylfuran-2-yl)propanoyl chloride (1.90 g, 11.0 mmol) and then stirred at room temperature for further 16 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4(s) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give N-(5-(4-(Dimethylamino)phenyl)-3-methylpyridin-2-yl)-3-(5-methylfuran-2-yl) propanamide (120): 1H NMR (500 MHz, DMSO-d6):δ: 9.99 (s, 1H), 8.46 (s, 1H), 7.84 (s, 1H), 7.55 (m, 2H), 6.81 (m, 2H), 5.98 (s, 1H), 5.94 (s, 1H), 2.94 (s, 6H), 2.87 (t, 2H), 2.65 (t, 2H), 2.21 (s, 3H), 2.16 (s, 3H).
Reaction SMILES: [C:1]1(C)C=CC=C[CH:2]=1.C(=O)(O)[O-].[Na+].[OH-].[K+].[C:15]([C:18]1[S:19][CH2:20][CH2:21][O:22][C:23]=1[CH3:24])([OH:17])=[O:16]>C1C=CC=CC=1>[CH3:24][C:23]1[O:22][CH2:21][CH2:20][S:19][C:18]=1[C:15]([O:17][CH2:1][CH3:2])=[O:16].[CH3:24][C:23]1[O:22][CH2:21][CH2:20][S:19][C:18]=1[C:15]([OH:17])=[O:16]
Reactant: Cc1ccccc1
Agent: CC1=C(C(=O)O)SCCO1
Agent: O=C([O-])O
Agent: [K+]
Solvent: c1ccccc1
Product: CCOC(=O)C1=C(C)OCCS1

Procedure:
Ethyl 5,6-dihydro-2-methyl-1,4-oxathiin-3-carboxylate was prepared by the method of U.S. Pat. No. 3,249,499 (col. 5, lines 36-55), with the following modifications: toluene was used as the solvent instead of benzene, sodium bicarbonate was used as the base instead of potassium hydroxide, and the azeotropic removal of water was carried out under reduced pressure at about 65° C. 5,6-Dihydro-2-methyl-1,4-oxathiin-3-carboxylic acid was prepared by hydrolysis of the ester as described in the same patent (col. 5, lines 56-68, where the acid is named 2,3-dihydro-5-carboxy-6-methyl-1,4-oxathiin).
Reaction SMILES: C(N(CC)CC)C.Br[C:9]1[CH:18]=[CH:17][C:16]2[NH:15][C:14](=[O:19])[C:13]3[NH:20][CH:21]=[CH:22][C:12]=3[C:11]=2[CH:10]=1.[CH2:23]([C:25]([O-:27])=[O:26])[CH3:24].Br[C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1.[O-]P(OP(OP([O-])([O-])=O)([O-])=O)(=O)[O-].[K+].[K+].[K+].[K+].[K+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[C:37]1([C:9]2[CH:18]=[CH:17][C:16]3[NH:15][C:14](=[O:19])[C:13]4[NH:20][CH:21]=[CH:22][C:12]=4[C:11]=3[CH:10]=2)[C:38]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[CH:35][CH:36]=1.[CH2:23]([C:25]([O-:27])=[O:26])[CH3:24]
Reactant: Brc1cccc2ccccc12
Reactant: O=c1[nH]c2ccc(Br)cc2c2cc[nH]c12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCC(=O)[O-]
Agent: O=P([O-])([O-])OP(=O)([O-])OP(=O)([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=c1[nH]c2ccc(-c3cccc4ccccc34)cc2c2cc[nH]c12
Temperature: 110 °C
Reaction time: 96 h
Yield: 14.4 %

Procedure:
68 mg (0.1 mmol) of dichlorobis(triphenylphosphine)-palladium (11), 149 mg (0.59 mmol) of bis(pinacolo)diborane and 273 μL (1.96 mmol) of triethylamine are added to a degassed solution of 200 mg (0.49 mmol) of 8-bromo-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate dissolved in 4 mL of anhydrous dioxan. The reaction mixture is stirred at 110° C. for 4 days. Water is added and the product is extracted with ethyl acetate. The organic phases are washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and evaporated. The residue is taken up in 5 mL of anhydrous dioxan. The solution is degassed with a stream of nitrogen before adding 81 μL (0.59 mmol) of 1-bromonaphthalene, 69 mg (0.1 mmol) of dichlorobis(triphenylphosphine)-palladium (II) and 1 mL (2 mmol) of a 2M aqueous solution of tribasic potassium triphosphate. The reaction mixture is stirred at 110° C. for 20 hours. Water is added and the product is extracted with ethyl acetate. The organic phases are washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and evaporated. The residue is purified by chromatography on silica (eluent dichloromethane/methanol 98/2) to give 27 mg (3% in two stages) of 8-naphthalen-1-yl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in the form of a beige solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=1)[CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].Cl>CO>[CH2:1]([O:8][C:9]([N:11]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:22][CH:23]=1)[CH3:12])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(CN(C)C(=O)OCc2ccccc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CN(Cc1ccc(C(=O)O)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 56.8 %

Procedure:
The methyl 4-(((benzyloxycarbonyl)(methyl)amino)methyl)benzoate was dissolved in methanol, then LiOH (0.35 g, 14.7 mmol) was added. The resulting mixture was maintained at room temperature for 2 days. The mixture was adjusted to pH=1˜2 with 2N aqueous hydrochloric acid then extracted with ethyl acetate (50 mL×3). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and condensed under vacuum. The residue was purified by silica gel chromatography (petrol ether:ethyl acetate=10:1) to yield a white solid of 4-(((benzyloxycarbonyl)(methyl)amino)methyl)benzoic acid (1.25 g, 56.8%), LC-MS (ESI) m/z 300 [M+1]+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]=[C:6]=[O:7].CO[C:10]([C@:12]1([CH3:34])[CH2:24][C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:25][CH3:26])[CH:21]=3)[NH:16][C:15]=2[C@@H:14]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=2)[NH:13]1)=[O:11]>>[Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[C:6](=[O:7])[N:13]2[C@H:14]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=3)[C:15]3[NH:16][C:17]4[C:22]([C:23]=3[CH2:24][C@@:12]2([CH3:34])[C:10]1=[O:11])=[CH:21][C:20]([O:25][CH3:26])=[CH:19][CH:18]=4
Reactant: COC(=O)[C@]1(C)Cc2c([nH]c3ccc(OC)cc23)[C@@H](c2cccc(O)c2)N1
Reactant: O=C=NCCCCl
Product: COc1ccc2[nH]c3c(c2c1)C[C@@]1(C)C(=O)N(CCCCl)C(=O)N1[C@@H]3c1cccc(O)c1

Procedure:
The title compound is prepared analogously to the procedure described for example 22, using chloro propyl isocyanate and (1R,3S)-1-(3-hydroxy-phenyl)-6-methoxy-3-methyl-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylic acid methyl ester. MS: m/z (MH+)=454.0
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.Cl.C(=O)(O)O.[NH2:15][NH:16][C:17]([NH2:19])=[NH:18].[OH-].[K+]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[N:15]/[NH:16][C:17](=[NH:18])[NH2:19])=[CH:4][CH:3]=1
Reactant: N=C(N)NN
Reactant: O=Cc1ccc(Cl)cc1
Agent: Cl
Agent: O=C(O)O
Agent: [K+]
Product: N=C(N)N/N=C/c1ccc(Cl)cc1
Yield: 88.2 %

Procedure:
A mixture of 4-chlorobenzaldehyde (2.0 g, 10.2 mmol), 20% hydrochloric acid (4 mL) was added to an aminoguanidine bicarbonate (1.39 g, 10.2 mmol) aqueous solution, and heated to reflux for 4 h. A solution of 40% aqueous potassium hydroxide (7 mL) was added dropwise, the mixture was heated at reflux for 10 min and the precipitate formed. The precipitate was filtered, washed with water, and recrystallized from ethanol to give 2-[(E)-1-(4-chlorophenyl)methylidene]-1-hydrazinecarboximidamide (1.77 g, 88%) as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[CH2:6][N:7]1C(=O)C2=CC=CC=C2C1=O)#[N:2].O.NN.C(Cl)Cl.[OH-].[Na+]>CO>[C:1]([C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[CH2:6][NH2:7])#[N:2]
Reactant: N#Cc1cccc(CN2C(=O)c3ccccc3C2=O)c1
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: N#Cc1cccc(CN)c1
Temperature: 25 °C
Yield: 80 %

Procedure:
A solution of the N-(3-cyanobenzyl)phthalimide (2.70 g, 10.4 mmol) and hydrazine hydrate (2.5 mL, 51 mmol) in MeOH (50 mL) was heated to reflux for 1 h. After cooling at room temperature, CH2Cl2 and aq. 1N NaOH were added. The CH2Cl2 layer was separated, washed with brine, dried over Na2SO4, concentrated in vacuo to give an oil (1.10 g), which was pure enough for the next reaction. MS 133 (M+H) and 116 (M−NH2)
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[C:13]([N:20]3[CH2:29][CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)[N:14]=[C:15]([C:17]([OH:19])=[O:18])[CH:16]=[C:11]2[C:10]([CH3:30])=[C:9]1[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+:33]>O1CCCC1>[Na+:33].[CH2:1]([N:8]1[C:12]2=[C:13]([N:20]3[CH2:29][CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)[N:14]=[C:15]([C:17]([O-:19])=[O:18])[CH:16]=[C:11]2[C:10]([CH3:30])=[C:9]1[CH3:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(C)n(Cc2ccccc2)c2c(N3CCc4ccccc4C3)nc(C(=O)O)cc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(C)n(Cc2ccccc2)c2c(N3CCc4ccccc4C3)nc(C(=O)[O-])cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
1-Benzyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid (28 mg, 0.068 mmol) prepared in Example 733 and sodium hydride (2.6 mg, 0.068 mmol) were dripped into anhydrous tetrahydrofuran (1 ml). The reaction mixture was stirred for 2 hours at room temperature and then concentrated under reduced pressure. The resulting residue was re-crystallized with methanol to give the titled compound as a white solid. (Yield: 82%)
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@@H:8]1[C@@:40]2([CH3:41])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:39]2[CH2:38][CH2:37][C@@:36]2([CH3:42])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH2:34][OH:35])[CH2:21][CH2:22][C@H:23]([F:33])[C:24]([O:27][CH:28]([O:30][CH2:31][CH3:32])[CH3:29])([CH3:26])[CH3:25])[CH2:11][C@@H:10]([O:43][CH:44]2[CH2:49][CH2:48][CH2:47][CH2:46][O:45]2)[CH2:9]1.[C:50]1([CH3:60])[CH:55]=[CH:54][C:53]([S:56](Cl)(=[O:58])=[O:57])=[CH:52][CH:51]=1>N1C=CC=CC=1>[CH3:60][C:50]1[CH:55]=[CH:54][C:53]([S:56]([O:35][CH2:34][C@@H:20]([C@@H:19]2[C@:36]3([CH3:42])[C@H:16]([C@H:15]4[C@H:39]([CH2:38][CH2:37]3)[C@:40]3([CH3:41])[C:12]([CH2:11][C@@H:10]([O:43][CH:44]5[CH2:49][CH2:48][CH2:47][CH2:46][O:45]5)[CH2:9][C@@H:8]3[O:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)=[CH:13][CH2:14]4)[CH2:17][CH2:18]2)[CH2:21][CH2:22][C@H:23]([F:33])[C:24]([O:27][CH:28]([O:30][CH2:31][CH3:32])[CH3:29])([CH3:26])[CH3:25])(=[O:58])=[O:57])=[CH:52][CH:51]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(C)OC(C)(C)[C@@H](F)CC[C@@H](CO)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Solvent: c1ccncc1
Product: CCOC(C)OC(C)(C)[C@@H](F)CC[C@@H](COS(=O)(=O)c1ccc(C)cc1)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C

Procedure:
A mixture of 0.19 g. (0.00027 mole) of [1α,3β,24S]-1,3-bis-[(tetrahydro-2H-pyran-2-yl)oxy]-25-(1-ethoxyethoxy)-24-fluorocholest-5-en-21-ol, 1 ml. of pyridine and 0.104 g. (0.00054 mole) of p-toluenesulfonyl chloride was stirred at 0° C. for 18 hr. The mixture was quenched with ice chips. The mixture was then poured into water and extracted with methylene chloride. The organic phase was washed with 10% aqueous sulfuric acid and saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness to yield oily [1α,3β,24S]-1,3-bis[(tetrahydro-2H-pyran-2-yl)oxy]-25-(1-ethoxyethoxy)-24-fluorocholest-5-en-21ol 21-(4-methylbenzenesulfonate).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=O.[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[N:21]1[CH2:28][C@H:27]2[NH:29][CH2:30][C@@H:22]1[CH2:23][CH:24]=[CH:25][CH2:26]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(OCC)(=O)C.C(O)(=O)C.ClCCCl>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[N:29]1[CH2:30][CH:22]2[N:21]([C:12]3[CH:13]=[CH:14][C:15]4[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:11]=3)[CH2:28][CH:27]1[CH2:26][CH:25]=[CH:24][CH2:23]2
Reactant: O=C1Cc2ccccc2C1
Reactant: C1=CC[C@H]2CN[C@@H](C1)CN2c1ccc2ccccc2c1
Agent: C1=C\C[C@H]2CN[C@@H](C/1)CN2c1ccc2ccccc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: C1=CCC2CN(c3ccc4ccccc4c3)C(C1)CN2C1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of indan-2-one (45 mg, 0.34 mmol), Z-(1S,6S)-7-naphthalen-2-yl-7,9-diaza-bicyclo[4.2.2]dec-3-ene (50 mg, 0.19 mmol), sodium triacetoxyborohydride (45 mg, 0.212 mmol), DCE (20 mL), acetic acid (13 μL) was stirred at room temperature overnight. To the reaction mixture was then added 1N NaOH and ethyl acetate. The organic layer was separated, dried with magnesium sulfate, filtered and the solvent evaporated under reduced pressure to yield a crude solid that was purified with flash chromatography gradient [20% Ethyl acetate/heptane to 100% Ethyl acetate] to yield the title compound as a residue.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8][CH:9]([OH:13])[CH2:10][CH:11]=[CH2:12])([CH3:4])([CH3:3])[CH3:2].[CH3:15][C:16]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])[CH3:17].N1C=CN=C1>C1COCC1>[C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8][CH:9]([O:13][Si:19]([C:16]([CH3:18])([CH3:17])[CH3:15])([CH3:21])[CH3:20])[CH2:10][CH:11]=[CH2:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCC(O)CNC(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: C=CCC(CNC(=O)OC(C)(C)C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.1 %

Procedure:
Rac-(2-hydroxy-pent-4-enyl)-carbamic acid tert-butyl ester (5 g, 24.8 mmol; prepared according to Tetrahedron Lett. (2006), 47, 3295) was added dropwise to a mixture of TBDMSCl (3.7 g, 1 eq.) and imidazole (1.7 g, 1 eq.) in THF (55 mL). The mixture was stirred at rt overnight, filtered and the filtrate washed with water and brine, dried over MgSO4 and concentrated. The residue was purified by FC (Hept/EA:1, EA) to give the title intermediate as a colourless oil (2.8 g, 36% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:20])[CH:5]=[C:4]([CH3:27])[N:3]=1.[CH3:28][NH2:29]>C1COCC1>[CH3:28][NH:29][C:2]1[N:3]=[C:4]([CH3:27])[CH:5]=[C:6]([S:8][CH2:9][C:10]2[C:11]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:20])[N:7]=1
Reactant: CN
Reactant: Cc1cc(SCc2cc3cccc(C)c3nc2-c2ccccc2)nc(Cl)n1
Solvent: C1CCOC1
Product: CNc1nc(C)cc(SCc2cc3cccc(C)c3nc2-c2ccccc2)n1
Yield: 10 %

Procedure:
A mixture of Example 85 (100 mg, 0.29 mmol), THF (1 mL) and 2M methylamine in THF (5 mL) was heated in a microwave at 120° C. for 1 h. The solvent was removed in vacuo. Purification by preparative HPLC (Method 1) gave the title compound as a white solid (12 mg, 10%). δH (DMSO-d6) 8.52-8.55 (m, 1H), 7.82 (dd, J 8.3, 0.4 Hz, 1H), 7.68-7.72 (m, 2H), 7.59-7.64 (m, 1H), 7.45-7.55 (m, 4H), 6.95-7.05 (m, 1H), 6.30 (s, 1H), 4.55-4.65 (m, 2H), 2.68-2.75 (m, 6H), 2.11 (s, 3H). LCMS (ES+) 387.3 (M+H)+, RT 3.26 minutes (Method 3).
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11]CC)=[O:10])=[C:7]([CH2:16][NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]3[N:25]=[C:26]([NH:32][C:33]4[CH:38]=[CH:37][C:36]([C:39]([N:41]5[CH2:46][CH2:45][O:44][CH2:43][CH2:42]5)=[O:40])=[CH:35][CH:34]=4)[C:27](=[O:31])[N:28]([CH3:30])[CH:29]=3)[C:19]=2[CH3:47])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].Cl>C1COCC1.CCO.O>[C:1]([C:5]1[CH:15]=[CH:14][C:8]([C:9]([OH:11])=[O:10])=[C:7]([CH2:16][NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]3[N:25]=[C:26]([NH:32][C:33]4[CH:38]=[CH:37][C:36]([C:39]([N:41]5[CH2:46][CH2:45][O:44][CH2:43][CH2:42]5)=[O:40])=[CH:35][CH:34]=4)[C:27](=[O:31])[N:28]([CH3:30])[CH:29]=3)[C:19]=2[CH3:47])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(C(C)(C)C)cc1CNc1cccc(-c2cn(C)c(=O)c(Nc3ccc(C(=O)N4CCOCC4)cc3)n2)c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(NCc2cc(C(C)(C)C)ccc2C(=O)O)cccc1-c1cn(C)c(=O)c(Nc2ccc(C(=O)N3CCOCC3)cc2)n1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To 25 mL round bottom flask charged with ester 101h (100 mg, 0.16 mmol) and LiOH (20 mg, 0.47 mmol) in THF (2 mL), EtOH (2 mL) and H2O (2 mL). After the mixture was stirred at 60° C. for 16 h, the pH was adjusted to 7 with aqueous 1M HCl. The aqueous phase was extracted with EtOAc (2×10 mL), and the combined organic extracts were washed with brine (10 mL), dried with Na2SO4 and concentrated. The crude 101i (97 mg, 99%) was used without further purification.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[CH:15]=[CH:14][N:13]=[CH:12][C:11]=3[N:10]=[CH:9]2)=[N:6][CH:7]=1.BrC1C=CC(F)=CN=1>>[N:6]1[CH:7]=[CH:2][CH:3]=[CH:4][C:5]=1[N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[N:10]=[CH:9]1
Reactant: Fc1ccc(-n2cnc3cnccc32)nc1
Agent: Fc1ccc(Br)nc1
Product: c1ccc(-n2cnc3cnccc32)nc1

Procedure:
Intermediate 3 was prepared in a manner analogous to Intermediate 1, substituting 2-bromopyridine for 2-bromo-5-fluoropyridine. MS (ESI): mass calculated for C11H8N4, 196.07; m/z found 197.1 [M+H]+.