Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]#[C:12][C:13]2[CH:14]=[N:15][C:16]([NH:19][C:20]3[C:25]([N+:26]([O-])=O)=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:29])=[N:17][CH:18]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]#[C:12][C:13]2[CH:14]=[N:15][C:16]([NH:19][C:20]3[C:25]([NH2:26])=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:29])=[N:17][CH:18]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cc(C#Cc2cnc(Nc3c(C)cccc3[N+](=O)[O-])nc2)cc(OC)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1cc(C#Cc2cnc(Nc3c(C)cccc3N)nc2)cc(OC)c1
Temperature: 85 °C
Reaction time: 1 h
Yield: 40.2 %

Procedure:
A mixture of 5-((3,5-dimethoxyphenyl)ethynyl)-N-(2-methyl-6-nitrophenyl)pyrimidin-2-amine (150 mg, 0.38 mmol), Iron (171 mg, 3.04 mmol) and ammonium chloride (246 mg, 4.56 mmol) in ethanol (20 mL) and water (2 mL) was stirred at 85° C. for 1 h. LCMS showed the reaction was completed. The reaction was cooled to RT, and the solid was filtered off. The filtrate was concentrated, and the residue was purified by Prep-HPLC to afford the title compound as a white solid (55 mg, 44%). MS (ES+) C21H20N4O2 requires: 360. Found: 361 [M+H]+. 1H-NMR (500 MHz, DMSO-d6) δ ppm 8.76 (s, 1H), 8.50-8.46 (br, 2H), 6.88 (t, 1H, J=7.0 Hz), 6.66 (s, 2H), 6.57 (d, 1H, J=7.5 Hz), 6.54 (s, 1H), 6.44 (d, 1H, J=6.5 Hz), 4.74 (s, 2H), 3.76 (s, 6H), 2.01 (s, 3H).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O=S(Cl)[Cl:19]>C1C=CC=CC=1>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([Cl:19])=[O:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCCCCC(=O)O
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CC(C)(C)[Si](C)(C)OCCCCCC(=O)Cl
Yield: 91.9 %

Procedure:
A solution of 0.5 g (2.03 mmol) of 6-[(tert-butyldimethylsilyl)oxy]-hexanoic acid in 4 ml of benzene is mixed with 362 mg (3.04 mmol, 1.5 equivalents) of SOCl2 and heated under reflux for 2 hours. It is allowed to cool, and the solvent is distilled off in a rotary evaporator. To remove excess SOCl2 from the reaction mixture, the residue is mixed again with benzene and again distilled off. 494 mg (1.865 mmol, 92%) of the 6-[(tert-butyldimethylsilyl)oxy]-hexanoyl chloride is obtained. This crude product is further reacted without purification and characterization.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[Cl:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[Cl:19][C:20]1[CH:25]=[C:24]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:12][C:13]3[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=3)[N:3]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Product: Cc1cc(Nc2cc3ccccc3c(-c3cccc(Cl)c3)n2)n[nH]1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 3-chloro-phenylboronic acid to give [1-(3-chloro-phenyl)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 335(MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([NH:11]C(=O)/C=C\C(O)=O)=[O:10])[CH:6]=[CH:5][N:4]=1.O=P(Cl)(Cl)Cl.[NH2:24][NH:25][C:26](=[N:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[Cl:42])[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=1[Cl:34].C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:34][C:28]1[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:27]=1[C:26]1[N:35]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[Cl:42])[C:6](/[CH:7]=[CH:8]/[C:3]2[O:10][C:9]([C:7]3[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[CH:8]=3)=[N:11][N:4]=2)=[N:24][N:25]=1
Reactant: COc1cc(C(=O)NC(=O)/C=C\C(=O)O)ccn1
Reactant: NNC(=Nc1ccccc1Cl)c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(-c2nnc(/C=C/c3nnc(-c4ccc(Cl)cc4Cl)n3-c3ccccc3Cl)o2)ccn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of (Z)-4-(2-methoxypyridine-4-carboamido)-4-oxobut-2-enoic acid 8 (0.2 g, 0.75 mmol) in CH3CN was added POCl3 (0.37 g, 2.4 mmol). The mixture was stirred under reflex for 16 hours, cooled to ambient temperature and concentrated under reduced pressure. The residue was dissolved in CH3CN, treated with a solution of N-amino-2,4-dichloro-N′-(2-chlorophenyl)benzamidine 4 (0.38 g, 1.2 mmol) in CH3CN and K2CO3 (0.38 g, 1.2 mmol). The mixture was stirred at ambient temperature for 1 hour, refluxed for 2 hours and filtered. The filtrate was concentrated. The residue was subjected to flash column chromatography (FCC) (50-60% EtOAc/hexanes) to afford the title compound 4-(5-((E)-2-(5-(2,4-dichlorophenyl)-4-(2-chlorophenyl)-4H-1,2,4-triazol-3-yl)vinyl)-1,3,4-oxadiazol-2-yl)-2-methoxypyridine as a white solid. Yield: 0.11 g, 28%.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[CH2:13][C:14]([NH2:16])=[O:15])(O)=[O:2]>ClC1C=CC=CC=1Cl>[N+:10]([C:7]1[CH:6]=[C:5]2[C:4](=[CH:9][CH:8]=1)[C:1](=[O:2])[NH:16][C:14](=[O:15])[CH2:13]2)([O-:12])=[O:11]
Reactant: NC(=O)Cc1cc([N+](=O)[O-])ccc1C(=O)O
Solvent: Clc1ccccc1Cl
Product: O=C1Cc2cc([N+](=O)[O-])ccc2C(=O)N1
Yield: 72.2 %

Procedure:
A stirred suspension of 11.1 g (49.3 mmol) of 2-carboxy-5-nitrobenzeneacetamide in 99 ml of 1,2-dichlorobenzene is refluxed for 3 h. The residue obtained after evaporation of the solvent under vacuum is washed with ether and dried to give 7.34 g (72%) of a tan solid, mp 255-260° (dec); 1H NMR (DMSO-d6) δ 11.6 (s, 1H), 8.2-8.3 (m, 3H), 4.17 (s, 2H); MS (ES−) m/z 205.2 (M−H)−
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1.[C:33](Cl)(=[O:35])[CH3:34]>>[C:33]([N:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1)(=[O:35])[CH3:34]
Reactant: O=C(N[C@@H]1CCNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N1CC[C@@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-pyrrolidin-3-ylamide hydrochloride (example A142) and acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:7])[S:5][CH:6]=1.Cl[C:9]1[CH:14]=[C:13]([O:15][CH:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18][CH2:17]2)[CH:12]=[CH:11][N:10]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:9]2[CH:14]=[C:13]([O:15][CH:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18][CH2:17]3)[CH:12]=[CH:11][N:10]=2)[S:5][CH:6]=1
Reactant: Cc1csc(N)n1
Reactant: Clc1cc(OC2CCCc3ccccc32)ccn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1csc(Nc2cc(OC3CCCc4ccccc43)ccn2)n1
Yield: 68.3 %

Procedure:
Using the method of Example 3, Step B, 4-methylthiazol-2-amine (11.59 mL, 4.637 mmol), 2-chloro-4-(1,2,3,4-tetrahydronaphthalen-1-yloxy)pyridine (1.095 g, 4.216 mmol), potassium phosphate (0.9844 g, 4.637 mmol), Pd2(dba)3 (0.09651 g, 0.1054 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.06586 g, 0.1138 mmol) were reacted to provide N-(4-methylthiazol-2-yl)-4-(1,2,3,4-tetrahydronaphthalen-1-yloxy)pyridin-2-amine (0.972 g, 68.33% yield). 1H NMR (d6-DMSO) δ 10.96 (s, 1H), 8.14 (d, 1H), 7.27 (m, 2H), 7.19 (t, 2H), 6.68 (m, 1H), 6.66 (s, 1H), 6.50 (d, 1H), 5.56 (t, 1H), 2.84 (m, 1H), 2.74 (m, 1H), 2.23 (s, 3H), 2.03 (m, 2H), 1.81 (m, 2H); Mass spectrum (apci) m/z=338.0 (M+H).
Reaction SMILES: C([O:5][C:6](=[O:52])[CH2:7][CH:8]1[CH2:13][CH:12]([CH2:14][CH2:15][N:16]2[CH:20]([CH:21]([CH3:23])[CH3:22])[CH:19]([C:24](=[O:32])[NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:18]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:17]2[C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=2)[O:11]B(C2C=CC=CC=2)[O:9]1)(C)(C)C.O.[O-2].[Ca+2:55]>C1COCC1>[CH3:23][CH:21]([C:20]1[N:16]([CH2:15][CH2:14][C@@H:12]([OH:11])[CH2:13][C@@H:8]([OH:9])[CH2:7][C:6]([O-:52])=[O:5])[C:17]([C:39]2[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=2)=[C:18]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:19]=1[C:24]([NH:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:32])[CH3:22].[CH3:23][CH:21]([C:20]1[N:16]([CH2:15][CH2:14][C@@H:12]([OH:11])[CH2:13][C@@H:8]([OH:9])[CH2:7][C:6]([O-:52])=[O:5])[C:17]([C:39]2[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=2)=[C:18]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:19]=1[C:24]([NH:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:32])[CH3:22].[Ca+2:55]
Reactant: CC(C)C1C(C(=O)Nc2ccccc2)C(c2ccccc2)C(c2ccc(F)cc2)N1CCC1CC(CC(=O)OC(C)(C)C)OB(c2ccccc2)O1
Agent: [Ca+2]
Agent: [O-2]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H](O)C[C@@H](O)CC(=O)[O-]
Temperature: 55 °C
Reaction time: 8 h

Procedure:
A mixture of (6-{2-[2-(4-Fluoro-phenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrolidin-1-yl]-ethyl}-2-phenyl-[1,3,2]dioxaborinan-4-yl)-acetic acid tert-butyl ester (50 g, 0.07 mol), water (2 L), THF (2 L) and calcium oxide (50 g, 0.9 mol) was stirred at 50-60° C. for 8 hours. After filtering the reaction mixture, the resulting clear filtrate was concentrated to about 1.5 L and washed with methyl tert-butyl ether (500 ml). The aqueous layer was evaporated and solid obtained was dissolved in THF (500 ml). The solution was filtered and concentrated to yield atorvastatin calcium.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].Cl(O)(=O)(=O)=O>C(OC(C)(C)C)(=O)C>[C:7]([O:5][C:4](=[O:6])[CH2:3][CH:2]([NH2:1])[C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1)([CH3:12])([CH3:8])[CH3:2]
Reactant: NC(CC(=O)O)c1ccc(O)cc1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)CC(N)c1ccc(O)cc1
Temperature: 15 °C
Reaction time: 1.5 h
Yield: 152.7 %

Procedure:
1.00 g (5.52 mmol) commercial 3-amino-3-(4-hydroxy-phenyl)-propionic acid were suspended in 20 ml tert-butyl acetate and the mixture cooled to 15° C. 0.90 ml (11.10 mmol) perchloric acid were slowly added and the mixture stirred at 20° C. for 1.5 hours. The solution was extracted with saturated sodium hydrogen carbonate solution. The aqueous layer was brought to pH=8 with sodium carbonate and extracted with ethyl acetate. The organic parts were combined, dried over sodium sulfate and concentrated to yield 1.0 g (60%) racemic 3-amino-3-(4-hydroxy-phenyl)-propionic acid tert-butyl ester. This was separated into the enantiomers by HPLC:
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12.[NH2:14][C@@H:15]1[CH2:20][C@@H:19]([NH:21][C:22](=[O:31])[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:18]([CH2:32][C:33]#[N:34])[CH2:17][CH2:16]1.C(N(CC)CC)C>C(O)(C)C>[C:33]([CH2:32][C@H:18]1[CH2:17][CH2:16][C@H:15]([NH:14][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]3[CH:11]=[CH:12][S:13][C:3]=23)[CH2:20][C@H:19]1[NH:21][C:22](=[O:31])[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)#[N:34]
Reactant: N#CC[C@H]1CC[C@H](N)C[C@H]1NC(=O)OCc1ccccc1
Reactant: O=[N+]([O-])c1cnc2ccsc2c1Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: N#CC[C@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3ccsc23)C[C@H]1NC(=O)OCc1ccccc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
A mixture of 7-chloro-6-nitrothieno[3,2-b]pyridine (22.0 mg, 0.102 mmol), benzyl [(1R,2R,5S)-5-amino-2-(cyanomethyl)cyclohexyl]carbamate (32 mg, 0.11 mmol) and triethylamine (35.7 μL, 0.256 mmol) in isopropyl alcohol (0.4 mL) was stirred at 90° C. for 2 h. The mixture was cooled and purified on silica gel, eluted with 10-90% EtOAc in hexanes to give 28 mg (59%) of the desired product. LCMS calculated for C23H24N5O4S (M+H)+: m/z=466.2. Found: 466.1.
Reaction SMILES: Br[CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1)[CH3:3].[Cl:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[O:20][C:19](=[O:24])[CH:18]=[C:17]2[NH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1>[C:10]([C:7]1[CH:8]=[CH:9][C:4]([CH:2]([N:29]2[CH2:30][CH2:31][CH:26]([NH:25][C:17]3[C:16]4[C:21](=[CH:22][CH:23]=[C:14]([Cl:13])[CH:15]=4)[O:20][C:19](=[O:24])[CH:18]=3)[CH2:27][CH2:28]2)[CH3:3])=[CH:5][CH:6]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)c1ccc(C(C)Br)cc1
Reactant: O=c1cc(NC2CCNCC2)c2cc(Cl)ccc2o1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C(C)N2CCC(Nc3cc(=O)oc4ccc(Cl)cc34)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 4.2 %

Procedure:
To a solution of 1-[4-(1-bromoethyl)-phenyl]-ethanone (0.35 g, 1.54 mmol) and 6-chloro-4-(piperidin-4-ylamino)-chromen-2-one (0.42 g, 1.50 mmol) in dry THF (15 mL) was added Cs2CO3 (2.44 g, 7.50 mmol). The reaction mixture was allowed to stir at room temperature for 12 h, after which time THF was removed in vacuo and the white residue was partitioned between H2O (250 mL) and ethyl acetate (250 mL). After removal of the organic layer, the aqueous layer was washed with an addition portion of ethyl acetate (250 mL), and the combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to provide a yellow oil. The crude product was purified by flash chromatography through a silica gel column with dichloromethane and methanol (95: 5 v/v). The resulting yellow residue was then treated with 4 M HCl in dioxane, solvent was removed in vacuo to provide a yellow solid. Crystallization from dichloromethane provided the HCl salt of the desired compound (0.027 g, 4%) as a white solid MS (ESI(+)Q1MS) m/z 425 (M+H)+; 1H NMR (300 MHz, DMSO) δ ppm 10.84-10.97 (m, 1H), 8.32-8.38 (m, 1H), 8.00-8.08 (m, 2H), 7.75-7.84 (m, 2H), 7.58-7.63 (m, 1H), 7.48-7.54 (m, 1H), 7.30-7.35 (m, 1H), 5.39 (s, 1H), 4.51-4.63 (m, 1H), 3.60-3.77 (m, 2H), 3.24-3.40 (m, 1H), 2.73-2.95 (m, 2H), 2.59 (s, 3H), 1.95-2.14 (m, 4H), 1.72 (d, 3H). The pure racemic mixture was separated into enantiomers by prep HPLC chiral chromatography using a CHIRALPAK AD column: 7.5/7.5/85 MeOH/EtOH/Hexanes at 0.8 ml/min. Enantiomers had retention times of 4.2 and 6.4 minutes.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([NH:11][C@H:12]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13]2)=[CH:3][CH:2]=1>ClCCl.FC(F)(F)C(O)=O>[NH:14]1[CH2:15][CH2:16][C@H:12]([NH:11][C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=[CH:2][CH:3]=2)[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2ccnc3ccccc23)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc2c(N[C@H]3CCNC3)ccnc2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
tert-Butyl (3S)-3-(4-quinolylamino)pyrrolidine-1-carboxylate (231 mg, 0.68 mmol) was dissolved in a 1:1 mixture of dichloromethane and trifluoroacetic acid (2 ml) and stirred at room temperature for 15 minutes. The mixture was evaporated to dryness under reduced pressure and the residue obtained was used directly in the next step.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:19]([O:21][C:22](=[O:46])[C:23]([CH3:45])([CH3:44])[C:24]([C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([O:36][Si](C(C)(C)C)(C)C)[CH:32]=2)[CH:27]=1)=[O:25])[CH3:20]>C1COCC1.C(OCC)(=O)C>[CH2:19]([O:21][C:22](=[O:46])[C:23]([CH3:45])([CH3:44])[C:24]([C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([OH:36])[CH:32]=2)[CH:27]=1)=[O:25])[CH3:20]
Reactant: CCOC(=O)C(C)(C)C(=O)c1ccc2cc(O[Si](C)(C)C(C)(C)C)ccc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)C(=O)c1ccc2cc(O)ccc2c1

Procedure:
Tetrabutylammonium floride 1M in THF (78 mL, 78 mmol) was added to a solution of 3-[6-(tert-butyl-dimethyl-silanyloxy)-naphthalen-2-yl]-2,2-dimethyl-3-oxo-propionic acid ethyl ester (77.1 mmol) in THF (300 mL) at room temperature for 0.5 h. The reaction was taken up in ethyl acetate, washed with water (2×) and brine, dried over magnesium sulfate, and concentrated to give the 3-(6-Hydroxy-naphthalen-2-yl)-2,2-dimethyl-3-oxo-propionic acid ethyl ester as a crude oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:13]([N+:14]([O-])=O)=[CH:12][N:11]=[C:10]([NH2:17])[CH:9]=2)[CH2:4][CH2:3]1>CCOC(C)=O.CCO.[Pd]>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:13]([NH2:14])=[CH:12][N:11]=[C:10]([NH2:17])[CH:9]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2cc(N)ncc2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN1CCN(c2cc(N)ncc2N)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.8 %

Procedure:
Pd on C, (10%, wet, Degussa) (140 mg, 0.1316 mmol) was added to a stirred solution of 4-(4-methylpiperazin-1-yl)-5-nitro-pyridin-2-amine (355 mg, 1.496 mmol) in a mixture of EtOAc (5 mL) and EtOH (50 mL). The reaction was placed under an atmosphere of hydrogen and stirred at ambient temperature for 16 hours. The catalyst was removed by filtration through a pad of celite and the filtrate concentrated in vacuo to give 4-(4-methylpiperazin-1-yl)pyridine-2,5-diamine as a brown solid (291 mg, 94% Yield). MS (ES+) 208.1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[CH2:32][C:33]#[N:34])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12.N1[CH2:41][CH2:40][CH2:39][CH2:38]C1.C1(C=O)CC1>CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31]([C:32](=[CH:38][CH:39]3[CH2:41][CH2:40]3)[C:33]#[N:34])=[O:35])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12
Reactant: N#CCC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3cccc(F)c3)cc2)c2c(N)ncnc21
Reactant: C1CCNCC1
Agent: O=CC1CC1
Solvent: CO
Product: N#CC(=CC1CC1)C(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3cccc(F)c3)cc2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 28.9 %

Procedure:
Into a 10-mL round-bottom flask, was placed 3-[(2R)-2-([4-amino-3-[4-(3-fluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidin-1-yl]-3-oxopropanenitrile (150 mg, 0.32 mmol, 1.00 equiv), piperidine (27 mg, 0.32 mmol, 1.00 equiv), cyclopropanecarbaldehyde (44.5 mg, 0.63 mmol, 2.00 equiv), methanol (5 mL). The resulting solution was stirred for 12 h at 25° C. and then concentrated under vacuum. The residue was loaded on a silica gel column and eluted with dichloromethane/methanol (50/1) to give 48.5 mg (29%) of the title compound as a off-white solid. LC-MS: (ES, m/z): MS (ESI, pos. ion) m/z: 524 (M+1). H-NMR: (CDCl3, ppm): 1HNMR (300MHz, CD3OD, ppm), 8.253 (1H, s), 7.686˜7.749 (2H, t), 7.363˜7.440 (1H, t), 7.185˜7.232 (2H, t), 6.833˜6.941 (3H, m), 6.450˜6.600 (1H, d), 4.301˜4.555(3H, m), 3.604˜3.638 (2H, m), 1.868˜2.005 (5H, m), 1.200˜1.294 (3H, m), 0.798˜0.810 (2H, m).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:6][CH2:5]1.C(Cl)Cl.[OH2:18].CC#N>O>[C:10]([O:9][C:8]([NH:7][C:4]1([CH2:3][C:2]([OH:18])=[O:1])[CH2:5][CH2:6]1)=[O:14])([CH3:11])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)NC1(CCO)CC1
Reactant: O
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
RuCl3.H2O (124 mg, 0.6 mmol) was added to a solution of tert-butyl 1-(2-hydroxyethyl)cyclopropylcarbamate (6.1 g, 30 mmol), and NaIO4 (19.0 g, 90 mmol) in DCM/H2O/CH3CN (20 mL/40 mL/20 mL). The mixture was stirred at rt for 3 hrs. The mixture was then diluted with H2O (100 mL), and extracted with DCM (3×). The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (0-30% gradient elution EtOAc/petroleum ether) to afford 2-(1-(tert-butoxycarbonylamino)cyclopropyl)acetic acid (6.0 g, 90%) as a white solid. ESI-MS (EI+, m/z): 238 [M+Na]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.C(N(CC)CC)C.[CH2:16]([S:18](Cl)(=[O:20])=[O:19])[CH3:17].[OH-].[Na+]>C(Cl)Cl.O.CO>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][S:18]([CH2:16][CH3:17])(=[O:20])=[O:19])[CH:5]=[N:6][CH:7]=1
Reactant: CCS(=O)(=O)Cl
Reactant: Nc1cncc(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)Nc1cncc(Br)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 5-bromopyridin-3-amine (1.73 g, 10 mmol) and triethylamine (4.05 g, 40 mmol) in DCM (100 mL) was added a solution of ethanesulfonyl chloride (3.86 g, 30 mmol) in DCM (20 mL) at 0° C. The mixture was stirred at 0° C. for 1 h. 1N NaOH in water (10 mL) and methanol (20 mL) were added and the mixture was concentrated in vacuo, Silica gel (20 g) and DCM (100 mL) were added and the mixture was concentrated in vacuo. The residue was purified by silica chromatography eluting with a 0 to 5% MeOH-DCM gradient to give N-(5-bromopyridin-3-yl)ethanesulfonamide. ESI-MS: m/z 265.2, 267.2 (M+H)+.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[OH:7][C:8]1[C:9]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:10][C:11]2[CH2:12][CH2:13][C@@H:14]3[C@@H:23]([C:24]=2[CH:25]=1)[CH2:22][CH2:21][C@@:19]1([CH3:20])[C@H:15]3[CH2:16][CH2:17][C@@H:18]1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[C:42]([CH2:46]I)([F:45])([F:44])[F:43]>CN(C=O)C>[F:43][C:42]([F:45])([F:44])[CH2:46][O:7][C:8]1[C:9]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:10][C:11]2[CH2:12][CH2:13][C@@H:14]3[C@@H:23]([C:24]=2[CH:25]=1)[CH2:22][CH2:21][C@@:19]1([CH3:20])[C@H:15]3[CH2:16][CH2:17][C@@H:18]1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: FC(F)(F)CI
Reactant: C[C@]12CC[C@@H]3c4cc(O)c(OCc5ccccc5)cc4CC[C@H]3[C@@H]1CC[C@@H]2OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@]12CC[C@@H]3c4cc(OCC(F)(F)F)c(OCc5ccccc5)cc4CC[C@H]3[C@@H]1CC[C@@H]2OCc1ccccc1
Temperature: 110 °C
Yield: 96.1 %

Procedure:
Powdered K2CO3 (1.5 g, 11 mmol) was added to a solution of estradiol (6) (4.0 g, 8.5 mmol) in anhydrous DMF (50 mL) followed by dropwise addition of CF3CH2I (5.0 mL, 51 mmol) at room temperature. The resulting reaction mixture was heated at 110° C. for 3 h. Additional K2CO3 (2.5 g) and CF3CH2I (6 mL) were added, and the mixture was heated again at 130° C. for 2 h. The mixture was cooled in an ice bath and poured onto ice cold 3N HCl (125 mL). The aqueous layer was extracted with ether (2×200 mL). The combined ether layer was washed with 3N HCl (100 mL), water (100 mL), brine (100 mL), and dried over anhydrous MgSO4. The ether layer was evaporated under reduced pressure and the resulting crude product on purification on a silica gel column gave estradiol (7)(4.5 g, 95%) as a colorless oil: IR (neat) 2910, 2850, 1600, 1500, 730, 690 cm-1 ; 1H NMR (CDCl3) δ 0.9 (s, 3H), 1.1-2.4 (m, 13H), 2.65-2.85 (m, 2H), 3.50 (t, J=8.5 Hz, 1H), 4.40 (q, J=8.5 Hz, 2H), 4.56 (s, 2H), 5.05 (s, 2H), 6.70 (s, 1H), 6.98 (s, 1H), 7.2-7.55 (m, 10H). Anal. (C34H37F3O3) C, H.