Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][N:2]1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][C:21]3[C:27]([CH:28]([CH3:30])[CH3:29])=[CH:26][C:25]([C:31]#[N:32])=[CH:24][C:22]=3[N:23]=2)=[CH:15][CH:14]=1)=[O:12].C(N(C(C)C)CC)(C)C.[F:42][C:43]([F:53])([F:52])[C:44]1[CH:51]=[CH:50][C:47]([CH2:48]Br)=[CH:46][CH:45]=1>ClCCl>[CH:28]([C:27]1[C:21]2[O:20][C:19]([C:16]3[CH:15]=[CH:14][C:13]([C:11]([N:2]4[CH2:3][CH2:4][C:5]5([CH2:10][CH2:9][N:8]([CH2:48][C:47]6[CH:46]=[CH:45][C:44]([C:43]([F:42])([F:52])[F:53])=[CH:51][CH:50]=6)[CH2:7][CH2:6]5)[CH2:1]4)=[O:12])=[CH:18][CH:17]=3)=[N:23][C:22]=2[CH:24]=[C:25]([C:31]#[N:32])[CH:26]=1)([CH3:30])[CH3:29]
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)N4CCC5(CCNCC5)C4)cc3)oc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)N4CCC5(CCN(Cc6ccc(C(F)(F)F)cc6)CC5)C4)cc3)oc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
To a solution of 2-[4-(2,8-diazaspiro[4.5]dec-2-ylcarbonyl)phenyl]-7-isopropyl-1,3-benzoxazole-5-carbonitrile (25 mg, 0.046 mmol, EXAMPLE 121, Step B) in dichloromethane (2 ml) were added diisopropylethylamine (20 μl, 0.115 mmol) and 4-(trifluoromethyl)benzyl bromide (17 mg, 0.071 mmol). The mixture was stirred at room temperature overnight, at which point LC/MS analysis showed a peak at the desired molecular weight. The reaction mixture was purified by flash chromatography on a Biotage Horizon, 25S column, eluting with 1 column volume of 100% dichloromethane followed by a gradient of 0 to 100% ethyl acetate in dichloromethane over 10 column volumes to provide the title compound (21.4 mg, 0.036 mmol, 79% yield). Mass spectrum (ESI) 587.3 (M+1).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:15]=[N:16][C:17]([N+:20]([O-])=O)=[CH:18][CH:19]=3)[CH:10]=[CH:9][N:8]=2)=[CH:5][N:6]=1.[NH4+].[Cl-]>C1COCC1.CO.[Zn]>[CH3:1][C:2]1[S:3][C:4]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[N:16][CH:15]=3)[CH:10]=[CH:9][N:8]=2)=[CH:5][N:6]=1
Reactant: Cc1ncc(-c2cc(Oc3ccc([N+](=O)[O-])nc3)ccn2)s1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ncc(-c2cc(Oc3ccc(N)nc3)ccn2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
A 0° C. solution of 2-methyl-5-(4-((6-nitropyridin-3-yl)oxy)pyridin-2-yl)thiazole (0.191 g, 0.608 mmol) in THF (3 mL) and MeOH (3 mL) was treated with NH4Cl (1.3 g, 24.31 mmol) followed by the slow addition of zinc dust (0.397 g, 6.08 mmol), the mixture allowed to warm to RT and stirred for 2 h. The mixture was treated with THF, the solids removed via filtration through diatomaceous earth, washed well with THF, the filtrate treated with EtOAc, washed with 1:1 brine/satd. NaHCO3, dried over Na2SO4 and concentrated to dryness to afford 5-((2-(2-methylthiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-amine (164 mg, 95%). 1H NMR (400 MHz, DMSO-d6): δ 8.34 (d, J=5.8 Hz, 1 H), 8.28 (s, 1 H), 7.82 (d, J=2.9 Hz, 1 H), 7.50 (d, J=2.4 Hz, 1 H), 7.29 (dd, J=8.9, 3.0 Hz, 1 H), 6.67 (dd, J=5.8, 2.4 Hz, 1 H), 6.51 (d, J=8.9 Hz, 1 H), 6.03 (s, 2 H), 2.64 (s, 3 H); MS (ESI) m/z: 285.1 (M+H+).
Reaction SMILES: [C:1](OCC1C=CC=CC=1)(=O)[CH:2]([CH3:4])O.[N:14](C(OCC)=O)=NC(OCC)=O.[CH2:26]([O:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[N:46]=[CH:45][C:44]([OH:47])=[CH:43][N:42]=2)=[C:37]([F:48])[CH:36]=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>>[CH2:26]([O:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[N:46]=[CH:45][C:44]([O:47][CH:2]([C:1]#[N:14])[CH3:4])=[CH:43][N:42]=2)=[C:37]([F:48])[CH:36]=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCOc1ccc(-c2ncc(O)cn2)c(F)c1
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: CC(O)C(=O)OCc1ccccc1
Product: CCCCCCCCOc1ccc(-c2ncc(OC(C)C#N)cn2)c(F)c1

Procedure:
Optically active benzyl lactate is etherified by means of diethyl azodicarboxylate (DEAD)/triphenylphosphine with 2-(4-octyloxy-2-fluorophenyl)-5-hydroxypyrimidine (prepared in accordance with Example 1) and the benzyl group is then split off hydrogenolytically. The acid so obtained is converted as usual into the nitrile (oxalyl chloride, ammonia, thionyl chloride). Optically active 2-(4-octyloxy-2-fluorophenyl)-5-(1-cyanoethoxy)-pyrimidine is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([C:23]([CH3:25])=[CH2:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][C:34]=2[OH:37])[CH2:29]1)=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:39][CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([C:23]([CH3:25])=[CH2:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][C:34]=2[O:37][CH2:39][CH2:40][CH2:41][N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)[CH2:29]1)=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)c1cc(C(=O)N2Cc3cccc(O)c3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: ClCCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=C(C)c1cc(C(=O)N2Cc3cccc(OCCCN4CCOCC4)c3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 90 °C
Yield: 71.5 %

Procedure:
A mixture of (2,4-bis-benzyloxy-5-isopropenyl-phenyl)-(4-hydroxy-1,3-dihydro-isoindol-2-yl)-methanone (2 g; 4.07 mmol), 4-(3-chloropropyl)morpholine (1.66 g; 2.5 equiv.) and caesium carbonate (8.3 g; 6.25 equiv) in DMF was heated at 90° C. overnight then evaporated. The residue was dissolved in EtOAc, washed with brine, dried (MgSO4) and evaporated. Purification of the crude material using a Biotage SP4 (40 S, 40 ml/min), using gradient elution form 0% to 10% MeOH/EtOAc gave 1.8 g of (2,4-bis-benzyloxy-5-isopropenyl-phenyl)-[4-(3-morpholin-4-yl-propoxy)-1,3-dihydro-isoindol-2-yl]-methanone as a pale yellow gum. MS: [M+H]+ 619.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9](Cl)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.CCN(CC)CC.Cl.[CH2:21]([O:23][C:24](=[O:28])[CH2:25][CH2:26][NH2:27])[CH3:22]>CC(C)=O>[CH2:21]([O:23][C:24](=[O:28])[CH2:25][CH2:26][NH:27][S:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:11])=[O:10])[CH3:22]
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Reactant: CCOC(=O)CCN
Agent: Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNS(=O)(=O)c1cccc(OC)c1
Reaction time: 0.5 h

Procedure:
m-Methoxybenzenesulfonyl chloride (3.53 g, 0.017 mol) and Et3N (4.76 mL, 0.034 mol) were dissolved in acetone (35 mL) at 0° C. β-Alanine ethyl ester hydrochloride (2.0 g, 0.017 mol) was added and stirring was continued at room temperature under N2 for 0.5 h. The reaction mixture was concentrated, partitioned between 0.1N HCl solution and EtOAc. The aqueous layer was washed with EtOAc, the organics combined, washed with H2O, brine, and dried (Na2SO4). Filtration and concentration to dryness gave the title compound which was used without further purification.
Reaction SMILES: C(O)(=O)C.[NH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([NH2:22])=[N:17][CH:16]=[CH:15]3)[CH2:7][CH2:6]1.[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C)C=O.O>[CH2:23]([N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([NH2:22])=[N:17][CH:16]=[CH:15]3)[CH2:7][CH2:6]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Nc1nccc2cc(OC3CCNCC3)ccc12
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: Nc1nccc2cc(OC3CCN(Cc4ccccc4)CC3)ccc12
Reaction time: 2 h

Procedure:
A drop of glacial acetic acid was added to a solution of 6-(piperidin-4-yloxy)-isoquinolin-1-ylamine (20 mg, 0.082 mmol) in N, N-dimethylformamide (0.5 ml), followed by addition of benzaldehyde (20 mL). The mixture was then treated with sodium triacetoxyborohydride (50 mg) and shaken for 2 h. Water (0.5 ml) was added, the mixture was stirred overnight and then purified by prep-HPLC to give 6-(1-benzyl-piperidin-4-yloxy)-isoquinolin-1--ylamine (28 mg), El-MS: m/z=334.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[N:10][C:11]2[CH:19]=[C:15]([C:16](Cl)=[O:17])[C:14]([OH:20])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[OH-].[NH4+:22]>C(O)(=O)C>[OH:20][C:14]1[CH:13]=[CH:12][C:11]([N:10]=[N:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:19][C:15]=1[C:16]([NH2:22])=[O:17]
Reactant: [NH4+]
Reactant: COc1ccc(N=Nc2ccc(O)c(C(=O)Cl)c2)cc1
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1ccc(N=Nc2ccc(O)c(C(N)=O)c2)cc1

Procedure:
5-(4-Methoxyphenylazo)salicoyl chloride (1 g) was carefully warmed with 0.880 ammonium hydroxide (10 ml) for 10 minutes. The mixture was then acidified with glacial acetic acid and the amide removed by filtration. The product was crystallized from ethanol (0.60 g), 65%, m.p. 231°-3°, λmax (methanol) = 352 nm.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9](C)[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[N:25]1([CH:32]=[O:33])[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>O1CCOCC1.CS(C)=O.CO>[CH:32]([N:25]1[CH2:31][CH2:30][CH2:29][N:28]([C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]3[CH:15]=[CH:16][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:18][CH:19]=3)[CH:3]=2)[CH2:27][CH2:26]1)=[O:33]
Reactant: O=CN1CCCNCC1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Solvent: CS(C)=O
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)(O)c1ccc(C(=O)Nc2cc(N3CCCN(C=O)CC3)n3nccc3n2)cc1
Temperature: 25 °C
Yield: 50 %

Procedure:
A solution of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 200 mg, 0.604 mmol) and 1,4-diazepane-1-carbaldehyde (116 mg, 0.906 mmol) in Dioxane (6 mL) was stirred at 85° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC, 5-95% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (127.7 mg, 50%). 1H NMR (METHANOL-d4) δ: 8.12 (s, 1H), 7.89-7.99 (m, 3H), 7.63-7.69 (m, 2H), 7.34 (s, 1H), 6.24-6.29 (m, 1H), 4.43 (t, J=5.8 Hz, 1H), 4.32-4.37 (m, 1H), 4.09 (t, J=6.2 Hz, 1H), 3.98-4.04 (m, 1H), 3.78 (t, J=5.9 Hz, 2H), 3.60-3.71 (m, 2H), 2.13-2.22 (m, 1H), 2.06 (t, 1H), 1.56 (s, 6H). ESI-MS: m/z 423.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]C(C)(C)C.[Sn:20](Cl)([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24].C([O-])(O)=O.[Na+]>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Sn:20]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:21][CH2:22][CH2:23][CH3:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)Nc1ccccc1
Agent: O=C([O-])O
Agent: [Li]C(C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccccc1NC(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 2 h
Yield: 48.5 %

Procedure:
To a solution of N-(t-butoxycarbonyl)aniline (2.0 g, 10.35 mmol) in dry THF (50 mL) at 78° C., a solution of t-BuLi (2.7M in pentane, 26 mL, 25.88 mmol) was added dropwise over 30 min. The resulting yellow solution was warmed to −20° C. and stirred at this temperature for 2.5 h. n-Bu3SnCl (4.2 mL, 15.52 mmol) in dry THF (10 mL) was added over 20 min, and the solution stirred at −20° C. for 2 h, then at room temperature for 12 h. The reaction mixture was poured into NaHCO3 solution and extracted with ether. The extract was washed with water, brine, and dried over MgSO4. The solvent was evaporated and the resulting oil purified by flash chromatography in hexanes/ether (20: 1) to give 2-tributylstannylphenylcarbamic acid t-butyl ester (2.42 g, 54%).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:17]([F:20])([F:19])[F:18])=[C:13]([CH:16]=1)[C:14]#[N:15].[C:21]([O:24][CH2:25][C:26](Cl)=[O:27])(=[O:23])[CH3:22]>C(Cl)Cl>[C:21]([O:24][CH2:25][C:26]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:17]([F:18])([F:19])[F:20])=[C:13]([C:14]#[N:15])[CH:16]=1)=[O:27])(=[O:23])[CH3:22]
Reactant: N#Cc1cc(N)ccc1C(F)(F)F
Reactant: CC(=O)OCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCC(=O)Nc1ccc(C(F)(F)F)c(C#N)c1
Reaction time: 0.25 h
Yield: 71.6 %

Procedure:
Triethylamine (1.09 g, 10.8 mmol) was added to a stirred solution of 5-amino-2-(trifluoromethyl)benzonitrile (Intermediate 37, 1.0 g, 5.37 mmol) in DCM (40 mL), at 0° C., and the mixture was stirred for 15 min. Chloro-2-oxoethyl acetate (1.10 g, 8.06 mmol) was added at 0° C. and the mixture was stirred for 4 h at room temperature. The reaction mixture was diluted with DCM and washed with ice water, and saturated brine solution. The organic layer was dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford the crude compound. This was purified by column chromatography (100-200 mesh silica gel), eluting with 20%-40% EtOAc/pet.ether to give the title compound (1.1 g).
Reaction SMILES: Cl.NO.C([N:6]([CH2:9][CH3:10])CC)C.[Br:11][C:12]1[CH:13]=C(C=O)[S:15][C:16]=1[Cl:17].C1(=O)OC(=O)C2=CC=CC=C12>C(#N)C.C(OCC)(=O)C>[Br:11][C:12]1[CH:13]=[C:10]([C:9]#[N:6])[S:15][C:16]=1[Cl:17]
Reactant: O=Cc1cc(Br)c(Cl)s1
Reactant: CCN(CC)CC
Agent: Cl
Agent: NO
Agent: O=C1OC(=O)c2ccccc21
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N#Cc1cc(Br)c(Cl)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
Hydroxylamine hydrochloride (Aldrich, 4.91 g, 70.66 mmol) and triethylamine (anhydrous, 11.2 mL, 80.36 mmol) were added to a 0° C. solution of 4-bromo-5-chloro-thiophene-2-carbaldehyde (Example 24: step a, 10.63 g, 47.14 mmol) in acetonitrile (anhydrous, 250 mL). The reaction mixture was warmed to room temperature and stirred for 1 hour. Phthalic anhydride was added and the reaction mixture was heated to 80° C. overnight. The mixture was cooled to room temperature, diluted with ethyl acetate (400 mL), and washed with aqueous citric acid, saturated NaHCO3, water, and brine. The organic layer was dried over magnesium sulfate, filtered, concentrated in vacuo, and purified by column chromatography (silica gel, 5% ethyl acetate/hexanes) to afford the title compound as a pale yellow solid (9.76 g, 93% yield). 1H-NMR (CDCl3): δ 7.47 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[CH2:3][NH:4][C:5]([CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:16]CC3C=CC=CC=3)[CH:13]=2)[N:8]1[C:24](=[O:36])[C@@H:25]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26][CH3:27])=[O:6].[H][H]>[Pd].C(OCC)(=O)C>[F:38][C:2]([F:1])([F:37])[CH2:3][NH:4][C:5]([CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:16])[CH:13]=2)[N:8]1[C:24](=[O:36])[C@@H:25]([NH:28][C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[CH2:26][CH3:27])=[O:6]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccc(OCc3ccccc3)cc2CC1C(=O)NCC(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccc(O)cc2CC1C(=O)NCC(F)(F)F

Procedure:
A mixture of 1-(N-t-butoxycarbonyl-2(S)-aminobutyryl)-5-benzyloxyindoline-2(R/S)-carboxylic acid 2,2,2-trifluoroethylamide (0.9 g, 1.68 mmol) and palladium on activated carbon (0.1 g, 10% wet) in ethyl acetate (20 mL) was hydrogenated under 30 psi hydrogen at room temperature overnight. Then the catalyst was removed by filtration over celite, and the filtrate was evaporated to provide a white solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][CH2:10][C@@H:11]2[CH2:16][CH2:15][NH:14][CH2:13][C@H:12]2[OH:17])[C:4]=1[C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C.[C:40](Cl)(=[O:43])[CH:41]=[CH2:42]>C1COCC1>[NH2:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][CH2:10][C@@H:11]2[CH2:16][CH2:15][N:14]([C:40](=[O:43])[CH:41]=[CH2:42])[CH2:13][C@H:12]2[OH:17])[C:4]=1[C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:20][CH:19]=1
Reactant: Nc1ncnc(NC[C@@H]2CCNC[C@H]2O)c1-c1ccc(Oc2ccccc2)cc1
Reactant: C=CC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)N1CC[C@@H](CNc2ncnc(N)c2-c2ccc(Oc3ccccc3)cc2)[C@H](O)C1
Reaction time: 8 h
Yield: 3.5 %

Procedure:
To a round bottom flask containing (3S,4S)-4-{[6-Amino-5-(4-phenoxy-phenyl)-pyrimidin-4-ylamino]-methyl}-piperidin-3-ol hydrochloride (591.95 mg; 1.38 mmol; 1.00 eq.) and DIPEA (0.69 ml; 4.15 mmol; 5.00 eq.) in THF (30.00 ml) was slowly added acryloyl chloride (0.11 ml; 1.38 mmol; 1.00 eq.) in 1 mL THF over 1 h. The reaction mixture was concentrated and purified with using preparative HPLC. Fractions containing the desired product were combined and lyophilized overnight to afford 1-((3S,4S)-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)prop-2-en-1-one as a white solid (21.5 mg, 2.7%). HPLC purity: 99%. MS: m/z=446 [M+H]+. 1H NMR (CD3OD) δ 8.25 (s, 1H), 7.10-7.45 (m, 9H), 6.73 (dd, 1H), 6.34 (d, 1H), 5.77 (d, 1H), 4.5 (m, 1H), 4.03 (m, 1H), 3.62 (m, 1H), 3.50 (m, 1H), 3.25 (m, 1H), 3.01 (m, 1H), 2.57 (m, 1H), 1.71 (m, 2H), 1.19 (m, 1H).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[N+:14]([O-])([OH:16])=[O:15]>FC(F)(F)C(O)=O.O>[N+:14]([C:3]1[CH:2]=[CH:1][C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=1)([O-:16])=[O:15]
Reactant: c1ccc2c(c1)oc1ccccc12
Reactant: O=[N+]([O-])O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)oc1ccccc12
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Dibenzofuran (30 g, 178 mmol) was dissolved in 276 ml, trifluoroacetic acid (TFA) and cooled in ice water bath. Fuming nitric acid 15 g (˜17 mL) was diluted with 3 mL water and then dissolved in 25 mL TFA and added to dibenzofuran solution drop wise. Reaction takes place almost instantly and a thick light green color precipitate forms. At the end of addition, flask was stirred for 20 minutes more and then poured over ice. Light green precipitate was then filtered off, washed with 2 M NaOH, dried and recrystallized from boiling ethanol 30 g (76%) of product was obtained.
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: O
Solvent: C1CCOC1
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][C:2]1[CH:3]=[CH:4][C:5]2[S:14][CH2:13][C:12]3[C:11]([C:15](=[O:28])[CH:16]([C:26]#[N:27])[C:17]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:18])=[N:10][N:9]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:8]=3[C:6]=2[CH:7]=1.[CH2:35]([N:37]([CH2:40][CH3:41])[CH2:38]C)[CH3:36].C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:45]>O1CCCC1>[C:26]([CH:16]([C:15]([C:11]1[C:12]2[CH2:13][S:14][C:5]3[CH:4]=[CH:3][C:2]([N:1]=[CH:38][N:37]4[CH2:40][CH2:41][O:45][CH2:36][CH2:35]4)=[CH:7][C:6]=3[C:8]=2[N:9]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:10]=1)=[O:28])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18])#[N:27]
Reactant: N#CC(C(=O)Nc1ccccc1)C(=O)c1nn(-c2ccccc2)c2c1CSc1ccc(N)cc1-2
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Product: N#CC(C(=O)Nc1ccccc1)C(=O)c1nn(-c2ccccc2)c2c1CSc1ccc(N=CN3CCOCC3)cc1-2
Temperature: -15 °C
Reaction time: 2 h

Procedure:
N-Formylmorpholine (7.58 g) dissolved in anhydrous ethyl ether (200 ml) is reacted with oxalyl chloride (8.02 g) under stirring at room temperature for 20 hours. The precipitate is filtered, washed with anhydrous ethyl ether and dried in vacuo at room temperature for 1 hour to yield 8.9 g of 4-chloromethylene-morpholinium chloride. This compound (5.47 g) is added portionwise at -15°60 C. to a stirred solution of 3-(8-amino-1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-2-cyano-3-oxo-N-phenyl-propanamide (3 g) in anhydrous tetrahydrofuran (130 ml) containing triethylamine (8.96 ml). The reaction mixture is kept under stirring at -15° C. for 2 hours and then at about 0° C. for 2 hours again. Finally it is diluted with ice water and acidified to pH 4 with citric acid. The precipitate is filtered, fired in vacuo at 50° C. and then purified over a SiO2 column using chloroform/methanol30% NH4OH 85/12/0.5 as eluent. The recovered product is crystallized from methanol to yield 1.4 g of 2-cyano-3(1,4-dihydro-8-morpholinomethyleneamino-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide, m.p. 205°-210° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH:12]2[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[CH:23][CH:22]=1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:35])[F:36])[CH:28]=4)=[CH:25][CH:26]=3)[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])(=[O:10])=[O:11])=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1cccc(-c2ccc(CBr)cc2)c1
Reactant: COc1ccc(S(=O)(=O)C2SC(=O)NC2=O)cc1
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)C2(Cc3ccc(-c4cccc(C(F)(F)F)c4)cc3)SC(=O)NC2=O)cc1

Procedure:
Prepared analogously to Example 9 from from 5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione and 4′-bromomethyl-3-(trifluoromethyl)biphenyl in N,N-dimethylformamide. Column chromatography provided a light yellow glass. 1H NMR: δ 7.93 (dm, J=9.0 Hz, 2H), 7.78 (br s, 2H), 7.72 (d, J=7.5 Hz, 1H), 7.49-7.62 (m, 4H), 7.28 (dm, J=8.7 Hz, 2H), 7.07 (dm, J=9.0 Hz, 2H), 3.98 A of AB, J=13.7 Hz, 1H), 3.92 (s, 3H), 3.40 (B of AB, J=13.7 Hz, 1H). MS (m/e): 520.0 (M−H)−. Anal: Calc for C24H18F3NO5S2: 55.27% C, 3.48% H, 2.69% N; Found: 55.23% C, 3.70% H, 2.69% N.