Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@:1]12([CH3:13])[C:7]([CH3:9])([CH3:8])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:10](Cl)=[O:11].[I:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([OH:25])[CH:22]([CH3:24])[CH3:23])=[C:17]([N+:26]([O-:28])=[O:27])[CH:16]=1>CN(C1C=CN=CC=1)C.ClCCl>[C@:1]12([CH3:13])[C:7]([CH3:9])([CH3:8])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:10]([O:25][C@@H:21]([C:18]1[CH:19]=[CH:20][C:15]([I:14])=[CH:16][C:17]=1[N+:26]([O-:28])=[O:27])[CH:22]([CH3:24])[CH3:23])=[O:11]
Reactant: CC1(C)C2CC[C@@]1(C)C(C(=O)Cl)C2
Reactant: CC(C)C(O)c1ccc(I)cc1[N+](=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)[C@@H](OC(=O)C1CC2CC[C@]1(C)C2(C)C)c1ccc(I)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 28.1 %

Procedure:
Under a nitrogen atmosphere (1S)-camphanic acid chloride (0.89 g, 4.09 mmol) was added to a solution of (RS)-1-(4-Iodo-2-nitrophenyl)-2-methyl-1-propanol (1.10 g, 3.41 mmol) and DMAP (0.50 g, 4.09 mmol) in anhydrous dichloromethane (30 mL). The mixture was stirred for 1.5 hours at room temperature and then concentrated in vacuo. The residue was purified by silica gel column chromatography to (RS)-1-(4-Iodo-2-nitrophenyl)-2-methyl-1-propyl (1S)-camphanates (1.44 g, 84%, 1:1 mixture of diastereomers) as a solid, which was dissolved in boiling methanol (70 mL) and left at room temperature overnight. Crystals formed were filtered to yield pure (R)-1-(4-iodo-2-nitrophenyl)-2-methyl-1-propyl (1S)-camphanate (0.465 g, 65%). The mother liquor was evaporated, and the residue was dissolved in boiling isopropanol (40 mL) and left at room temperature overnight. Crystals formed were filtered and recrystallized from boiling isopropanol (20 mL) to yield pure (S)-1-(4-iodo-2-nitrophenyl)-2-methyl-1-propyl (1S)-camphanate (0.288 g, 40%). 1H NMR (400 MHz, CDCl3) for (R,S)-camphanate: δ 8.30 (d, 1 H, J=1.8 Hz, Ph-H), 7.92 (dd, 1 H, J=1.8 and 8.3 Hz, Ph-H), 7.56 (d, 1 H, J=8.3 Hz, Ph-H), 6.27 (d, 1 H, J=6.8 Hz, Ph-CH), 2.40 (m, 1H), 2.23 (m, 1H), 2.06 (m, 1H), 1.92 (m, 1H), 1.72 (m, 1H), 1.11 (s, 3 H, CH3), 1.03 (d, J=6.8 Hz, 3 H, CH3), 1.02 (s, 1 H, CH3), 0.98 (d, J=6.8 Hz, 3 H, CH3), 0.82 (s, 3 H, CH3); 13C NMR (100 MHz, CDCl3) for (R,S)-camphanate: δ 178.21 (C), 166.92 (C), 148.67 (C), 142.07 (CH), 134.80 (C), 133.34 (CH), 129.73 (CH), 92.59 (C), 90.75 (C), 76.07 (CH), 54.79 (C), 54.34 (C), 33.27 (CH), 31.03 (CH2), 28.88 (CH2), 19.07 (CH3), 17.40 (CH3), 16.70 (CH3), 16.66 (CH3), 9.61 (CH3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([CH:21]=1)[C:7]([NH:9][CH2:10][CH2:11][C:12]1[S:13][C:14]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:15][CH:16]=1)=[O:8].[O:24]([C:26]#[N:27])[K]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([CH:21]=1)[C:7]([NH:9][CH2:10][CH2:11][C:12]1[S:13][C:14]([S:17]([NH:18][C:26]([NH2:27])=[O:24])(=[O:19])=[O:20])=[CH:15][CH:16]=1)=[O:8]
Reactant: COc1ccc(Cl)cc1C(=O)NCCc1ccc(S(N)(=O)=O)s1
Reactant: N#CO[K]
Solvent: CCN(CC)CC
Product: COc1ccc(Cl)cc1C(=O)NCCc1ccc(S(=O)(=O)NC(N)=O)s1

Procedure:
299 mg (0.8 mmol of 2-[2-(5-chloro-2-methoxybenzoylamino)ethyl]-5-sulfamoylthiophene were treated with 448 mg of KOCN and 0.6 ml of triethylamine, and the mixture was then heated to reflux for 4 h. The cooled solution was filtered and evaporated to dryness. The residue was stirred with 40 ml of H2O, 25 ml of triethylamine and 25 ml of ethyl acetate. The organic phase was extracted 3 times with water/1% triethylamine. The combined aqueous phases were acidified with 2N hydrochloric acid. The precipitate formed was stirred in an ice bath for 3 hours and filtered off with suction.
Reaction SMILES: [CH2:1]([N:8]1[C:15](=[O:16])[C@@H:14]([OH:17])[C@H:13]2[C@@H:9]1[CH2:10][CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl.O>[CH2:1]([N:8]1[C:15](=[O:16])[C@@H:14]([O:17][S:26]([CH3:25])(=[O:28])=[O:27])[C@H:13]2[C@@H:9]1[CH2:10][CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1[C@@H](O)[C@@H]2OCC[C@@H]2N1Cc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)O[C@@H]1C(=O)N(Cc2ccccc2)[C@H]2CCO[C@@H]12
Reaction time: 8 h

Procedure:
15 g of the (1R*,5S*,8S*)-6-benzyl-8-hydroxy-7-oxo-2-oxa-6-azabicyclo[3.3.0]octane obtained in the step 2 of Example A was added to 300 ml of methylene chloride, and cooled with ice. To this mixture was added 16.3 ml of triethylamine. Then, 7.5 ml of methanesulfonyl chloride was added dropwise thereto, followed by stirring overnight. Thereafter, water and methylene chloride were added to the reaction mixture so as to extract the desired product in an organic layer. After this organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 20.6 g of (1R*,5S*,8S*)-6-benzyl-8-mesyloxy-7-oxo-2-oxa-6-azabicyclo[3.3.0]octane.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([C:18]2[C:19]3[C:20]4[CH:34]=[CH:33][S:32][C:21]=4[C:22](=[O:31])[NH:23][C:24]=3[C:25]([CH3:30])=[CH:26][C:27]=2[O:28][CH3:29])[CH:15]=[CH:14][C:3]=1[CH2:4][CH2:5][NH:6]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>>[ClH:1].[NH2:6][CH2:5][CH2:4][C:3]1[CH:14]=[CH:15][C:16]([C:18]2[C:19]3[C:20]4[CH:34]=[CH:33][S:32][C:21]=4[C:22](=[O:31])[NH:23][C:24]=3[C:25]([CH3:30])=[CH:26][C:27]=2[O:28][CH3:29])=[CH:17][C:2]=1[Cl:1]
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc(CCNC(=O)OC(C)(C)C)c(Cl)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc(CCN)c(Cl)c1
Product: Cl
Yield: 124 %

Procedure:
Following General Procedure C, tert-butyl 2-chloro-4-(8-methoxy-6-methyl-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenethylcarbamate (50 mg, 0.10 mmol) was reacted with TFA (3.0 mL) to afford the desired product as a light yellow solid (27 mg, 68%): 1H NMR (500 MHz, MeOD) δ 7.62 (t, J=5.8 Hz, 1H), 7.53 (d, J=7.8 Hz, 1H), 7.35 (d, J=1.6 Hz, 1H), 7.29 (s, 1H), 7.21 (dd, J=7.7, 1.7 Hz, 1H), 6.11 (d, J=5.4 Hz, 1H), 3.75 (d, J=7.4 Hz, 3H), 3.38-3.16 (m, 4H), 2.64 (s, 3H); ESI MS m/z 399 [C21H19ClN2O2S+H]+; HPLC 98.8% (AUC), tR=9.50 min.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[S:11](=[O:20])(=[O:19])[NH:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.S(Cl)([Cl:23])=O.Cl.C(OC(C)C)(C)C>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:23])=[O:7])=[CH:4][C:3]=1[S:11](=[O:20])(=[O:19])[NH:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(Cl)c(S(=O)(=O)NC2CCCCC2)c1
Agent: Cl
Solvent: CC(C)OC(C)C
Product: O=C(Cl)c1ccc(Cl)c(S(=O)(=O)NC2CCCCC2)c1

Procedure:
30 g of 4-chloro-3-cyclohexylsulfamoylbenzoic acid were reacted as prescribed in Example 74(a) with thionyl chloride and worked up analogously after HCl had finished to develop. Colorless crystals, melting point 119° C. (from diisopropyl ether.)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[NH2:21][C:22]([C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1)=[O:23]>>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][C:24]([C:22]([NH2:21])=[O:23])=[CH:25][CH:26]=3)=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: NC(=O)c1ccc(C(=O)O)cc1
Product: NC(=O)c1ccc(C(=O)NCc2cn(-c3ccccc3)c3cc(Cl)ccc3c2=O)cc1

Procedure:
N-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-terephthalamide was prepared starting from intermediate D and 4-(aminocarbonyl)benzoic acid. MS calcd. for C24H18ClN3O3 [(M+H)+] 431.9, obsd. 432.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH2:11][CH:10]([C:14](OC)=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.[BH4-].[Na+].C1COCC1>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH:10]([CH2:14][OH:15])[CH2:11][C:12]2=[O:13])=[CH:4][CH:3]=1
Reactant: COC(=O)C1CC(=O)N(c2ccc(F)cc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C1CC(CO)CN1c1ccc(F)cc1

Procedure:
A 500 mL round-bottomed flask was charged with methyl 1-(4-fluorophenyl)-5-oxopyrrolidine-3-carboxylate 52 (7.50 g, 31.6 mmol), sodium borohydride (1.32 g, 34.8 mmol), and 100 mL of THF. After being heated to reflux, 15 mL of MeOH was slowly added. After 1 h at reflux, the reaction was concentrated, 100 mL of water was added, and the mixture was extracted with DCM. The combined extracts were dried and concentrated to give 1-(4-fluorophenyl)-4-(hydroxymethyl)pyrrolidin-2-one 53.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[NH:10][C:9]2[CH:11]=[C:12]([C:15]3[CH:16]=[CH:17][C:18]4[O:24][CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][C:19]=4[CH:32]=3)[CH:13]=[CH:14][C:8]=2[N:7]=1)=[O:4].CO.[ClH:35]>O1CCOCC1.C(OCC)C>[ClH:35].[ClH:35].[O:24]1[C:18]2[CH:17]=[CH:16][C:15]([C:12]3[CH:13]=[CH:14][C:8]4[N:7]=[C:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[NH:10][C:9]=4[CH:11]=3)=[CH:32][C:19]=2[CH2:20][NH:21][CH2:22][CH2:23]1
Reactant: COC(=O)Nc1nc2ccc(-c3ccc4c(c3)CN(C(=O)OC(C)(C)C)CCO4)cc2[nH]1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: CCOCC
Product: COC(=O)Nc1nc2ccc(-c3ccc4c(c3)CNCCO4)cc2[nH]1
Reaction time: 0.5 h
Yield: 95 %

Procedure:
1,1-Dimethylethyl 7-(2-{[(methyloxy)carbonyl]amino}-1H-benzimidazol-6-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (517 mg, 1.18 mmol) was taken into methanol (2 mL) and 4M hydrogen chloride in dioxane (2 mL) and the mixture was allowed to stand at room temperature for 30 minutes. The suspension obtained was diluted with excess ethyl ether and the solid collected by filtration to give methyl [6-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-benzimidazol-2-yl]carbamate dihydrochloride salt (462 mg, 95% yield) as a white solid. MS (EI) for C18H18N4O3: 339 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([NH:8][CH:9]2[CH2:11][CH2:10]2)=[N:6][CH:7]=1.[CH3:12][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14].CCN(C(C)C)C(C)C.CN(C=O)C>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.[Cu]I.O>[CH:9]1([NH:8][C:5]2[N:4]=[CH:3][C:2]([C:17]#[C:16][Si:13]([CH3:15])([CH3:14])[CH3:12])=[CH:7][N:6]=2)[CH2:11][CH2:10]1
Reactant: C#C[Si](C)(C)C
Reactant: Brc1cnc(NC2CC2)nc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)C#Cc1cnc(NC2CC2)nc1
Temperature: 80 °C
Reaction time: 15 h
Yield: 95.1 %

Procedure:
5-Bromo-N-cyclopropylpyrimidin-2-amine (1.06 g, 5 mmol), trimethylsilylacetylene (2.5 g, 25 mmol), Pd(PPh3)4 (289 mg, 0.25 mmol) and CuI (71 mg, 0.375 mmol) were placed in a two neck flask with a rubber plug. The mixture underwent 3 cycles of vacuum and filling with Ar2, a solution of DIPEA (968 mg, 0.45 mmol) and DMF (10 mL) was injected to the flask. The mixture was stirred at 80° C. for 15 hrs, and then was poured into 50 mL water, extracted with EtOAc (30 mL×3), organic layer was washed with brine, dried with Na2SO4, filtered, and the filtrate was evaporated in vacuo. The residue was purified by chromatography on silica gel (PE/EtOAc 82:18 to 64:36) to give 1.1 g N-cyclopropyl-5-(2-(trimethylsilyl)ethynyl)pyrimidin-2-amine. This compound was dissolved in 20 mL CH2Cl2, a solution of TBAF (1.3 g, 5 mmol) in 10 mL CH2Cl2 was added into the above solution. The mixture was stirred at rt for 1 h, evaporated in vacuo. The residue was purified by chromatography on silica gel (PE/EtOAc 82:18 to 64:36) to give 0.55 g product as a pale yellow solid (72.8%). 1H NMR (300 MHz, CDCl3) δ: 8.43 (2 H, s), 5.77 (1 H, brs), 3.18 (1 H, s), 2.76-2.81 (1 H, m), 0.82-0.87 (2 H, m), 0.54-0.59 (2 H, m). LCMS: m/z [M+H]+ 160.0863.
Reaction SMILES: [H-].[Na+].[Cl-].[C:4]([CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:5].[F:26][C:27]1[CH:32]=[C:31]([CH:33]=O)[CH:30]=[CH:29][N:28]=1.CO>O1CCCC1.CN(C)C=O>[F:26][C:27]1[CH:32]=[C:31](/[CH:33]=[CH:6]\[C:4]#[N:5])[CH:30]=[CH:29][N:28]=1
Reactant: N#CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccnc(F)c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: C1CCOC1
Product: N#C/C=C\c1ccnc(F)c1
Reaction time: 48 h

Procedure:
To a suspension of 2.80 g (0.038 mol) sodiumhydride (60% in oil) in 120 ml tetrahydrofurane and 120 ml dimethylformamide were added 21.6 g (0.064 mol) (cyanomethyl)triphenyl-phosphonium chloride. After stirring for 1 hour at room temperature a solution of 4.00 g (0.032 mol) 2-fluoro-4-pyridinecarboxaldehyde in 35 ml tetrahydrofurane were added and stirring was continued for 2 days. Then 30 ml methanol were added, the solvents were evaporated and the residue chromatographed on silicagel with ethylacetate/hexane 1/2 to yield 0.45 g (10%) (E)-and (Z)-3-(2-fluoro-pyridin-4-yl)-acrylonitrile as light yellow solid. MS m/e (%): 148 (M+, 100), 128 (43).
Reaction SMILES: [CH3:1][C:2]1([CH2:14][C:15]([OH:17])=O)[CH2:6][C:5]2[C:7]([CH3:13])=[CH:8][C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.O.ON1C2C=CC=CC=2N=N1.Cl.[CH2:30]([N:32]=[C:33]=NCCCN(C)C)C.CNC>CN(C)C=O.O>[CH3:30][N:32]([CH3:33])[C:15](=[O:17])[CH2:14][C:2]1([CH3:1])[CH2:6][C:5]2[C:7]([CH3:13])=[CH:8][C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1cc(C)c2c(c1C)OC(C)(CC(=O)O)C2
Agent: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)c2c(c1C)OC(C)(CC(=O)N(C)C)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
To a solution of 2,4,6,7-tetramethyl-2,3-dihydrobenzofuran-2-yl acetic acid (3.0 g, 12.8 mmol) in dimethylformamide (30 ml) were added 1-hydroxy-1H-benzotriazole monohydrate (HOBt) (2.1 g, 14.1 mmol) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (WSC) (3.7 g, 19.2 mmol). The mixture was stirred at room temperature for 1 hour. Then, 50% dimethylamine aqueous solution (3 ml) was added and the resulting mixture was stirred for additional 30 minutes. The reaction mixture was diluted with water and the product was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified by column chromatography on silica gel (isopropyl ether) to obtain the desired compound (3.1 g, yield: 92.6% yield) as oil.
Reaction SMILES: C(OC([NH:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[CH2:16][CH2:17][N:18](C(OC(C)(C)C)=O)[CH2:19][CH:20]=2)=[CH:11][C:10]=1[C:28]1[O:29][C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N:31][N:32]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(N(CC)CC)C.[CH2:53]([S:55](Cl)(=[O:57])=[O:56])[CH3:54]>C(Cl)Cl>[CH2:53]([S:55]([N:18]1[CH2:19][CH:20]=[C:15]([C:12]2[CH:11]=[C:10]([C:28]3[O:29][C:30]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)=[N:31][N:32]=3)[C:9]([NH2:8])=[N:14][CH:13]=2)[CH2:16][CH2:17]1)(=[O:57])=[O:56])[CH3:54]
Reactant: CC(C)(C)OC(=O)Nc1ncc(C2=CCN(C(=O)OC(C)(C)C)CC2)cc1-c1nnc(-c2ccccc2)o1
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N1CC=C(c2cnc(N)c(-c3nnc(-c4ccccc4)o3)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.7 %

Procedure:
tert-Butyl 4-[6-(tert-butoxycarbonylamino)-5-(5-phenyl-1,3,4-oxadiazol-2-yl)-3-pyridyl]-3,6-dihydro-2H-pyridine-1-carboxylate (141.7 mg, 0.2727 mmol) was dissolved in DCM (2 mL) and treated with TFA (373.1 mg, 252.1 μL, 3.272 mmol) at ambient temperature. The reaction was allowed to stir at ambient temperature for 3 hours and then concentrated in vacuo. The resultant residue was redissolved in DCM and treated with triethylamine (55.19 mg, 76.02 μL, 0.5454 mmol) followed by ethanesulfonyl chloride (17.54 mg, 12.93 μL, 0.1364 mmol). The mixture was allowed to stir at ambient temperature for 16 hours and then concentrated in vacuo. The resultant residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound as an off-white solid (47 mg, 42% Yield). 1H NMR (400.0 MHz, DMSO) δ 1.25 (t, 3H), 2.67 (br s, 2H), 3.16 (br s, 2H), 3.47 (br s, 2H), 3.94 (br s, 2H), 6.25 (br s, 1H), 7.44 (s, 2H), 7.64-7.69 (m, 3H), 8.22-8.24 (m, 2H), 8.29 (s, 1H) and 8.39 (s, 1H) ppm; MS (ES+) 411.95.
Reaction SMILES: Br[C:2]1[O:3][C:4]2[CH:16]=[CH:15][C:14]([CH2:17][Br:18])=[CH:13][C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N+:19]([O-:24])([N+]([O-])=O)=[O:20].C1(C(O)=O)CC=CCC1>C(O)(=O)C>[Br:18][CH2:17][C:14]1[CH:15]=[CH:16][C:4]2[O:3][C:2]([N+:19]([O-:24])=[O:20])=[C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:5]=2[CH:13]=1
Reactant: BrCc1ccc2oc(Br)c(-c3ccccc3)c2c1
Reactant: O=[N+]([O-])[N+](=O)[O-]
Agent: O=C(O)C1CC=CCC1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1oc2ccc(CBr)cc2c1-c1ccccc1
Temperature: 45 °C

Procedure:
To a solution of 50 g. (0.137 mole) of the product of step A in 1100 ml. of acetic acid is added 18.9 g. (0.206 mole) of dinitrogen tetraoxide and 26.0 g. (0.206 mole) of 4-cyclohexene carboxylic acid in 25 ml. of acetic acid dropwise. The reaction mixture is maintained at 45° C. for about four hours, then allowed to cool to about 20° C. The yellow solid is collected, washed with water and petroleum ether and dried to provide 5-bromomethyl-2-nitro-3-phenylbenzofuran, crude melting point 171°-180° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:21]3=[N:22][CH:23]=[CH:24][CH:25]=[C:20]3[N:19]([CH2:26][CH3:27])[N:18]=2)=[CH:13][CH:12]=1.CI.[C:30]([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:26]([N:19]1[C:20]2[C:21](=[N:22][CH:23]=[CH:24][CH:25]=2)[C:17]([C:14]2[CH:15]=[CH:16][C:11]([O:10][C:2]3[N:1]([CH3:30])[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=3)=[CH:12][CH:13]=2)=[N:18]1)[CH3:27]
Reactant: O=C([O-])[O-]
Reactant: CCn1nc(-c2ccc(Oc3nc4ccccc4[nH]3)cc2)c2ncccc21
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CCn1nc(-c2ccc(Oc3nc4ccccc4n3C)cc2)c2ncccc21
Temperature: 40 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
A suspension of 3-[4-(1H-benzimidazol-2-yloxy)phenyl]-1-ethyl-1H-pyrazolo[4,3-b]pyridine (150 mg), MeI (0.039 mL), and K2CO3 (117 mg) in DMF (1.5 ml) was stirred overnight at 40° C. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was crystallized from hexane/AcOEt to give the title compound (128 mg).
Reaction SMILES: [CH:1]([C:3]1[S:11][C:10]2[C:9](=[O:12])[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][NH:6][C:5]=2[CH:4]=1)=[O:2].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl.C(Cl)Cl>[OH:2][CH2:1][C:3]1[S:11][C:10]2[C:9](=[O:12])[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][NH:6][C:5]=2[CH:4]=1
Reactant: CCOC(=O)c1c[nH]c2cc(C=O)sc2c1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: ClCCCl
Product: CCOC(=O)c1c[nH]c2cc(CO)sc2c1=O
Temperature: 0 °C
Reaction time: 24 h
Yield: 76.8 %

Procedure:
To a 0° C. mixture of ethyl 2-formyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxylate (Preparation 6, 0.628 g, 2.5 mmol) and acetic acid (0.71 mL, 12.5 mmol) in 1,2-dichloroethane (23 mL) was added sodium triacetoxyborohydride (1.06 g, 5.0 mmol). The mixture was stirred at 0° C. for 5 minutes and at room temperature for 24 hrs. A saturated solution of sodium bicarbonate (25 mL) and methylene chloride (25 mL) were added. After stirring vigorously for 5 minutes, the mixture was filtered. The collected solid was washed with water and methylene chloride, then dried in vacuo, leaving the title compound as a pale yellow solid (0.486 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=O)[CH2:5][C:6]([O:8][CH3:9])=[O:7].S(Cl)(Cl)(=O)=O.ClC(C(=O)COC)C(OC)=O.[NH2:27][C:28]([NH2:30])=[S:29]>CCO.C(Cl)Cl>[NH2:30][C:28]1[S:29][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:3][O:2][CH3:1])[N:27]=1
Reactant: COCC(=O)CC(=O)OC
Reactant: NC(N)=S
Agent: COCC(=O)C(Cl)C(=O)OC
Solvent: O=S(=O)(Cl)Cl
Solvent: CCO
Solvent: ClCCl
Product: COCc1nc(N)sc1C(=O)OC
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a 100 mL round-bottomed flask was added methyl 4-methoxy-3-oxobutanoate (4.43 mL, 34.2 mmol) and DCM (30.00 mL). Sulfuryl chloride (2.91 mL, 35.9 mmol) was added dropwise with a syringe to the reaction mixture. The mixture was then stirred for 1 hour at 20° C. The solution was reduced to an oil under reduced pressure and dissolved in EtOH (50 mL). To this solution was added methyl 2-chloro-4-methoxy-3-oxobutanoate (6.18 g, 34 mmol) and thiourea (1.9 mL, 34 mmol). The reaction was then stirred at reflux for approximately 12 hours. LCMS indicated that the reaction was complete, and the solvent was removed under reduced pressure. Saturated aqueous sodium bicarbonate was added, and the resulting solid was filtered and recrystallized from water and <5 mL EtOH to give methyl 2-amino-4-(methoxymethyl)thiazole-5-carboxylate as rust colored crystals (4.85 g, 68%). LCMS (M+H) 203 calc. for C7H11N2O3S 203.2. 1H NMR (400 MHz, CD3OD): δ ppm 4.64 (s, 2H), 3.77 (s, 3H), 3.37 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13](/[CH:14]=[CH:15]/[C@@H:16]([OH:24])[CH2:17][C@@H:18]([OH:23])[CH2:19][C:20]([OH:22])=[O:21])=[C:12]([CH:25]([CH3:27])[CH3:26])[N:11]=[C:10]([N:28]([CH3:33])[S:29]([CH3:32])(=[O:31])=[O:30])[N:9]=2)=[CH:4][CH:3]=1.O.O.[Cl-].[Ca+2:37].[Cl-]>O>[Ca:37].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13](/[CH:14]=[CH:15]/[C@@H:16]([OH:24])[CH2:17][C@@H:18]([OH:23])[CH2:19][C:20]([OH:22])=[O:21])=[C:12]([CH:25]([CH3:27])[CH3:26])[N:11]=[C:10]([N:28]([CH3:33])[S:29]([CH3:32])(=[O:31])=[O:30])[N:9]=2)=[CH:4][CH:3]=1
Reactant: [Ca+2]
Agent: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1/C=C/[C@@H](O)C[C@@H](O)CC(=O)O
Agent: [Cl-]
Solvent: O
Product: [Ca]
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
(E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid TRIS salt (17.7 g) was dissolved in degassed water (120 ml) at 20° C. then the solution was heated to 40° C. A solution of calcium chloride dihydrate (2.6 g) in water (25 ml) was added dropwise at about 40° C. over 20 minutes. The mixture was stirred for 15 minutes, allowed to cool to 20° C. over 60 minutes, held at this temperature for a further 60 minutes and the resultant solid filtered. The solid was washed with water (140 ml) and dried under a flow of nitrogen to give non-crystalline calcium salt of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[N+:20]([C:23]1[CH:24]=[C:25]2[C:30](=O)[O:29][C:27](=[O:28])[C:26]2=[CH:32][CH:33]=1)([O-:22])=[O:21]>ClCCl>[F:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[C:30](=[O:29])[C:25]5=[CH:24][C:23]([N+:20]([O-:22])=[O:21])=[CH:33][CH:32]=[C:26]5[C:27]4=[O:28])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: NCCN1CCC(c2noc3cc(F)ccc23)CC1
Solvent: ClCCl
Product: O=C1c2ccc([N+](=O)[O-])cc2C(=O)N1CCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A stirred mixture of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylamine (2.63 g, 0.01 mole) and 4-nitrophthalic anhydride (1.93 g, 0.01 mole) in dichloromethane (200 ml) is stirred at room temperature for 3 hours. The solvent is then removed under reduced pressure and the residual material is purified by flash chromatography. The product is purified further by recrystallization to give N-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-4-nitrophthalimide.