Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:20]([CH3:22])([CH2:21][C@@H:2]12)[C@@H:19]1[C@H:8]([C@H:9]2[C@:16]([CH3:24])([CH2:17][C:18]1=[O:23])[C@@H:12]([C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]2)[CH2:7][CH2:6]3.CCOCC.[C:30]([CH2:32][CH2:33][OH:34])#[N:31].C(=O)(O)[O-].[Na+]>B(F)(F)F.CCOCC.C(OCC)(=O)C>[C:30]([CH2:32][CH2:33][O:34][C@H:2]1[CH2:21][C@@:20]2([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[C:18](=[O:23])[CH2:17][C@@:16]2([CH3:24])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:13](=[O:15])[CH3:14])[CH2:4][C@@H:3]1[OH:1])#[N:31]
Reactant: N#CCCO
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](OCCC#N)C[C@]4(C)[C@H]3C(=O)C[C@]12C

Procedure:
2α,3α-Epoxy-5α-pregnane-11,20-dione (2 g), dry ether (50 ml) and 2-cyanoethanol (10 ml.) were sirred at room temperature until the solid had dissolved. Boron trifluoride diethyl etherate (10 drops) was added. After 2 hours at room temperature a further quantity of etherate (10 drops) was added. After 1 hour further etherate (10 drops) was added and after a further hour, the mixture was neutralised with saturated sodium bicarbonate solution, ethyl acetate (50 ml.) added and the organic layer washed with water (3 × 200 ml.). The washed solution was dried over anhydrous sodium sulphate and evaporated to a white foam which was purified by preparative T.L.C. using ethyl acetate. The main band (Rf 0.4) gave the title compound (740 mg;) m.p. 194°-196°C. [α]D + 85° .
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O)(=O)C.[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[OH:32])[CH:27]=O.[BH3-]C#N.[Na+]>CO.CN1C(=O)N(C)CC1>[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[OH:32])[CH2:27][NH:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1
Reactant: O=Cc1ccc(O)c(Cl)c1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CN1CCN(C)C1=O
Solvent: CO
Solvent: CC(=O)O
Product: Oc1ccc(CNc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1Cl

Procedure:
Analogously to Example 21, 1.00 mmol of 3-amino-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine in 26 ml of methanol, 13 ml of DMEU and 3.0 mmol of acetic acid are first reacted with 3-chloro-4-hydroxy-benzaldehyde and then reduced with 7.00 mmol of NaCNBH3 (5-7 days). 3-(3-Chloro-4-hydroxy-benzylamino)-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine is obtained; m.p. 220° C.; HPLC: TRet (Grad5-40)=18.7.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:37])[CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23]([OH:36])([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][CH2:18]2)=[CH:9][C:8]1([CH3:39])[CH3:38])(=O)C.[OH-].[Na+]>CO>[OH:36][C:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH:20]1[CH2:21][CH2:22][N:17]([CH2:16][CH2:15][CH2:14][C:13]([C:10]2[CH:11]=[CH:12][CH:7]([CH2:6][CH2:5][OH:4])[C:8]([CH3:39])([CH3:38])[CH:9]=2)=[O:37])[CH2:18][CH2:19]1
Reactant: CC(=O)OCCC1C=CC(C(=O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)=CC1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)C=C(C(=O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)C=CC1CCO
Temperature: 68 °C

Procedure:
Dissolve 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-2,2-dimethylphenethyl acetate (69.0 g, 0.131 mol) in methanol (2.5 L) and add 10% aqueous sodium hydroxide (769 mL, 1.92 mol). Stir at reflux for 1.5 hours, cool to 68° C. and evaporate the solvent in vacuo to a residue (700 mL). Add chloroform (1 L) and stir until solids are dissolved. Separate the organic phase and extract the aqueous phase with chloroform (3×300 mL). Combine the organic phases, dry (MgSO4) and evaporate the solvent in vacuo and recrystallize (toluene) to give the title compound as a cream-colored powder; mp 135°-137° C.
Reaction SMILES: [OH:1][CH:2]([CH:6]([OH:31])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([C:28]#[N:29])[CH:19]=3)[CH2:16][O:15][N:14]=2)=[C:9]([CH3:30])[CH:8]=1)[C:3]([O-:5])=[O:4].C(OC1C=CC(C2N=C(C3C=CC(CCC(OC)=O)=CC=3C)ON=2)=CC=1C(F)(F)F)(C)C>>[OH:1][CH:2]([CH:6]([OH:31])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([C:28]#[N:29])[CH:19]=3)[CH2:16][O:15][N:14]=2)=[C:9]([CH3:30])[CH:8]=1)[C:3]([OH:5])=[O:4]
Reactant: Cc1cc(C(O)C(O)C(=O)[O-])ccc1C1=NOCN1c1ccc(OC(C)C)c(C#N)c1
Agent: COC(=O)CCc1ccc(-c2nc(-c3ccc(OC(C)C)c(C(F)(F)F)c3)no2)c(C)c1
Product: Cc1cc(C(O)C(O)C(=O)O)ccc1C1=NOCN1c1ccc(OC(C)C)c(C#N)c1

Procedure:
The title compound was prepared using the procedure analogous to that described for EXAMPLE 75, Step E substituting methyl erythro(+/−)-2,3-dihydroxy-3-(4-(4-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-3-methylphenyl)propanoate (from Step A) for methyl 3-(4-(3-(4-isopropoxy-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)-3-methylphenyl)propanoate: 1H NMR (500 MHz, CD3OD) δ 1.45 (d, J=6.2, 6H), 2.65 (s, 3H), 4.37 (d, J=5.3, 1H), 4.93-4.96 (m, 2M), 7.40-7.44 (m, 3H), 8.00 (d, J=8.2, 1H), 8.42 (dd, J=2.1, 9.0, 1H), 8.44 (d, J=2.1, 11H).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH:6]1[CH2:10][C:9](=[O:11])[CH:8]=[CH:7]1>CN(C)C=O.C(OCC)(=O)C>[N:1]([CH:6]1[CH2:10][C:9](=[O:11])[CH:8]=[CH:7]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1C=CC(Br)C1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NC1C=CC(=O)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
To a solution of sodium azide (2.12 g, 32.6 mmol) in dimethylformamide (15 mL) cooled to 0° C. was added dropwise with stirring 4-bromocyclopent-2-enone (DePuy, C. H.; Isaks, M.; Eilers, K. L.; Morris, G. F. J. Org. Chem. 1964. 29, 3503; 3.5 g, 21.7 mmol) in dimethyl-formamide (5 mL) over a period of 5 min. The reaction mixture was stirred at 0° C. for 30 min and diluted with ethyl acetate (20 mL). The reaction mixture was washed with water (2×20 mL) and brine (20 mL), dried (MgSO4), filtered, and concentrated in vacuo to furnish an oily residue. Purification of the crude oil by flash column chromatography (10-15% ethyl acetate in hexane) gave 1.9 g (71%) of 4-azidocyclopent-2-enone as a light-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].C(O)C.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([N:36]=[C:37]=[S:38])=[O:35])=[CH:30][CH:29]=1>C1(C)C=CC=CC=1>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([NH:36][C:37]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([O:9][C:10]3[C:19]4[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]=[CH:12][CH:11]=3)=[CH:8][C:2]=2[Cl:1])=[S:38])=[O:35])=[CH:30][CH:29]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: O=C(N=C=S)c1ccc(Cl)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(Cl)cc4)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 4-chloro-1-benzenecarbonyl isothiocyanate was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (49 mg, yield 61%).
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)(=O)=O.[N-:29]=[N+:30]=[N-:31].[Na+]>>[N:29]([CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)=[N+:30]=[N-:31]
Reactant: CCOC(=O)C(Cc1ccc(OCCOS(C)(=O)=O)cc1)Oc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: CCOC(=O)C(Cc1ccc(OCCN=[N+]=[N-])cc1)Oc1ccccc1
Yield: 97.7 %

Procedure:
In a similar manner to that described in Reference example 3(h), a reaction was carried out using ethyl 3-[4-(2-methanesulfonyloxyethoxy)phenyl]-2-phenoxypropionate (4.00 g), which is the product of Reference example 4(f), and sodium azide (1.93 g) and the reaction mixture was treated to afford the desired compound (3.40 g) as a syrup.
Reaction SMILES: [CH3:1][S:2]([CH3:4])=O.C(OC(=O)C)(=O)C.C([O-])(=O)C.[Na+].[C:17]1([CH3:26])[CH:22]=[CH:21][C:20]([S:23]([O-:25])=[O:24])=[CH:19][CH:18]=1.[Na+]>[Cl-].[Na+].O.C(O)(=O)C>[CH3:1][S:2][CH2:4][S:23]([C:20]1[CH:21]=[CH:22][C:17]([CH3:26])=[CH:18][CH:19]=1)(=[O:25])=[O:24]
Reactant: Cc1ccc(S(=O)[O-])cc1
Reactant: CS(C)=O
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CSCS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Yield: 34 %

Procedure:
Dimethylsulfoxide (9.25 g, 118 mmol) and acetic anhydride (15.6 g, 153 mmol) were heated to 80° C. for 24 hours. The reaction solution was cooled to room temperature, then glacial acetic acid (90 ml), sodium acetate (9.7 g, 118 mmol) and sodium p-toluenesulfinate (31.6 g, 178 mmol, dried in vacuo overnight with P2O5 at 50° C.) were added. The mixture was heated to 100° C. for 24 hours. Brine (150 ml) was added and the solution was extracted with methylene chloride (5X, 100 ml). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give a gummy solid. The solid was recrystallized from 95% ethanol (3B) to yield 8.68 g of white crystals of (methylthio)(p-toluenesulfonyl)methane: m.p. 81°-83° C.
Reaction SMILES: [C-]#N.[K+].Cl[CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[O:18][C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[CH2:11][C:10]=2[CH:19]=1.[CH3:20][N:21](C)C=O>O>[C:20]([CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[O:18][C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[CH2:11][C:10]=2[CH:19]=1)#[N:21]
Reactant: CN(C)C=O
Reactant: ClCc1ccc2c(c1)Cc1cccnc1O2
Agent: [C-]#N
Agent: [K+]
Solvent: O
Product: N#CCc1ccc2c(c1)Cc1cccnc1O2
Reaction time: 2 h

Procedure:
A solution of 7.8 g of potassium cyanide in 20 ml of water is added dropwise to a mixture of 23 g of 7-chloromethyl-5H-[1]benzopyrano[2,3-b]-pyridine and 200 ml of dimethylformamide. The mixture is allowed to stand at 55°-60°C for 2 hours, and then poured into a large amount of water. The resulting crystalline precipitate is filtered off, washed with water, and recrystallized from aqueous dioxane to give 20 g of 7-cyanomethyl-5H-[1]-benzopyrano[2,3-b]pyridine melting at 166°-167°C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[CH2:7][CH2:8]O)([O-:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:32]1(=[O:42])[NH:36][C:35](=[O:37])[C:34]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:33]12.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[CH2:7][CH2:8][N:36]1[C:35](=[O:37])[C:34]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:33]2[C:32]1=[O:42])([O-:3])=[O:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=[N+]([O-])c1cccc(CCO)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In tetrahydrofuran (225 ml) was dissolved 15 g of 3-nitrophenethyl alcohol, followed by adding triphenylphosphine (26 g) and phthalimide (13.9 g). Then, the resulting mixture was ice-cooled, followed by dropwise addition of diethyl azodicarboxylate (15.5 ml). After stirring at room temperature for 1 hour, the resulting crystals were collected by filtration, washed with diethyl ether and dried, to give N-(3-nitrophenethyl)phthalimide as colorless crystals.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[C:10]([C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]2[CH:21]=[CH:20][N:19]3[N:22]=[CH:23][C:24]([C:25]([OH:27])=O)=[C:18]3[N:17]=2)=[CH:9][C:8]([F:28])=[CH:7][N:6]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>CN(C=O)C>[F:28][C:8]1[CH:9]=[C:10]2[C:5](=[N:6][CH:7]=1)[CH2:4][CH2:3][CH2:2][NH:1][C:25](=[O:27])[C:24]1=[C:18]3[N:17]=[C:16]([CH:21]=[CH:20][N:19]3[N:22]=[CH:23]1)[N:12]1[C@@H:11]2[CH2:15][CH2:14][CH2:13]1
Reactant: NCCCc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1NCCCc2ncc(F)cc2[C@H]2CCCN2c2ccn3ncc1c3n2
Reaction time: 3 h
Yield: 39 %

Procedure:
To (R)-5-(2-(2-(3-aminopropyl)-5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (16 mg, 0.042 mmol) in DMF (5 mL) was added HATU (63 mg, 0.17 mmol) and N-ethyl-N-isopropylpropan-2-amine (22 mg, 0.17 mmol). The reaction mixture was stirred for 3 hours and concentrated under reduced pressure. The crude residue was purified by silica column chromatography using 100% EtOAc to afford the title compound (6.0 mg, 39% yield). MS (apci) m/z=367.3 (M+H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=1[C:14]([F:17])([F:16])[F:15])(=[O:4])=[O:3].[Cl-].[NH4+].O>C(O)C.[Fe]>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[C:14]([F:15])([F:16])[F:17])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc([N+](=O)[O-])cc1C(F)(F)F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)c1ccc(N)cc1C(F)(F)F
Yield: 76.2 %

Procedure:
A mixture of 4-(methylsulfonyl)-3-(trifluoromethyl)nitrobenzene (1.55 g, 5.76 mmol), iron powder (1.61 g, 28.8 mmol), and ammonium chloride (0.031 g, 0.58 mmol) in ethanol (30 mL), and water (8 mL) was heated at reflux temperature for 1 hour. After cooling, insolubles were filtered off by Celite, and volatiles were removed by evaporation. The residue was redissolved in ethyl acetate (50 mL) and the whole washed with water and brine. After dried over MgSO4 and concentration in vacuo. The residue was washed with hexane to give the subtitle compound (1.05 g, 76.2%, yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH2:10])[C:5]#[N:6].[C:11](N1C=CN=C1)(N1C=CN=C1)=[O:12]>>[O:12]=[C:11]1[NH:10][C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=2[NH:1]1
Reactant: N#Cc1ccc(N)c(N)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Product: N#Cc1ccc2[nH]c(=O)[nH]c2c1

Procedure:
3,4-Diaminobenzonitrile (3.171 g, 23.8 mmol, Oakwood) was reacted with 1,1′-carbonyldiimidazole (3.862 g, 23.8 mmol, Aldrich) under the conditions of Example 1b to give the title compound as an amorphous solid. MS (ESI, pos. ion) m/z: 160 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[C:17]([NH:24][C:25]3[S:26][C:27]([C:37](=[O:39])[NH2:38])=[C:28]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=4)[N:29]=3)[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:40](OCC)(OCC)OCC>C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]3[N:21]=[CH:40][N:24]([C:25]4[S:26][C:27]([C:37](=[O:39])[NH2:38])=[C:28]([C:30]5[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=5)[N:29]=4)[C:17]=3[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])c(Nc3nc(-c4cccc(Cl)c4)c(C(N)=O)s3)c2)CC1
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3ncn(-c4nc(-c5cccc(Cl)c5)c(C(N)=O)s4)c3c2)CC1

Procedure:
The crude 4-{3-[5-carbamoyl-4-(3-chloro-phenyl)-thiazole-2-ylamino]-4-nitro-phenoxy}-piperidine-1-carboxylic acid tert-butyl ester (VII.21) was dissolved in 4 mL of acetic acid and 0.14 mL (0.84 mmole) of triethyl orthoformate. The mixture was heated at 70 degrees for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate and saturated aqueous sodium carbonate solution. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with ethyl acetate-dichloromethane (gradient 50:50-100:0) to give 0.10 g of 4-{3-[5-carbamoyl-4-(3-chloro-phenyl)-thiazole-2-yl]-3H-benzoimidazol-5-yloxy}-piperidine-1-carboxylic acid tert-butyl ester (I.21a).
Reaction SMILES: C(OC(=O)[CH:7]([Cl:19])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([N+:16]([O-:18])=[O:17])=[CH:10][N:9]=1)(C)(C)C>C(O)(=O)C>[Cl:19][CH2:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([N+:16]([O-:18])=[O:17])=[CH:10][N:9]=1
Reactant: COc1cc(C(Cl)C(=O)OC(C)(C)C)ncc1[N+](=O)[O-]
Solvent: CC(=O)O
Product: COc1cc(CCl)ncc1[N+](=O)[O-]

Procedure:
A mixture of chloro-(4-methoxy-5-nitro-pyridin-2-yl)-acetic acid tert-butyl ester (2.98 g, 9.84 mole) and acetic acid (25 mL) is refluxed for 6 hours, cooled and evaporated. The residue is dissolved in dichloromethane, passed thru a pad of magnesol, evaporated to dryness and crystallized from 3:1 hexanes/ethyl acetate to give a light yellow solid, 1.78 g, (89%); MS (ES+): m/z 203.2, 205.2 (M+H).
Reaction SMILES: ON1C2C=CC=CC=2N=N1.[CH3:11][CH:12]([NH2:23])[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1.CN1CCOCC1.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:46][N:47]([CH3:65])[C:48]1([C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([F:64])[CH:59]=2)[CH2:53][CH2:52][C:51](=[CH:54][C:55](O)=[O:56])[CH2:50][CH2:49]1.[OH-].[Na+]>CN(C)C=O.O>[CH3:65][N:47]([CH3:46])[C:48]1([C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([F:64])[CH:59]=2)[CH2:53][CH2:52][C:51](=[CH:54][C:55]([NH:23][CH:12]([CH3:11])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)=[O:56])[CH2:50][CH2:49]1
Reactant: CN(C)C1(c2cccc(F)c2)CCC(=CC(=O)O)CC1
Reactant: CC(N)Cc1c[nH]c2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: CC(Cc1c[nH]c2ccccc12)NC(=O)C=C1CCC(c2cccc(F)c2)(N(C)C)CC1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
1-Hydroxybenzotriazole (1.43 g, 10.6 mmol), DL-α-methyltryptamine (923.3 mg, 5.3 mmol), N-methylmorpholine (1.07 g, 10.6 mmol) and dicyclohexylcarbodiimide (2.19 g, 10.6 mmol) were added to a solution of [4-dimethylamino-4-(3-fluoro-phenyl)-cyclohexylidene]acetic acid (1.4 g, 5.3 mmol) in dry dimethylformamide (50 ml) under argon and the mixture was stirred at RT for 6 d. Working up of the mixture was carried out by separating off the urea which had precipitated out and introducing the filtrate into a mixture of saturated NaCl solution (40 ml) and saturated NaHCO3 solution (10 ml). Still further urea thereby precipitated out and was separated off. The aqueous phase was diluted with water (300 ml), 5 M sodium hydroxide solution (7 ml, 35 mmol) was added and the mixture was stored at 5° C. for 20 h. The crude product thereby precipitated out as a yellow solid (1.2 g). The product was a mixture of the two diastereoisomer amides, which were separated by chromatography on silica gel G [100 g; EtOAc/MeOH (10:1)]. The less polar diastereoisomer was obtained in a yield of 410.6 mg (18%) with an m.p. of 163-166° C. and the more polar diastereoisomer was obtained in a yield of 249.3 mg (11%), as a colourless oil.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH2:11].C(N(CC)CC)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[CH3:44][C:45]1([CH3:52])[C:49]([CH3:51])([CH3:50])[O:48][BH:47][O:46]1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:10][O:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([B:47]2[O:48][C:49]([CH3:51])([CH3:50])[C:45]([CH3:52])([CH3:44])[O:46]2)=[C:3]([NH2:11])[CH:4]=1
Reactant: COc1cc(C)c(Br)c(N)c1
Reactant: CC1(C)OBOC1(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1cc(C)c(B2OC(C)(C)C(C)(C)O2)c(N)c1
Yield: 99 %

Procedure:
A solution of 2-bromo-5-methoxy-3-methyl-phenylamine ((Example 198: step c) 2.04 g, 6.18 mmol) in dry dioxane (100 mL) was treated with triethylamine (5.26 mL, 37.7 mmol), 2-(dicyclohexylphosphino)biphenyl (0.662 g, 1.89 mmol), and Pd(OAc)2 (0.106 g, 0.472 mmol). 4,4,5,5-Tetramethyl-1,3,2-dioxaborolane (4.09 mL, 28.3 mmol) was added slowly and the mixture heated to reflux for 1 h. The dioxane was evaporated in vacuo. The residue was taken up in EtOAc and washed with water (2×75 mL). The organic layer was filtered by gravity to remove the palladium residue, dried over MgSO4 and concentrated in vacuo. Silica gel chromatography (10–25% EtOAc in hexanes raised in 5% increments) afforded the product 5-methoxy-3-methyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (1.61 g, 98%) as a light brown solid. 1H NMR (CDCl3): δ 7.361 (d, 1H, J=7.6 Hz), 7.279 (d, 1H, J=8.0 Hz), 3.815 (s, 3H), 2.46 (s, 3H), 1.356 (s, 12H).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]2[S:17][C:16]3[N:18]=[CH:19][CH:20]=[N:21][C:15]=3[N:14](COC)[C:13]=2[CH:25]=1)(=O)=O.[NH:26]1[CH:30]=[CH:29][N:28]=[CH:27]1>>[N:26]1([CH2:6][CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][C:12]3[S:17][C:16]4[N:18]=[CH:19][CH:20]=[N:21][C:15]=4[NH:14][C:13]=3[CH:25]=2)[CH:30]=[CH:29][N:28]=[CH:27]1
Reactant: COCN1c2cc(CCCOS(C)(=O)=O)ccc2Sc2nccnc21
Reactant: c1c[nH]cn1
Product: c1cn(CCCc2ccc3c(c2)Nc2nccnc2S3)cn1

Procedure:
Similar to Example 1094, 3-[10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl]propyl methanesulfonate was reacted with imidazole and then treated by the same method as the one of Example 434 to thereby give the following compound.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([S:5]([C:8]1[CH:35]=[CH:34][C:11]([O:12][C:13]2[C:14]([CH:28]([OH:33])[C:29]([O:31]C)=[O:30])=[CH:15][C:16]3[N:20]=[C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[NH:18][C:17]=3[CH:27]=2)=[CH:10][CH:9]=1)(=[O:7])=[O:6])[CH3:4]>CO>[CH2:3]([S:5]([C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13]2[C:14]([CH:28]([OH:33])[C:29]([OH:31])=[O:30])=[CH:15][C:16]3[N:20]=[C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[NH:18][C:17]=3[CH:27]=2)=[CH:34][CH:35]=1)(=[O:6])=[O:7])[CH3:4]
Reactant: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2C(O)C(=O)OC)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2C(O)C(=O)O)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Sodium borohydride (15 mg) was added to a methanol (1 ml) solution of methyl (6-(4-(ethylsulfonyl)phenoxy)-2-pyridin-2-yl-1H-benzimidazol-5-yl)(hydroxy)acetate (21 mg) obtained in Example 31 (step 2), and the reaction liquid was stirred overnight at 60° C. The solvent was evaporated away under reduced pressure, and the reaction mixture was purified through reversed-phase middle-pressure liquid chromatography (ODS-AS-360-CC (by YMC), mobile phase: water/acetonitrile/0.1% trifluoroacetic acid), and the resulting fraction was diluted with ethyl acetate, washed with aqueous saturated sodium bicarbonate and saturated saline water in that order, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure to obtain the entitled compound.