Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C@H:4]1[C@H:8]([O:9][CH3:10])[CH2:7][N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5]1)=[N+]=[N-].[H][H].C>CO.O=[Pt]=O>[NH2:1][C@H:4]1[C@H:8]([O:9][CH3:10])[CH2:7][N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5]1
Reactant: [H][H]
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1N=[N+]=[N-]
Agent: O=[Pt]=O
Solvent: CO
Product: CO[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1N
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of (3R,4R)-tert-butyl 3-azido-4-methoxypyrrolidine-1-carboxylate (2.04 g, 8.420 mmol) and PtO2 (0.096 g, 0.42 mmol) in MeOH (100 mL) was charged with hydrogen (1 atmosphere) and stirred at ambient temperature for 2 days. Charcoal (2 g) was added to the solution and. The catalyst was removed by filtration and washed with MeOH (20 mL). The solvent was removed and dried to give (3R,4R)-tert-butyl 3-amino-4-methoxypyrrolidine-1-carboxylate. It was dissolved in dioxane (10 mL) and water (10 mL). Na2CO3 (1.34 g, 12.63 mmol) was added, followed by Cbz-Cl (1.87 mL, 12.63 mmol) at ambient temperature. The reaction mixture was stirred at ambient temperature for 3 hours. Ethyl acetate (50 ml) was added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue obtained was purified by flash chromatography on silica gel (1:1 hexane/ethyl acetate) to give (3R,4R)-tert-butyl 3-(benzyloxycarbonylamino)-4-methoxypyrrolidine-1-carboxylate (2.90 g, 98.3% yield) as oil.
Reaction SMILES: O=[C:2]([C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[CH2:22][CH2:21]2)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[C:13]([CH3:17])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[BH4-].[Na+].CC(C)=O.[OH-].[Na+]>CO.CCOCC>[C:13]1([CH3:17])[CH:14]=[CH:15][CH:16]=[C:11]([N:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH:3]=[CH:2][C:18]3[CH:19]=[C:20]4[C:25](=[CH:26][CH:27]=3)[NH:24][C:23](=[O:28])[CH2:22][CH2:21]4)[CH2:6][CH2:7]2)[CH:12]=1
Reactant: Cc1cccc(N2CCN(CCC(=O)c3ccc4c(c3)CCC(=O)N4)CC2)c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CO
Solvent: CCOCC
Product: Cc1cccc(N2CCN(CC=Cc3ccc4c(c3)CCC(=O)N4)CC2)c1
Reaction time: 0.5 h

Procedure:
5.0 Grams of 6-{1-oxo-3-[4-(3-tolyl)-1-piperazinyl]-propyl}-3,4-dihydrocarbostyril was suspended in 250 ml of methanol, and 2.5 g of sodium borohydride was added gradually to this solution under ice-cooling condition and the mixture was stirred for 30 minutes. Then 10 ml of acetone was added to the mixture and the reaction mixture was concentrated under a reduced pressure to dryness. To the residue thus obtained were added 10N-NaOH and ether and stirred at a room temperature for 30 minutes. The crystals thus formed were collected by filtration and were suspended in 250 ml of dioxane then added 10 ml of concentrated hydrochloric acid. The mixture was refluxed for 15 minutes then concentrated under a reduced pressure to dryness. The residue thus obtained was separatedby a silica-gel chromatography and recrystallized from ethanol to obtain 6-{3-[4-(3-tolyl)-1-piperazinyl]-1-propenyl}-3,4-dihydrocarbostyril in colorless prism-like crystals. Yield: 2.9 g.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:25]([NH:27][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][C:33]=2[N:34]2[CH2:39][CH2:38][CH2:37][C@H:36]([NH2:40])[CH2:35]2)=[O:26])=[N:4][C:5]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[C:11]([O:16]CC3C=CC=CC=3)[C:10]=2[F:24])=[C:6]([F:8])[CH:7]=1>CO.[Pd]>[NH2:1][C:2]1[C:3]([C:25]([NH:27][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][C:33]=2[N:34]2[CH2:39][CH2:38][CH2:37][C@H:36]([NH2:40])[CH2:35]2)=[O:26])=[N:4][C:5]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[C:11]([OH:16])[C:10]=2[F:24])=[C:6]([F:8])[CH:7]=1
Reactant: Nc1cc(F)c(-c2c(F)ccc(OCc3ccccc3)c2F)nc1C(=O)Nc1cnccc1N1CCC[C@H](N)C1
Agent: [Pd]
Solvent: CO
Product: Nc1cc(F)c(-c2c(F)ccc(O)c2F)nc1C(=O)Nc1cnccc1N1CCC[C@H](N)C1

Procedure:
Method 2 of Example 49 was followed using 3-amino-N-(4-((S)-3-aminopiperidin-1-yl)pyridin-3-yl)-6-(3-(benzyloxy)-2,6-difluorophenyl)-5-fluoropicolinamide with 20 wt % Pd/C in methanol (0.1 M solution). The Boc protected product was purified by preparative HPLC. After volatile materials were removed, the crude material was stirred in 30% TFA in dichloromethane. After volatile materials were removed in vacuo, 3-amino-N-(4-((S)-3-aminopiperidin-1-yl)pyridin-3-yl)-6-(2,6-difluoro-3-hydroxyphenyl)-5-fluoropicolinamide was obtained by preparative HPLC. LCMS (m/z): 459.2 (MH+); LC Rt=2.10 min.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[I-].[Na+].[Cl:7][C:8]1[C:9]2[CH:24]=[C:23]([O:25]C)[C:22]([O:27]C)=[CH:21][C:10]=2[S:11][C:12]=1[C:13]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14].Cl.S([O-])([O-])=O.[Na+].[Na+]>O.C(#N)C>[Cl:7][C:8]1[C:9]2[CH:24]=[C:23]([OH:25])[C:22]([OH:27])=[CH:21][C:10]=2[S:11][C:12]=1[C:13]([N:15]1[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1)=[O:14]
Reactant: COc1cc2sc(C(=O)N3CCOCC3)c(Cl)c2cc1OC
Agent: Cl
Agent: O=S([O-])[O-]
Agent: [Al+3]
Solvent: CC#N
Solvent: O
Product: O=C(c1sc2cc(O)c(O)cc2c1Cl)N1CCOCC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Aluminum chloride (6.62 g) was gradually added into cool acetonitrile (14.7 ml) at 10° C. and then sodium iodide (5.57 g) was added. The solution was stirred at room temperature 30 min. (3-Chloro-5,6-dimethoxy-benzo[b]thiophen-2-yl)-morpholin-4-yl-methanone (2.1 g) from Example 8 was added. The solution was stirred at 50° C. five hours and at room temperature overnight. 2N HCl (8.4 ml) was added into the cool reaction solution and then sodium sulfite (1.58 g) and water (35 ml) were added. The mixture was stirred at 40° C. 30 min. The product was filtered, washed with water and dried in vacuum.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[O:5][C:6]1[CH:13]=[C:12]([CH2:14][N:15]2[C:19]([CH2:20]O)=[CH:18][N:17]=[CH:16]2)[CH:11]=[CH:10][C:7]=1[C:8]#[N:9].C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:38]=[N+:39]=[N-:40].[Na+]>C(Cl)Cl.CN(C=O)C>[N:38]([CH2:20][C:19]1[N:15]([CH2:14][C:12]2[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([O:5][C:4]3[CH:22]=[CH:23][CH:24]=[CH:25][C:3]=3[Cl:2])[CH:13]=2)[CH:16]=[N:17][CH:18]=1)=[N+:39]=[N-:40]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(Cn2cncc2CO)cc1Oc1ccccc1Cl
Agent: CS(=O)(=O)Cl
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1ccc(Cn2cncc2CN=[N+]=[N-])cc1Oc1ccccc1Cl
Reaction time: 1 h

Procedure:
To a solution of 2-(2-chloro-phenoxy)-4-(5-hydroxymethyl-imidazol-1-ylmethyl)-benzonitrile hydrochloride, as described in Example 15, (0.07 g, 0.186 mmol) in CH2Cl2 (4.0 mL), and triethylamine (0.078 mL, 0.558 mmol) at 0° C. was added methanesulfonyl chloride (0.016 mL, 0.205 mmol). The cooling bath was removed and the mixture was stirred for 1 hr. To this solution was added sodium azide (0.018 g, 0.277 mmol) in DMF (1.0 mL). After 1 hr. the reaction mixture was partitioned between EtOAc and saturated NaHCO3 solution. The EtOAc layer was washed with H2O, brine, and dried (MgSO4). Filtration and concentration in vacuo gave the title product which was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([NH:11][C:12]3[CH:22]=[CH:21][C:15]([C:16]([N:18]([CH3:20])[CH3:19])=[O:17])=[C:14]([CH3:23])[CH:13]=3)=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[F:24][C:25]1[CH:37]=[C:36]([Sn](C)(C)C)[CH:35]=[CH:34][C:26]=1[CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>COCCOC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:24][C:25]1[CH:37]=[C:36]([C:2]2[C:10]3[O:9][C:8]([NH:11][C:12]4[CH:22]=[CH:21][C:15]([C:16]([N:18]([CH3:20])[CH3:19])=[O:17])=[C:14]([CH3:23])[CH:13]=4)=[N:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH:35]=[CH:34][C:26]=1[CH2:27][N:28]1[CH2:29][CH2:30][O:31][CH2:32][CH2:33]1
Reactant: C[Sn](C)(C)c1ccc(CN2CCOCC2)c(F)c1
Reactant: Cc1cc(Nc2nc3cccc(Br)c3o2)ccc1C(=O)N(C)C
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: Cc1cc(Nc2nc3cccc(-c4ccc(CN5CCOCC5)c(F)c4)c3o2)ccc1C(=O)N(C)C
Temperature: 150 °C
Reaction time: 1 h

Procedure:
0.1 g (0.267 mmol) 4-(7-bromo-benzooxazol-2-ylamino)-2,N,N-trimethyl-benzamide and 0.17 g (0.305 mmol) 4-(2-fluoro-4-trimethylstannanyl-benzyl)-morpholine are dissolved in 2 ml 1,2-dimethoxy-ethane and a stream of argon is bubbled through the mixture in order to exclude oxygen from the reaction mixture. Tetrakis (triphenylphosphine) palladium (0.020 g, 0.016 mmol) is added and the reaction mixture is stirred at 150° C. for 1 h. After that the reaction mixture is poured on water and extracted 3× with EtOAc. The combined organic layers are washed with water and saturated NaCl solution, dried over MgSO4, filtered and the filtrate is concentrated in vacuo. The residue is purified by chromatography (silicagel, EtOAc:MeOH=95:5; column chromatography followed by thick-layer chromatography) to afford the title compound. Rt=1.67 min (Waters Symmetry C8, 2.1×50 mm, detection 210-250 nM, 5% to 100% CH3CN in H2O in 2 min+0.05% TFA, flow rate 1.0 ml/min); MS: 375 (M+1)+.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][C:4](=[S:6])[NH2:5].Br[CH2:10][C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13]>C1COCC1>[F:1][C:2]([F:8])([F:7])[CH2:3][C:4]1[S:6][CH:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:5]=1
Reactant: NC(=S)CC(F)(F)F
Reactant: CCOC(=O)C(=O)CBr
Solvent: C1CCOC1
Product: CCOC(=O)c1csc(CC(F)(F)F)n1

Procedure:
A solution of 3,3,3-trifluoropropanethioamide (example 67, step b) (4 g) and ethyl 3-bromo-2-oxopropanoate (5.45 g) in THF (120 mL) was heated at reflux for 2 hours. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography using 17% ethyl acetate in isohexane as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 1.9 g.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[CH2:12][NH:11][CH2:10][CH:9]3[F:16])[CH2:3][CH2:2]1.C(OC(=O)[NH:23][C@H:24]([C:26]1[CH:31]=[CH:30][C:29]([CH:32]=O)=[CH:28][CH:27]=1)[CH3:25])(C)(C)C.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[CH2:12][N:11]([CH2:32][C:29]2[CH:30]=[CH:31][C:26]([C@@H:24]([NH2:23])[CH3:25])=[CH:27][CH:28]=2)[CH2:10][CH:9]3[F:16])[CH2:2][CH2:3]1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C=O)cc1
Reactant: FC1CNCc2ccc(OCC3CC3)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C[C@H](N)c1ccc(CN2Cc3ccc(OCC4CC4)cc3C(F)C2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To 170 mg (0.660 mmol) 6-cyclopropylmethoxy-4-fluoro-1,2,3,4-tetrahydro-isoquinoline (example XLVII.5) and 164 mg (0.660 mmol) [(S)-1-(4-formyl-phenyl)-ethyl]-carbamic acid tert-butyl ester (example II) in 2 mL THF are added 113 μL (1.98 mmol) AcOH and the mixture is stirred at r.t. for 10 min. The resulting mixture is cooled to 0° C., 210 mg (0.989 mmol) sodium triacetoxyborohydride are added and the reaction mixture is stirred at r.t. for 2 h. The reaction is quenched by the addition of 200 μL water and purified by HPLC (ACN/H2O/NH3).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:20]=[CH:19][N:18]2[C:21]([Cl:24])=[CH:22][N:23]=[C:17]2[CH:16]=1.N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[Cl:24][C:21]1[N:18]2[CH:19]=[CH:20][C:15]([N:10]3[CH2:11][CH2:12][N:8]([C:3]4[CH:4]=[N:5][CH:6]=[CH:7][C:2]=4[CH3:1])[C:9]3=[O:13])=[CH:16][C:17]2=[N:23][CH:22]=1
Reactant: Clc1cnc2cc(Br)ccn12
Reactant: Cc1ccncc1N1CCNC1=O
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2ccn3c(Cl)cnc3c2)C1=O
Yield: 6.5 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 165 mg, 0.932 mmol) was reacted with 7-bromo-3-chloro-imidazo[1,2-a]pyridine (278 mg, 1.21 mmol), 1,4-dioxane (6 mL), copper iodide (17.71 mg, 0.093 mmol), trans-1,2-diamino cyclohexane (32.01 mg, 0.279 mmol) and potassium phosphate (493.96 mg, 2.33 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in CHCl3), followed by preparative HPLC afforded 20 mg of the product (6.57% yield).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:17][C:18](O)=[O:19].B.C1COCC1>C1COCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:17][CH2:18][OH:19]
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1CC(=O)O
Agent: B
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1CCO

Procedure:
7.33 g of the above prepared [5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-acetic acid (25.7 mmol) was dissolved in 120 ml of abs. THF and treated at 0° C. with 64 ml 1M BH3THF (2.5 eq.). The reaction mixture was then kept over night et ambient temperature. Careful quenching with MeOH and ice, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents left a crude product which was refluxed for 30 min. in MeOH to liberate quantitatively the free alcohol. Flash chromatography (SiO2, hexane/AcOEt=7/3) delivered finally 6.38 g of the title compound as off-white crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([O-:3])=[O:2].Cl.CO[NH2:19].CC(C)([O-])C.[K+]>CN(C=O)C.[Cu]Cl>[NH2:19][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: CON
Reactant: O=[N+]([O-])c1ccccc1-c1ccccc1
Agent: Cl[Cu]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: CN(C)C=O
Product: Nc1cccc(-c2ccccc2)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 20 h
Yield: 27.1 %

Procedure:
A suspension of 2-nitrobiphenyl (2.061 g, 10.34 mmol) and O-methylhydroxylamine hydrochloride (1.088 g, 13.02 mmol) in DMF (15 mL) was added to a cold (0° C.) solution of potassium tert-butoxide (5.993 g, 53.40 mmol) and copper(I) chloride (0.246 g, 2.48 mmol) in DMF (35 mL). The cooling bath was removed and the resultant slurry was stirred at room temperature for 20 hours. The reaction mixture was poured into saturated aqueous NH4Cl (50 mL) and the mixture was extracted with CH2Cl2 (4×50 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by column chromatography on silica gel (4:1 hexanes-ethyl acetate followed by 2:1 hexanes-ethyl acetate) provided 0.600 g (27%) 2-amino-6-phenyl-nitrobenzene as a yellow oil. 1H NMR (CDCl3) □ 4.99 (br s, 2H), 6.70 (dd, 1H, J=7.2, 1.2 Hz), 6.80 (dd, 1H, J=8.4, 1.2 Hz), 7.29-7.41 (m, 6H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](Cl)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:3]=1.[CH3:22][C@H:23]1[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]1.C[C@@H]1OCCN(C2C3C(C4C=C(C=CC=4)C#N)=CNC=3N=CN=2)C1>>[Br:1][C:2]1[C:10]2[C:9]([N:25]3[CH2:26][CH2:27][CH2:28][C@H:23]([CH3:22])[CH2:24]3)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(Br)c3c(Cl)ncnc32)cc1
Reactant: C[C@H]1CCCNC1
Agent: C[C@H]1CN(c2ncnc3[nH]cc(-c4cccc(C#N)c4)c23)CCO1
Product: Cc1ccc(S(=O)(=O)n2cc(Br)c3c(N4CCC[C@H](C)C4)ncnc32)cc1

Procedure:
5-Bromo-4-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (P3) was reacted with the hydrochloride salt of (3S)-3-methylpiperidine according to the method described for preparation of 3-{4-[(2S)-2-methylmorpholin-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}benzonitrile (6) in Example 6. In this case, purification was effected via silica gel chromatography (Eluent: 5:1 petroleum ether/ethyl acetate), providing the product as a white solid. Yield: 4.3 g, 9.6 mmol, 92%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[NH:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[N:22]=3)[CH2:17][CH2:16]2)=[CH:9][CH:8]=1)([CH3:6])[CH3:5].CC(C)([O-])C.[K+].[CH2:37]([O:39][CH2:40][CH2:41]CS([O-])(=O)=O)[CH3:38].CN(C=O)C>C(OC(=O)C)C.O>[CH3:1][O:2][C:3](=[O:30])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][CH:18]([C:21]3[N:22]([CH2:38][CH2:37][O:39][CH2:40][CH3:41])[C:23]4[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=4[N:25]=3)[CH2:19][CH2:20]2)=[CH:9][CH:8]=1)([CH3:5])[CH3:6]
Reactant: COC(=O)C(C)(C)c1ccc(CCN2CCC(c3nc4ccccc4[nH]3)CC2)cc1
Reactant: CCOCCCS(=O)(=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOCCn1c(C2CCN(CCc3ccc(C(C)(C)C(=O)OC)cc3)CC2)nc2ccccc21
Yield: 84.9 %

Procedure:
In a reaction vessel, 2-(4-{2-[4-(1H-benzoimidazol-2-yl)-piperidin-1-yl]-ethyl}-phenyl)-2-methyl-propionic acid methylester (0.5 g) prepared in the Example 13, potassium-t-butoxide (0.14 g), ethoxyethylmesylate (0.25 g) and DMF (20 mL) were introduced, and the mixture was reacted at 50□ for 3 hours. Distilled water (50 mL) and ethylacetate (50 mL) were added thereto, and the mixture was stirred to separate a layer. Separated organic layer was washed with distilled water (50 mL), dehydrated, and condensed under reduced pressure to obtain 2-[4-(2-{4-[1-(2-ethoxy-ethyl)-1H-benzoimidazol-2-yl]-piperidin-1-yl}-ethyl)-phenyl]-2-methyl-propionic acid methylester (0.5 g, yield 85%, HPLC purity 98.5% or more).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[CH:7]1([NH:13][S:14](=[O:17])(=O)[OH:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.P(Cl)(Cl)([Cl:20])=O>ClCCCl>[CH:7]1([NH:13][S:14]([Cl:20])(=[O:17])=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=S(=O)(O)NC1CCCCC1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCCl
Product: O=S(=O)(Cl)NC1CCCCC1
Temperature: 95 °C
Yield: 95 %

Procedure:
54.2 parts of phosphorus pentachloride are added in portions to 89.6 parts of cyclohexylsulfamic acid, suspended in a mixture of 113 parts of 1,2-dichloroethane and 134 parts of phosphorus oxychloride, at 20° C, whilst stirring. The reaction mixture is then heated to 95° C in the course of 30 minutes and is stirred at from 95° to 98° C for 71/2 hours. After removing the solvent under reduced pressure distillation of the residue gives 94 parts (95% of theory) of cyclohexylsulfamic acid chloride of boiling point 103°-111° C/0.05 mm Hg (melting point 42°-44°).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH3:11].O=P(Cl)(Cl)Cl.CN(C1C=CC=CC=1)[CH:19]=[O:20]>>[CH3:10][O:9][C:6]1[CH:5]=[C:4]([CH3:11])[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[CH:19]=[O:20]
Reactant: COc1ccc(OC)c(C)c1
Reactant: CN(C=O)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(C=O)c(OC)cc1C

Procedure:
To a solution of 2,5-dimethoxytoluene (4.66 g, 30.6 mmol) in 60 mL of N-methyl-N-phenyl-formamide was added at 0° C. POCl3 (8.41 mL, 3 eq.), and the mixture was heated for 60 Min. to 80° C. After cooling, the reaction mixture was poured onto crashed ice, twofold extracted with AcOEt, washed with water, dried over sodium sulfate, and evaporated to dryness. Flash chromatography (SiO2, hexane/AcOEt=9/1) afforded 4.153 g of the title compound as off-white solid.
Reaction SMILES: [Br:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH3:16][N:17]1[C:21]([NH2:22])=[N:20][N:19]=[N:18]1.C(Cl)(=O)C(Cl)=O>N1C=CC=CC=1>[Br:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=[CH:7][C:3]=1[C:4]([NH:22][C:21]1[N:17]([CH3:16])[N:18]=[N:19][N:20]=1)=[O:5]
Reactant: Cn1nnnc1N
Reactant: COc1c([N+](=O)[O-])ccc(C(=O)O)c1Br
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Product: COc1c([N+](=O)[O-])ccc(C(=O)Nc2nnnn2C)c1Br
Temperature: 65 °C
Yield: 48 %

Procedure:
2-bromo-3-methoxy-4-nitrobenzoic acid (95 mg, 0.344 mmol) and 1-methyl-1H-tetrazol-5-amine (44 mg, 0.447 mmol) are dissolved in pyridine (6 ml). Oxalyl chloride (41 μl, 0.465 mmol) is slowly added dropwise, and the reaction mixture is subsequently warmed to 65° C. for 2 hours. The solvent is stripped off and the residue is separated by preparative HPLC. This gives 59 mg (0.165 mmol, yield 48%) of 2-bromo-3-methoxy-N-(1-methyl-1H-tetrazol-5-yl)-4-nitrobenzamide.
Reaction SMILES: [CH3:1][C:2]([CH3:28])([CH3:27])[CH2:3][O:4][C:5]([C:7]1[CH:8]=[C:9]([C:21]#[C:22][Si](C)(C)C)[CH:10]=[C:11]2[C:16]=1[O:15][C:14]([CH3:18])([CH3:17])[CH2:13][C:12]2([CH3:20])[CH3:19])=[O:6].C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:1][C:2]([CH3:28])([CH3:27])[CH2:3][O:4][C:5]([C:7]1[CH:8]=[C:9]([C:21]#[CH:22])[CH:10]=[C:11]2[C:16]=1[O:15][C:14]([CH3:17])([CH3:18])[CH2:13][C:12]2([CH3:20])[CH3:19])=[O:6]
Reactant: CC(C)(C)COC(=O)c1cc(C#C[Si](C)(C)C)cc2c1OC(C)(C)CC2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cc(C(=O)OCC(C)(C)C)c2c(c1)C(C)(C)CC(C)(C)O2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
A solution of 2,2,4,4-tetramethyl-6-trimethylsilanylethynylchroman-8-carboxylic acid 2,2-dimethylpropyl ester (Intermediate 47, 0.396 g, 1 mmol) in methanol (5 mL) was treated with potassium carbonate (1.4 g, 10 mmol) and the resulting reaction mixture was stirred at ambient temperature for 30 minutes. The solvent was evaporated in vacuo, the residue was diluted with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title compound as a brown oil (0.227 g, 70%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][N:3]=1.N1C=CC=CC=1.Cl[C:16]([O:18][CH2:19][C:20]([Cl:23])([Cl:22])[Cl:21])=[O:17].O>O1CCCC1>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:16](=[O:17])[O:18][CH2:19][C:20]([Cl:23])([Cl:22])[Cl:21])=[CH:6][CH:7]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1ccc(N)nc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O
Product: Nc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cn1
Yield: 18.1 %

Procedure:
To a solution of 2,5-diaminopyridine (1.00 g, 9.16 mmol) and pyridine (0.889 ml, 11.0 mmol) in tetrahydrofuran (30 ml) was added, under ice-cooling, 2,2,2-trichloroethyl chloroformate (1.52 ml, 11.0 mmol), and the mixture was stirred at room temperature for 1 hour. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give 471 mg (18.1%) of the desired product as a solid.
Reaction SMILES: [H-].[Na+].[C:3]12([C:13]3[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=3[OH:23])[C:16]([O:18][CH3:19])=[O:17])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.[CH3:24][O:25][CH2:26]Cl.O>CN(C=O)C>[C:3]12([C:13]3[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=3[O:23][CH2:24][O:25][CH3:26])[C:16]([O:18][CH3:19])=[O:17])[CH2:4][CH:5]3[CH2:11][CH:9]([CH2:8][CH:7]([CH2:6]3)[CH2:12]1)[CH2:10]2
Reactant: COC(=O)c1ccc(O)c(C23CC4CC(CC(C4)C2)C3)c1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1ccc(C(=O)OC)cc1C12CC3CC(CC(C3)C1)C2

Procedure:
9 g (0.3 mol) of sodium hydride (80% in oil) and 50 ml of DMF were introduced into a three-necked flask under a stream of nitrogen. A solution of 71.6 g (0.25 mol) of methyl 3-(1-adamantyl)-4-hydroxybenzoate in 500 ml of DMF was added dropwise and the mixture was stirred until the evolution of gas had ceased. 22.8 ml (0.3 mol) of methoxymethyl chloride were then added and the mixture was stirred at room temperature for one hour. The reaction medium was poured into water and extracted with ethyl ether. The organic phase was separated out after settling had taken place, dried over magnesium sulfate and evaporated. 67.7 g (82%) of the expected compound were recovered in the form of an oil.