Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[C:13]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[N:12][C:11]2[C:6]1=[N:7][CH:8]=[N:9][C:10]=2[NH2:23])[CH2:2][CH2:3][CH3:4].[I:24]NC(=O)CCC(N)=O.C([O-])([O-])=O.[K+].[K+]>CC(O)=O.C(Cl)Cl>[CH2:1]([N:5]1[C:13]([CH2:14][C:15]2[CH:16]=[C:17]([O:21][CH3:22])[CH:18]=[CH:19][C:20]=2[I:24])=[N:12][C:11]2[C:6]1=[N:7][CH:8]=[N:9][C:10]=2[NH2:23])[CH2:2][CH2:3][CH3:4]
Reactant: NC(=O)CCC(=O)NI
Reactant: CCCCn1c(Cc2cccc(OC)c2)nc2c(N)ncnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCCn1c(Cc2cc(OC)ccc2I)nc2c(N)ncnc21
Reaction time: 3 h

Procedure:
4.1 To a solution of 9-butyl-8-(3-methoxy-benzyl)-9H-purin-6-ylamine (1.24 g, 4 mmol) in AcOH (6 ml) was added N-iodo-succinamide (NIS) (1.8 g, 8 mmol). After 3 h at r.t., additional NIS (1.8 g, 8 mmol) was added, and the mixture was stirred for another 24 h. The reaction mixture was diluted with CH2Cl2 (500 ml), and carefully neutralized with a solution of sat. aq. K2CO3 (2×100 ml), then washed with 0.1 N Na2S2O3 (3×100 ml), brine (3×100 ml), dried (Na2SO4), evaporated, and purified by flash chromatography (CH2Cl2:MeOH=100:5) to give the 9-Butyl-8-(2-iodo-5-methoxy-benzyl)-9H-purin-6-ylamine (4.1), as a colorless powder (0.53 g, 30%); rt=7.7 min.; 1HNMR (CDCl3-d) δ 8.36 (s, 1H), 7.77 (d, J=7.9 Hz, 1H), 6.68 (s, 1H), 6.61 (d, J=7.9 Hz, 1H), 5.62 (s, 2H), 4.33 (s, 2H), 4.06 (t, J=7.7 Hz, 2H), 3.72 (s, 3H), 1.67 (quint., J=7.7 Hz, 2H), 1.36 (sext., J=7.5 Hz, 2H), 0.92 (t, J=7.4 Hz, 3H).
Reaction SMILES: [NH2:1][C:2](=[N:16][OH:17])[CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([F:28])[CH:27]=1)[C:22](Cl)=O.C(N(CC)CC)C.C(OCC)(=O)C>C1COCC1.O>[F:18][C:19]1[CH:20]=[C:21]([C:22]2[O:17][N:16]=[C:2]([CH:3]3[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[CH2:7][CH2:8]3)[N:1]=2)[CH:25]=[C:26]([F:28])[CH:27]=1
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=NO)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2noc(-c3cc(F)cc(F)c3)n2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
To a solution of tert-butyl 4-[amino(hydroxyimino)methyl]piperidine-1-carboxylate (3.0 g) in THF (30 mL) were added 3,5-difluorobenzoyl chloride (2.4 g) and triethylamine (3.44 mL) under ice-cooling, followed by stirring at room temperature for 2 hours. To the reaction liquid were added ethyl acetate and water, and the organic phase was separated. The organic phase was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To the residue were added THF (25 mL) and a 1 M tetrabutylammonium fluoride/THF solution (12.4 mL), followed by stirring at 50° C. for 30 minutes. The reaction liquid was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform). To the purified product was added diisopropyl ether, and the resulting solid was collected by filtration and dried to obtain tert-butyl 4-[5-(3,5-difluorophenyl)-1,2,4-oxadiazol-3-yl]piperidine-1-carboxylate (4.22 g) as an orange solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([Mg]CCCC)CCC.C([Li])CCC.[O:28]=[C:29]1[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]1>CCCCCCC.CCCCCC.C1COCC1>[C:38]([O:37][C:35]([N:32]1[CH2:33][CH2:34][C:29]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3([C:11]([OH:13])=[O:12])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)([OH:28])[CH2:30][CH2:31]1)=[O:36])([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=C(O)C1(c2ccc(Br)cc2)CC1
Agent: CCCC[Mg]CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(C3(C(=O)O)CC3)cc2)CC1
Reaction time: 1 h

Procedure:
A solution of 1-(4-bromophenyl)cyclopropanecarboxylic acid (1000.0 mg, 0.0041480 mol) in tetrahydrofuran (30 mL, 0.4 mol) was cooled below −20° C. under a N2 atmosphere and dibutylmagnesium in heptane (1.0 M, 2.2 mL) was slowly added to the solution while the reaction temperature was maintained below −20° C. Then 2.5 M of n-butyllithium in hexane (1.8 mL) was slowly added to the mixture below −20° C. under effective stirring. After stirring below −20° C. for 1 h, a solution of tert-butyl 4-oxo-1-piperidinecarboxylate (0.909 g, 0.00456 mol) in THF (20.0 mL) was added to the mixture below −20° C. After stirring below −20° C. for 1 h, the reaction was quenched with ammonium chloride. The product was extracted with EtOAc and the combined extract was washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated and then purified by Combiflash, eluting with 5% methanol in methylene chloride.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][S:5](=[O:8])(=[O:7])[NH:4][CH2:3]1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])=[C:12]([F:32])[CH:11]=1>>[CH3:30][C:29]1[C:24]([N:21]2[CH2:22][CH2:23][N:18]([C:16]([C:13]3[CH:14]=[CH:15][C:10]([N:4]4[CH2:3][C@@H:2]([CH3:1])[CH2:6][S:5]4(=[O:8])=[O:7])=[CH:11][C:12]=3[F:32])=[O:17])[CH2:19][CH2:20]2)=[N:25][CH:26]=[C:27]([CH3:31])[CH:28]=1
Reactant: C[C@@H]1CNS(=O)(=O)C1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C[C@@H](C)CS4(=O)=O)cc3F)CC2)c(C)c1
Yield: 12.6 %

Procedure:
Using (R)-4-methylisothiazolidine 1,1-dioxide (320 mg) described in Preparation Example 7 and (4-bromo-2-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (439 mg) described in Preparation Example 114 and by the reaction and treatment in the same manner as in Example 1, the title compound (63 mg) was obtained.
Reaction SMILES: O[NH:2][C:3]([C:5]1[CH:26]=[CH:25][C:8]([CH2:9][NH:10][C:11](=[O:24])[CH:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2[OH:23])[O:13][CH3:14])=[CH:7][CH:6]=1)=[NH:4]>C(O)C.C(O)(=O)C.[Pd]>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:11](=[O:24])[CH:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2[OH:23])[O:13][CH3:14])=[CH:25][CH:26]=1)(=[NH:2])[NH2:4]
Reactant: COc1ccc(C(OC)C(=O)NCc2ccc(C(=N)NO)cc2)c(O)c1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc(C(OC)C(=O)NCc2ccc(C(=N)N)cc2)c(O)c1
Reaction time: 7.5 h

Procedure:
A suspension of (RS)-N-[4-(N-hydroxycarbamimidoyl)-benzyl]-2-(2-hydroxy-4-methoxy-phenyl)-2-methoxy-acetamide (240 mg) in ethanol (9 ml) and acetic acid (0.38 ml) was hydrogenated for 7.5 h using 10% Pd/C as a catalyst. The reaction mixture was filtered and the solvent was evaporated. The product was purified by chromatography (silica gel, CH2Cl2=>CH2Cl2/MeOH 4:1) to give (RS)-N-(4-carbamimidoyl-benzyl)-2-(2-hydroxy-4-methoxy-phenyl)-2-methoxy-acetamide actetate (12 mg) as an off-white, amorphous solid. MS 344.2 ([M+H]+)
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][C:13](=[O:15])[CH3:14])[CH:8]=2)[CH:3]=1.C(OC(=O)C)(=[O:18])C.[Br-].[NH4+]>O.O.O.O.C([O-])(=O)C.[Co+2].C([O-])(=O)C.O.O.O.O.C([O-])(=O)C.[Mn+2].C([O-])(=O)C.C(O)(=O)C>[C:13]([O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([CH:1]=[O:18])[CH:11]=[CH:10]2)(=[O:15])[CH3:14]
Reactant: CC(=O)Oc1ccc2cc(C)ccc2c1
Reactant: CC(=O)OC(C)=O
Agent: [Co+2]
Agent: [Mn+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Oc1ccc2cc(C=O)ccc2c1
Temperature: 120 °C
Reaction time: 2.5 h

Procedure:
A 200 cc titanium pressure vessel equipped with a stirrer was charged with 10 parts of 2-methyl-6-acetyloxynaphthalene, 80 parts of acetic acid, 20 parts of acetic anhydride, 0.249 parts (Co=590 wt. ppm) of cobalt acetate tetrahydrate, 0.245 parts (Mn=550 wt. ppm) of manganese acetate tetrahydrate, and 0.250 parts (Br=2040 wt. ppm) of ammonium bromide. The vessel was pressurized with air to 25 kg/cm2 -G, and the mixture was heated to 120° C. Air was introduced into the vessel at a rate of 10 Nl/hr. When the absorption of oxygen ceased, the reaction was terminated. The reaction time was 2.5 hours. The vessel was cooled, and the contents were withdrawn and analyzed. The conversion of 2-methyl-6-acetyloxynaphthalene was 100 mole %, and the yield of 6-acetyloxy-2-naphthoic acid was 68.5 mole % (selectivity 68.5 mole %). At this time, 23.5 mole % of 6-acetyloxy-2-naphthaldehyde was also formed.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)O1.Br[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[F:26].[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[F:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[N:13]1[C:14]2[C:10](=[CH:9][CH:17]=[CH:16][CH:15]=2)[CH:11]=[CH:12]1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Reactant: Fc1ccccc1Br
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Fc1ccccc1-n1ccc2ccccc21
Temperature: 75 °C
Reaction time: 15 h
Yield: 63.9 %

Procedure:
To a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (3, 2.431 g, 10.0 mmol), and 2-bromofluorobenzene (1.75 g, 10.1 mmol) in THF (34 mL)) were added Palladium catalyst Pd(PPh3)4 (0.347 g, 0.30 mmol) and the freshly prepared sodium hydroxide solution (1.20 g, 30.0 mmol in 14 mL water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 75° C. oil bath for 15 hours. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4, and concentrated. The crude product was purified by a silica gel column eluting with hexanes—EtOAc (9:1) to provide 1.35 g (64%) of the product 4-(2-fluoro-phenyl)-1H-indole as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[H-].[Na+].C(OC([N:19]1[CH2:24][CH2:23][N:22]([C:25]([C:27]2[C:35]3[C:30](=[N:31][CH:32]=[CH:33][C:34]=3[CH2:36][CH2:37][CH3:38])[N:29]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:28]=2Cl)=[O:26])[CH2:21][CH2:20]1)=O)(C)(C)C>CN1C(=O)CCC1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][C:28]1[N:29]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:30]2=[N:31][CH:32]=[CH:33][C:34]([CH2:36][CH2:37][CH3:38])=[C:35]2[C:27]=1[C:25]([N:22]1[CH2:23][CH2:24][NH:19][CH2:20][CH2:21]1)=[O:26]
Reactant: Cc1cccc(C)c1O
Reactant: CCCc1ccnc2c1c(C(=O)N1CCN(C(=O)OC(C)(C)C)CC1)c(Cl)n2-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCCc1ccnc2c1c(C(=O)N1CCNCC1)c(Oc1c(C)cccc1C)n2-c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 35.1 %

Procedure:
To a solution of 2,6-dimethylphenol (152 mg, 1.24 mmol) in NMP (3 ml) was added sodium hydride (50 mg, 1.24 mmol, 60% dispersion in mineral oil), and the suspension was stirred at room temperature under an argon atmosphere for 20 min. After addition of 100 mg (207 μmol) of the compound of step 7, the reaction mixture was stirred for 2 h at 140° C. After cooling, the reaction mixture was quenched with water and extracted with EA. The organic phases were concentrated and the remaining residue was dissolved in DCM (12 ml) and TFA (3 ml) and stirred at room temperature for 2 h. The solvents were evaporated and the resulting solid was purified by preparative HPLC. The fractions containing the title compound were combined and lyophilized overnight. The obtained solid was dissolved in a small quantity of MOH, mixed with hydrochloric acid (0.1 M) and lyophilized overnight to give 34 mg of the title compound in the form of the [2-(2,6-dimethyl-phenoxy)-1-phenyl-4-propyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperazin-1-yl-methanone dihydrochloride.
Reaction SMILES: Br[C:2]1[S:10][C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[Br:11].[CH3:12][C:13]([OH:17])([C:15]#[CH:16])[CH3:14].CCN(C(C)C)C(C)C>O1CCOCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:11][C:3]1[C:4]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[S:10][C:2]=1[C:16]#[C:15][C:13]([CH3:14])([OH:17])[CH3:12]
Reactant: Brc1sc2cnccc2c1Br
Reactant: C#CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(O)C#Cc1sc2cnccc2c1Br
Temperature: 50 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
To a suspension of 2,3-dibromothieno[2,3-c]pyridine (400 mg, 1.37 mmol), 2-methyl-3-butyn-2-ol (121 μL, 1.24 mmol), copper (I) iodide (24 mg, 0.12 mmol) and DIPEA (2.16 mL, 12.41 mmol) in 1,4-dioxane (16 mL) was added Pd(PPh3)2Cl2 (174 mg, 0.25 mmol). The mixture was evacuated and refilled with nitrogen (3×), then stirred at 50° C. for 2 h. Solvent was evaporated and the resultant mixture was dissolved in EtOAc. The organic solution was washed with water and brine, dried over anhydrous sodium sulfate, and purified by ISCO column chromatography (0 to 5% MeOH:DCM) to afford 319 mg (87%) of the title compound as a light-yellow solid. MS (ESI): 296.38, 298.35 [M+H]+; HPLC tR=0.94 min (HPLC: Analytical—2 min).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][SH:16])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][N:34]([C:37](Cl)=[O:38])[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].O>C1COCC1.CN(C1C=CN=CC=1)C>[C:24]([O:28][C:29]([N:31]1[CH2:32][CH2:33][N:34]([C:37](=[O:38])[S:16][CH2:15][C:12]2[CH:11]=[CH:10][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:14][CH:13]=2)[CH2:35][CH2:36]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Cl)CC1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CS)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)SCc2ccc(O[Si](C)(C)C(C)(C)C)cc2)CC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
to a stirred solution of 4-(tert-butyldimethylsilyloxy)-benzenemethanethiol (10.5 g, 41 mmol) and triethylamine (69 mmol, 9.6 mL) in THF (500 mL) at 0° C. was added 4-tert-butoxycarbonyl-1-chlorocarbonylpiperazine (8.56 g, 34 mmol) and DMAP (6.9 mmol, 0.84 g). The reaction mixture was warmed to 50° C. and stirred for 3 h then poured into water (500 mL) and extracted with EtOAc (2×250 mL). The combined organic extracts were washed with water (250 mL) then brine (500 mL), then dried (MgSO4) and concentrated to reveal a brown oil. Chromatography [SiO2: 90/10, hexane/EtOAc)] gave the product as a yellow oil which crystallised on standing (13.4 g, 85%): m.p. 53–54° C. 1H-NMR (400 MHz, CDCl3): 0.18 (6H, s), 0.96 (9H, s), 1.46 (9H, s), 3.42–3.51 (8H, m), 4.12 (2H, s), 6.75 (2H, d, J=8.5 Hz) and 7.18 (2H, d, J=8.5 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([O:11][C:12]2[C:17]([C:18]([N:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]([CH:30]4[CH2:32][CH2:31]4)[CH2:22][CH2:21]3)=[O:19])=[CH:16][N:15]=[C:14]([CH3:33])[CH:13]=2)[C:8]([Cl:34])=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:35][C:36]1[NH:40][N:39]=[N:38][N:37]=1>>[Cl:1][C:2]1[CH:10]=[C:9]([O:11][C:12]2[C:17]([C:18]([N:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]([CH:30]4[CH2:31][CH2:32]4)[CH2:22][CH2:21]3)=[O:19])=[CH:16][N:15]=[C:14]([CH3:33])[CH:13]=2)[C:8]([Cl:34])=[CH:7][C:3]=1[C:4]([NH:35][C:36]1[NH:40][N:39]=[N:38][N:37]=1)=[O:6]
Reactant: Nc1nnn[nH]1
Reactant: Cc1cc(Oc2cc(Cl)c(C(=O)O)cc2Cl)c(C(=O)N2CCN(C3CC3)c3ccccc32)cn1
Product: Cc1cc(Oc2cc(Cl)c(C(=O)Nc3nnn[nH]3)cc2Cl)c(C(=O)N2CCN(C3CC3)c3ccccc32)cn1
Yield: 15 %

Procedure:
The title compound was prepared in analogy to Example 39, from 2,5-dichloro-4-[5-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-2-methyl-pyridin-4-yloxy]-benzoic acid (Example 66) and 5-amino-1H-tetrazole (commercially available, CAS RN 4418-61-5). The compound was purified twice by preparative HPLC (Phenomenex Gemini column) with a gradient of acetonitrile:water (containing 0.05% formic acid) (50:50 to 95:5) to give 17 mg (15%) of the title compound as a white solid. MS (ESI): m/z=563.109 [M+H]+.
Reaction SMILES: C(OC([NH:8][NH:9][C:10](=[S:18])[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=O)(C)(C)C.[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22].C1(SC)C=CC=CC=1>C(Cl)Cl>[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22].[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]([NH:9][NH2:8])=[S:18])=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)NNC(=S)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: NNC(=S)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic salt. To a solution of N′-(4-fluoro-thiobenzoyl)-hydrazinecarboxylic acid tert-butyl ester (1.97 mmol) in CH2Cl2 is added trifluoroacetic acid (3 mL) and thioanisole (2.7 mmol). The mixture is stirred at room temperature for 1 hour. After evaporation of the solvent the mixture is purified by automated column chromatography (hexanes/EtOAc) to yield 4-fluoro-thiobenzoic acid hydrazide trifluoroacetic acid salt: 1H NMR (400 MHz, CDCl3) δ 9.5 (bs, 3H), 7.8-7.76 (m, 2H), 7.05 (t, J=8.4 Hz, 2H); LC/MS: (ES+) 171 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][C:14]3[NH:17][N:18]=[CH:19][C:13]=3[CH:12]2[CH2:20][OH:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:22][N:23]([CH3:27])[C:24](Cl)=[O:25].ClC1C=CC(S(N2C(CC)CC3(OCCO3)CC2CO)(=O)=O)=CC=1>>[CH3:22][N:23]([CH3:27])[C:24](=[O:25])[O:21][CH2:20][CH:12]1[C:13]2[CH:19]=[N:18][NH:17][C:14]=2[CH2:15][CH2:16][N:11]1[S:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)(=[O:9])=[O:10]
Reactant: O=S(=O)(c1ccc(Cl)cc1)N1CCc2[nH]ncc2C1CO
Reactant: CN(C)C(=O)Cl
Agent: CCC1CC2(CC(CO)N1S(=O)(=O)c1ccc(Cl)cc1)OCCO2
Product: CN(C)C(=O)OCC1c2cn[nH]c2CCN1S(=O)(=O)c1ccc(Cl)cc1

Procedure:
Prepared by treatment of (5-(4-chlorophenylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-4-yl)methanol with dimethylcarbamyl chloride as described for compound 111 in Example 14.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Si]([O:18][CH2:19][C@H:20]1[C@H:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:23][N:22]([C:31](=[O:36])[C:32]([F:35])([F:34])[F:33])[CH2:21]1)(C(C)(C)C)(C)C>ClCCl>[C:25]1([C@@H:24]2[CH2:23][N:22]([C:31](=[O:36])[C:32]([F:34])([F:35])[F:33])[CH2:21][C@H:20]2[CH2:19][OH:18])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1CN(C(=O)C(F)(F)F)C[C@H]1c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C(N1C[C@@H](CO)[C@H](c2ccccc2)C1)C(F)(F)F
Reaction time: 0.5 h

Procedure:
A 1.00 g portion of DMSO was dissolved in 10 ml of dichloromethane, and 0.56 ml of oxalyl chloride was added thereto while keeping the internal temperature at −60° C. or less. After 30 minutes of stirring, a dichloromethane (10 ml) solution of 581 mg of [(3S,4R)-4-phenyl-1-(trifluoroacetyl)pyrrolidin-3-yl]methanol which had been obtained from (3S,4R)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-phenyl-1-(trifluoroacetyl)pyrrolidine in the same manner as in Reference Example 3 was added thereto while keeping the internal temperature at −60° C. or less and stirred for 45 minutes. A 2.70 ml portion of triethylamine was added to the reaction solution while keeping the internal temperature at −60° C. or less, the internal temperature was allowed to warm to 0° C. over 30 minutes or more, and this was further stirred at 0° C. for 60 minutes. Under ice-cooling, the reaction solution was mixed with water to quench the reaction, extracted with chloroform and dried with anhydrous sodium sulfate. By concentrating under a reduced pressure, (3S,4R)-4-phenyl-1-(trifluoroacetyl)pyrrolidine-3-carboaldehyde was obtained as a crude product. A 1.35 g portion of sodium triacetoxyborohydride was added at room temperature to a mixture of the thus obtained crude product, 365 mg of (R)-(+)-1-(1-naphthyl)ethylamine, a catalytically effective amount of acetic acid and 20 ml of 1,2-dichloroethane, and stirred at room temperature for 14Hours. The reaction solution was washed with saturated sodium bicarbonate aqueous solution until it became neutral, and the combined washing solution was extracted with chloroform. The organic layer was dried with anhydrous sodium sulfate and concentrated under a reduced pressure. The thus obtained residue was purified by a silica gel column chromatography (chloroform-ethyl acetate) to obtain 886 mg of (1R)-1-(1-naphthyl)-N-{[(3R,4R)-4-phenyl-1-(trifluoroacetyl)pyridin-3-yl]methyl}ethanamine as a colorless oily substance. EP: 427.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:22][C:23]1[CH:32]=[C:31]2[C:26]([CH:27]=[CH:28][CH:29]=[N:30]2)=[CH:25][CH:24]=1.[OH-].[Na+]>CN(C=O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][N:3]=[C:2]2[O:22][C:23]1[CH:32]=[C:31]2[C:26]([CH:27]=[CH:28][CH:29]=[N:30]2)=[CH:25][CH:24]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Oc1ccc2cccnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Oc3ccc4cccnc4c3)c2cc1OC
Temperature: 100 °C
Reaction time: 5 h
Yield: 24 %

Procedure:
6,7-Dimethoxy-3,4-dihydroquinazolin-4-one (290 mg, 1.4 mmol) was suspended in thionyl chloride (5 ml) and DMF (2 drops) and heated at reflux for 2 hours. The thionyl chloride was evaporated under vacuum and the residue azeotroped with toluene three times to give 4-chloro-6,7-dimethoxyquinazoline. A mixture of the crude 4-chloro-6,7-dimethoxyquinazoline, potassium carbonate (970 mg, 7 mmol) and 7-hydroxyquinoline (235 mg, 1.62 mmol) in DMF (10 ml) was stirred at 100° C. for 5 hours and allowed to cool to ambient temperature overnight. The reaction mixture was treated with 1M aqueous sodium hydroxide solution and stirred at ambient temperature for a few minutes. The reaction mixture was extracted with ethyl acetate (×4) and the organic extracts washed with water and brine. The organic extracts were dried (MgSO4), filtered and the solvent removed under vacuum. The residue was triturated with ethyl acetate and then recrystallised from hot ethyl acetate to give 6,7-dimethoxy-4-(quinolin-7-yloxy)quinazoline (110 mg, 24%) as a white solid.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([N-]C(C)C)(C)C.[Li+].CN(P(N(C)C)(N(C)C)=O)C>C1COCC1>[C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH2:11][CH:10]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]2=[O:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCCCN1Cc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: O=C1C(Cc2ccccc2)CCCN1Cc1ccccc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
1-Phenylmethyl-2-piperidinone (See: Yamaguchi M, Hirao I (1985) "A direct synthesis of [(tert-butoxycarbonyl)methylidene]-azacycloalkanes from N-alkyllactams" J. Org. Chem., 50, 1975-1977) (3.40 g, 18 mmol) was reacted with benzyl bromide (4.84 g, 28.3 mmol) in the presence of lithium diisopropylamide (prepared by treating diisopropylamine (2.73 g, 27 mmol) with butyllithium in hexanes (2.5M, 10.3 mL, 25.7 mmol)) in THF (45 mL) and HMPA (2.7 mL, 15.5 mmol) as described above in the preparation of Example 7. After the addition of benzyl bromide, the reaction mixture was stirred for 2 h at -78° C., and then quenched with saturated NH4Cl (50 mL). The reaction mixture was extracted with ether (3×40 mL) and the combined ether extract washed with brine (40 mL) and dried over MgSO4. The solvent was removed in vacuo, and the residue (8.40 g) thus obtained, was chromatographed over silica gel (hexanes-CHCl3 -EtOAC, 15:4:1 and then 7:2:1) to give the product lactam (3.14 g, 63%) as a colorless solid: mp 94°-95° C. (CH2Cl2 -hexanes).