Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[NH:12][CH:13]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:14]([C:15]4[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=4)[C:5]([C:6]=23)=[N:4][NH:3]1.[BH4-].[Na+]>CO>[OH:20][CH2:19][C:18]1[CH:21]=[CH:22][C:15]([CH:14]2[C:5]3=[N:4][NH:3][C:2](=[O:1])[C:11]4[CH:10]=[CH:9][CH:8]=[C:7]([C:6]=43)[NH:12][CH:13]2[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:16][CH:17]=1
Reactant: O=Cc1ccc(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=c1[nH]nc2c3c(cccc13)NC(c1ccccc1)C2c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 12.9 %

Procedure:
A mixture of 4-(3-oxo-8-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-9-yl)benzaldehyde (140 mg, 0.42 mmol) and 27% methylamine alcohol solution (194 mg, 1.69 mmol) in methanol (15 mL) was stirred at room temperature for 40 min. Then the mixture was cooled to 0° C. Sodium borohydride (48 mg, 1.26 mmol) was added. After the addition, the mixture was stirred at room temperature for 4 hr. TLC (petroleum ether/ethyl acetate=2:1) show the reaction was complete. Methanol was removed under reduced pressure. The residue was washed with ethyl acetate and filtered. The filtrate was concentrated to give 9-(4-(hydroxymethyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)— one (20 mg, yield: 13%) as a light yellow solid. 1H-NMR (400 MHz, CD3OD) δ: 4.33-4.35 (d, J=8.0 Hz, 1H), 4.53 (s, 2H), 4.74-4.76 (d, J=8.0 Hz, 1H), 7.08-7.10 (d, J=8.0 Hz, 2H), 7.18-7.24 (m, 6H), 7.27-7.29 (d, J=6.8 Hz, 2H), 7.54-7.56 (d, J=7.6 Hz, 1H), 7.62-7.66 (t, J=8.0 Hz, 1H); LC-MS (ESI) m/z: 370 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5]>C1COCC1.CO>[CH3:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: Cc1cc([N+](=O)[O-])ccc1C(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc([N+](=O)[O-])ccc1CO
Temperature: 80 °C
Yield: 102.5 %

Procedure:
To a solution of 2-methyl-4-nitrobenzoic acid (5 g, 27.6 mmol, Aldrich) in THF) (95 ml) was added dropwise 1.0 M borane-tetrahydrofuran complex (55 ml, 55.0 mmol, Aldrich) at ambient temperature under nitrogen. The resulting red solution was heated to 80° C. for 2 h. To the solution at ambient temperature was added methanol (30 ml) and then heated to 80° C. for 30 min. The solvent was evaporated in vacuo to leave a yellow oil. The residue was dissolved in methanol (80 ml) and the solvent evaporated in vacuo to leave (2-methyl-4-nitrophenyl)methanol as a yellow solid (4.73 g).
Reaction SMILES: [C:1]([C:4]([NH:9][C:10]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1)=O)([CH3:8])[CH:5]([CH3:7])[CH3:6])(=[O:3])[NH2:2].[H-].[Na+].O>C1(C)C(C)=CC=CC=1>[CH:5]([C:4]1([CH3:8])[NH:9][C:10]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)=[N:2][C:1]1=[O:3])([CH3:7])[CH3:6]
Reactant: CC(C)C(C)(NC(=O)c1ccc2ccccc2n1)C(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1C
Product: CC(C)C1(C)NC(c2ccc3ccccc3n2)=NC1=O
Yield: 78.3 %

Procedure:
To a slurry of N-(1-carbamoyl-1,2-dimethylpropyl)-2-quinolinecarboxamide (16.04 g, 0.0562 mol) in xylene (610 ml) under nitrogen is added a 50% oil dispersion of sodium hydride (2.7 g, 0.056 mol) at 20° C. The reaction is heated to reflux for 2 hours, cooled and water (50 ml) added. The aqueous layer is extracted with methylene chloride and the organic layers combined and evaporated to give a yellow oil, 17 g. Purification is accomplished by passing through a silica gel column using hexane-ethyl acetate as solvent. A pale yellow solid is obtained and is recrystalized from ethyl acetate to give 11.77 g (78%) of white product, mp 112°-117° C. Anal. calcd. for C16H17N3O: C, 71.88; H, 6.41; N, 15.72. Found: C, 71.91; H, 6.47; N, 15.70.
Reaction SMILES: Br[C:2]1[C:3]([Cl:30])=[C:4]([O:20][C:21]2[CH:26]=[C:25]([C:27]#[N:28])[CH:24]=[C:23]([Cl:29])[CH:22]=2)[C:5]([F:19])=[C:6]([CH2:8][NH:9][C:10]([C:12]2[NH:16][C:15]([CH3:17])=[N:14][C:13]=2[Cl:18])=[O:11])[CH:7]=1.[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32].[CH3:38][N:39](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[F:34][C:33]([F:36])([F:35])[C:31]([OH:37])=[O:32].[Cl:18][C:13]1[N:14]=[C:15]([CH3:17])[NH:16][C:12]=1[C:10]([NH:9][CH2:8][C:6]1[CH:7]=[C:2]([C:38]#[N:39])[C:3]([Cl:30])=[C:4]([O:20][C:21]2[CH:26]=[C:25]([C:27]#[N:28])[CH:24]=[C:23]([Cl:29])[CH:22]=2)[C:5]=1[F:19])=[O:11]
Reactant: Cc1nc(Cl)c(C(=O)NCc2cc(Br)c(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)[nH]1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(Cl)c(C(=O)NCc2cc(C#N)c(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)[nH]1
Yield: 7 %

Procedure:
A solution of N-({5-bromo-4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-4-chloro-2-methyl-1H-imidazole-5-carboxamide (70 mg, 0.131 mmol), zinc cyanide (7.72 mg, 0.066 mmol) and tetrakis(triphenylphosphine)palladium(0) (30.4 mg, 0.026 mmol) in DMF (1.5 ml) was irradiated for 35 minutes at 130° C. in a microwave reactor. The reaction mixture was purified via reverse phase HPLC to give 4-chloro-N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-5-cyano-2-fluorophenyl}methyl)-2-methyl-1H-imidazole-5-carboxamide trifluoroacetate (5.8 mg, 9.79 μmol, 7% yield) as the TFA salt. 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.79 (d, 1H), 7.58 (s, 1H), 7.37 (s, 1H), 7.32 (s, 1H), 4.62 (s, 2H), 2.33 (s, 3H). LC-MS (ES+) m/z 477.95, [M+H].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4](=O)[CH:5]([CH3:18])[C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1.[CH3:21][NH:22][NH2:23]>>[CH3:1][O:2][C:3]([C:4]1[C:5]([CH3:18])=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[N:22]([CH3:21])[N:23]=1)=[O:20]
Reactant: COC(=O)C(=O)C(C)C(=O)c1cccc(C(F)(F)F)c1
Reactant: CNN
Product: COC(=O)c1nn(C)c(-c2cccc(C(F)(F)F)c2)c1C

Procedure:
A solution of 500 mg (2.47 mmol) of trifluoromethylpropiophenone and 0.335 mL (2.47 mmol) of diethyloxalate in 10 mL of MeOH was treated with 133 mg (2.47 mmol) of sodium methylate and stirred at room temperature for 3 hrs. The reaction was quenched by the addition of 10% aqueous KHSO4 and extracted with EtOAc (3×). The organic phases were washed with 10% aqueous KHSO4 and brine, dried over magnesium sulfate and evaporated to give crude 3-methyl-2,4-dioxo-4-(3-trifluoromethyl-phenyl)-butyric acid methyl ester. In analogy to the procedure described in Example 16A], crude 3-methyl-2,4-dioxo-4-(3-trifluoromethyl-phenyl)-butyric acid methyl ester and methylhydrazine gave after purification by flash column chromatography (n-heptane/AcOEt 2:1) 79.2 mg (3%) of the title compound as a rose powder. MS: 299.1 (MH+).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.C(N(C(C)C)CC)(C)C.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>C(O)C>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc3[nH]cnc23)CC1

Procedure:
To a solution of 6-chloropurine [CAS No. 87-42-3] (7.73 g) in ethanol (100 mL), diisopropylethylamine (26.1 mL) and piperazine-1-carboxylic acid t-butylester (11.16 g) were added, and this was heated under reflux for 16 hours. The solvent was removed under reduced pressure, and the residue was suspended in water (200 mL). The precipitate was collected by filtration, and then washed twice with 50 mL of water and twice with 50 mL of t-butyl methyl ether to give the title compound (13.99 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]([F:23])([F:22])[C:17](OCC)=[O:18]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:17](=[O:18])[C:16]([F:23])([F:22])[F:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CN
Reactant: CCOC(=O)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CNC(=O)C(F)(F)F
Reaction time: 3 h
Yield: 100.4 %

Procedure:
(S)-2-aminomethyl-pyrrolidine-l-carboxylic acid tert-butyl ester (10 g, 49.93 mmol) was dissolved in THF (200 ml) followed by the dropwise addition, within 5 min, of ethyl trifluoroacetate (9.75 g, 67.95 mmol) dissolved in THF (50 ml). Stirring was continued for 3 h at RT. The reaction mixture was concentrated under reduced pressure and the residue dried at HV to give the expected compound (14.86 g). LC-MS: tR=0.93 min; [M+H]−=297.29.
Reaction SMILES: C([O:3][C:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13]/[C:14](=[C:21]2\[C:22](=[O:40])[NH:23][C:24]3[C:29]\2=[CH:28][C:27]([NH:30][S:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)(=[O:33])=[O:32])=[CH:26][CH:25]=3)/[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)=[O:5])C.[OH-].[Na+]>CO.ClCCl>[C:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13]/[C:14](=[C:21]2\[C:22](=[O:40])[NH:23][C:24]3[C:29]\2=[CH:28][C:27]([NH:30][S:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)(=[O:33])=[O:32])=[CH:26][CH:25]=3)/[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:9][CH:8]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)Cc1ccc(N/C(=C2\C(=O)Nc3ccc(NS(=O)(=O)c4ccccc4)cc32)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: O=C(O)Cc1ccc(N/C(=C2\C(=O)Nc3ccc(NS(=O)(=O)c4ccccc4)cc32)c2ccccc2)cc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
720 mg (1.3 mmol) of (Z)-3-[1-(4-ethoxycarbonylmethyl-phenylamino)-1-phenyl-methylidene]-5-phenylsulphonylamino-2-indolinone are dissolved in a mixture of 20 ml of methanol and 20 ml of dichloromethane. 4 ml of 1 N sodium hydroxide solution are added and the mixture is stirred for 18 hours at ambient temperature and for another 1 hour at 40° C. The reaction solution is evaporated down to half the volume and the pH is adjusted to 4–5 with 1 N hydrochloric acid. The precipitate formed is suction filtered, washed with water, a little isopropanol and ether.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[CH:14][C:13]([CH:16]=[O:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[BH4-].[Na+]>CCO>[F:19][C:2]([F:1])([F:18])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: O=Cc1ccc(-c2ccc(OC(F)(F)F)cc2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1ccc(-c2ccc(OC(F)(F)F)cc2)nc1

Procedure:
6-(4-Trifluoromethoxy-phenyl)-pyridine-3-carbaldehyde (2.0 g, 7.48 mmol) was dissolved in EtOH (37 ml) and treated at 0° C. with NaBH4 (0.28 g, 7.48 mmol). After 10 min the cooling bath was removed and stirring was continued at ambient temperature. Pouring onto crashed ice, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents afforded 2.08 g (7.7 mmol, quant.) of the title compound as off-white solid of mp. 57–58° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[C:5]([O:28][CH3:29])[C:4]=1B(O)O.[CH2:33]([O:35][C:36](=[O:57])[C@H:37]([CH2:49][C:50]1[CH:55]=[CH:54][C:53](Br)=[CH:52][CH:51]=1)[NH:38][C:39](=[O:48])[C:40]1[C:45]([Cl:46])=[CH:44][CH:43]=[CH:42][C:41]=1[Cl:47])[CH3:34].C([O-])([O-])=O.[K+].[K+]>COCCOC.O>[CH2:33]([O:35][C:36](=[O:57])[C@H:37]([CH2:49][C:50]1[CH:55]=[CH:54][C:53]([C:4]2[C:3]([O:2][CH3:1])=[CH:8][C:7]([CH2:9][O:10][Si:11]([C:24]([CH3:27])([CH3:25])[CH3:26])([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:6][C:5]=2[O:28][CH3:29])=[CH:52][CH:51]=1)[NH:38][C:39](=[O:48])[C:40]1[C:41]([Cl:47])=[CH:42][CH:43]=[CH:44][C:45]=1[Cl:46])[CH3:34]
Reactant: COc1cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc(OC)c1B(O)O
Reactant: CCOC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1c(Cl)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)[C@H](Cc1ccc(-c2c(OC)cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc2OC)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 80 °C
Yield: 97.9 %

Procedure:
A mixture of 2,6-dimethoxy-4-[(t-butyldiphenylsilyloxy)methyl]benzeneboronic acid (5.2 g), N-(2,6-dichlorobenzoyl)-4-bromo-L-phenylalanine ethyl ester (1.71 g), Pd(Ph3)4 (0.44 g) and K2CO3 (1.59 g) in DME/H2O (20 mL/0.5 mL) was heated at 80° C. for 24 h under N2. The mixture was worked up and purified in a similar procedure as described in Example 8-3) to yield 2.9 g of N-(2,6-dichlorobenzoyl)-4-[2,6-dimethoxy-4-[(t-butyldiphenylsilyloxy)methyl]phenyl]-L-phenylalanine ethyl ester. ESMS: m/z 770 (MH+).
Reaction SMILES: C(NC(C)C)(C)C.[Li].C(NC(C)C)(C)C.C([Li])CCC.CN(C)CCN(C)C.[Br:29][C:30]1[CH:45]=[CH:44][C:33]([CH2:34][N:35]2[C:39]([CH2:40][CH2:41][CH2:42]Cl)=[CH:38][N:37]=[CH:36]2)=[CH:32][CH:31]=1>O1CCCC1>[Br:29][C:30]1[CH:45]=[CH:44][C:33]([CH:34]2[N:35]3[CH:36]=[N:37][CH:38]=[C:39]3[CH2:40][CH2:41][CH2:42]2)=[CH:32][CH:31]=1
Reactant: ClCCCc1cncn1Cc1ccc(Br)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Brc1ccc(C2CCCc3cncn32)cc1
Reaction time: 3.5 h

Procedure:
A solution of lithium diisopropylamine, prepared at 0° from 0.12 ml of diisopropylamine and 0.33 ml of n-butyllithium (2.5M) in 2 ml of tetrahydrofuran under nitrogen, is added to a solution of 0.13 ml of N,N,N',N'-tetramethyl-ethylenediamine and 0.124 g of 1-(p-bromobenzyl)-5-(3-chloropropyl)-1H-imidazole in 2 ml of tetrahydrofuran at -78°. The reaction mixture is stirred for 3.5 h, quenched at -78° with saturated ammonium chloride solution and extracted with methylene chloride (3×10 ml). The organic extracts and dried over sodium sulfate and evaporated to yield the title compound which is purified by conversion to the hydrochloride salt, m.p. 216°.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.Cl.[N:19]1[CH:24]=[CH:23][C:22]([C:25](Cl)=[O:26])=[CH:21][CH:20]=1>>[N:19]1[CH:24]=[CH:23][C:22]([C:25]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([C:11]4[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:26])=[CH:21][CH:20]=1
Reactant: CN1CC=C(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Product: CN1CC=C(c2c[nH]c3ccc(NC(=O)c4ccncc4)nc23)CC1
Yield: 61.4 %

Procedure:
Beginning with 0.200 gm (0.88 mMol) 5-amino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[3,2-b]pyridine and 0.188 gm (1.06 mMol) 4-pyridinecarbonyl chloride hydrochloride, 0.180 gm (61%) of the title compound were prepared as an ivory solid essentially by the procedure described in Example 8. An analytical sample was crystallized from aqueous ethanol. m.p.=202.8° C. (dec.) MS(m/e): 333(M+) Calculated for C19H19N5O: Theory: C, 68.45; H, 5.74; N, 21.01. Found: C, 68.28; H, 5.68; N, 21.21.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.[Cl:29][C:30]1[N:31]=[CH:32][S:33][C:34]=1[CH:35]=O.C(O)(=O)C.[OH-].[Na+]>ClCCCl>[C:25]([O:24][C:22]([N:19]1[CH2:18][CH2:17][CH:16]([NH:15][CH2:35][C:34]2[S:33][CH:32]=[N:31][C:30]=2[Cl:29])[CH2:21][CH2:20]1)=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=Cc1scnc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(NCc2scnc2Cl)CC1
Yield: 74 %

Procedure:
Add sodium triacetoxyborohydride (30.50 g, 144 mmol) to a stirred solution of 4-amino-1-N-Boc-piperidine (18.00 g, 89.9 mmol), 4-chloro-thiazole-5-carbaldehyde (13.09 g, 88.7 mmol), acetic acid (5.5 mL, 96.1 mmol), and 1,2-dichloroethane (350 mL). Stir the reaction for 18 hours at room temperature under nitrogen. Pour the reaction into 2N NaOH (400 mL) and extract with ethyl acetate (3×150 mL). Wash the ethyl acetate with brine (2×150 mL). Dry the ethyl acetate over sodium sulfate and then filter off the sodium sulfate. Concentrate on a rotary evaporator and purify the crude product by flash chromatography on silica gel eluting with 75% ethyl acetate/hexanes then with 100% ethyl acetate to yield 21.78 g (74%) of 4-{[(4-chloro-thiazol-5-yl)methyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester: mass spectrum (ion spray): m/z=332.1 (M+1); 1H NMR (CDCl3): δ=8.67 (s, 1H), 4.10-4.02 (m, 4H), 2.88-2.82 (m, 2H), 2.74-2.67 (m, 1H), 1.92-1.89 (m, 2H), 1.49 (s, 9H), 1.37-1.28 (m, 3H).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25](O)=[O:26])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O[N:29]=[C:30]([CH:32]1[CH2:35][CH2:34][CH2:33]1)[NH2:31]>>[CH:32]1([C:30]2[N:31]=[C:25]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[O:8])[CH2:10]3)[O:26][N:29]=2)[CH2:35][CH2:34][CH2:33]1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: NC(=NO)C1CCC1
Product: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(C3CCC3)no2)C1

Procedure:
150 mg (0.388 mmol) of the compound from Example 81A and 88 mg (0.776 mmol) of N′-hydroxycyclobutanecarboximidamide were reacted according to the General Method 2. Yield: 124 mg (65% of theory)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([F:11])[CH:10]=1)=[O:5])[CH3:2].Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:27][CH2:26][N:25]([C:28](=[O:33])[C:29]([F:32])([F:31])[F:30])[CH2:24][CH2:23]2)=[CH:18][CH:17]=1)=[O:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:13][C:14](=[O:15])[C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][N:25]([C:28](=[O:33])[C:29]([F:32])([F:30])[F:31])[CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH:8]=[C:9]([F:11])[CH:10]=1)=[O:5])[CH3:2]
Reactant: O=C(CBr)c1ccc(C2CCN(C(=O)C(F)(F)F)CC2)cc1
Reactant: CCOC(=O)c1cc(F)c[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cc(F)cn1CC(=O)c1ccc(C2CCN(C(=O)C(F)(F)F)CC2)cc1
Temperature: 25 °C

Procedure:
4-Fluoro-1H-pyrrole-2-carboxylic acid ethyl ester (1.07 g; 6.83 mmol) and 1-{4-[4-(2-bromo-acetyl)-phenyl]-piperidin-1-yl}-2,2,2-trifluoro-ethanone (2.00 g; 5.26 mmol) are dissolved in acetone (20 ml). To this clear brown solution potassium carbonate (1.45 g; 10.51 mmol) is added and the reaction mixture is stirred at ambient temperature over night. The reaction mixture is diluted with acetone, filtered off by suction and washed with acetone. The filtrate is evaporated to dryness. The crude product is purified by flashchromatography to afford 4-fluoro-1-(2-oxo-2-{4-[1-(2,2,2-trifluoro-acetyl)-piperidin-4-yl]-phenyl}-ethyl)-1H-pyrrole-2-carboxylic acid ethyl ester as off-white solid; HPLC/MS 2.67 min (A), [M+H] 455.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[N:7][C:6]=1[NH2:12])[CH3:2].[I:14]N1C(=O)CCC1=O.O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([I:14])[C:8]([NH2:11])=[N:7][C:6]=1[NH2:12])[CH3:2]
Reactant: CCOC(=O)c1ccc(N)nc1N
Reactant: O=C1CCC(=O)N1I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(I)c(N)nc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.5 %

Procedure:
To a solution of 2,6-diamino-nicotinic acid ethyl ester described in Preparation Example A-14 (1.4 g, 7.7 mmol) in N,N-dimethylformamide (15 mL) was added N-iodosuccinimide (2.09 g, 9.3 mmol), and the solution was stirred for 1 hour at room temperature. The reaction mixture was poured into an aqueous solution of saturated sodium thiosulfate pentahydrate, and the solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1) and the title compound (0.84 g, 2.7 mmol, 35.5%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OCC)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[CH3:19].[OH-].[K+]>C(O)CCC>[Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[CH:4][C:3]=1[CH3:19]
Reactant: CCOC(=O)N1CCN(c2cc(C)c(Cl)nn2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Product: Cc1cc(N2CCNCC2)nnc1Cl
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 22 parts of ethyl 4-(6-chloro-5-methyl-3-pyridazinyl)-1-piperazinecarboxylate, 28 parts of potassium hydroxide and 160 parts of 1-butanol was stirred overnight at reflux temperature. The reaction mixture was evaporated. Water was added. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. 2,2'-Oxybispropane was added. The product was filtered off and dried, yielding 17 parts (100%) of 3-chloro-4-methyl-6-(1-piperazinyl)pyridazine (compound 224).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[N:10]([S:13]([C:16]1[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19])(=[O:15])=[O:14])=[C:11]=[O:12]>C(Cl)Cl>[CH3:8][C:6]1[CH:5]=[C:4]([CH3:9])[N:3]=[C:2]([NH:1][C:11]([NH:10][S:13]([C:16]2[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=2[C:18]([O:20][CH3:21])=[O:19])(=[O:15])=[O:14])=[O:12])[CH:7]=1
Reactant: Cc1cc(C)nc(N)c1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: ClCCl
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1cc(C)cc(C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.4 %

Procedure:
To 1.2 g of 2-amino-4,6-dimethylpyridine in 30 ml of methylene chloride at ambient temperature was added dropwise, with stirring 2.4 g of methyl 2-isocyanatosulfonylbenzoate. After stirring for one hour at room temperature a solid precipitated from the mixture. Filtration yielded 1.8 g of a crystalline white solid which melted at 181°-182° C. and showed absorption peaks by infrared spectroscopy at 1750, 1700, 1630 and 1580 cm-1. The nuclear magnetic resonance spectrum (60 mc) showed peaks at 7-8.6 δ (multiplet) for o-substituted benzene, 4.36 δ (singlet) for OCH3 and 2.76, 2.7 δ (singlets) for the two methyl groups on the pyridine ring.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([OH:28])([CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.CO>[OH:28][C:11]1([CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:19][CH:18]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CCCc2ccc(-c3nnn[nH]3)cc2)CC1
Agent: Cl
Solvent: CO
Product: OC1(CCCc2ccc(-c3nnn[nH]3)cc2)CCNCC1

Procedure:
A solution of 105 mg (0.27 mmol) of 1-t-butoxycarbonyl-4-hydroxy-4-(3-(4-(1H-tetrazol-5-yl)phenyl)-propyl)piperidine (from EXAMPLE 2, Step E) in 5 mL of 0.5 N HCl in MeOH was stirred at rt for 20 h. The solution was concentrated and dried under vacuum to afford the title compound: HPLC B: 3.10 min.