Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[C:19]([Cl:21])[N:18]=[N:17][C:16]=2Cl)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:24][NH2:25]>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[C:19]([Cl:21])[N:18]=[N:17][C:16]=2[NH:24][NH2:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)nnc2Cl)CC1
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)nnc2NN)CC1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
4-(3,6-Dichloro-pyridazin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (9.73 g; 28.03 mmol) was dissolved in 20 ml EtOH and treated with Hydrazine Hydrate (14.03 g; 280.33 mmol). It was stirred at 70° C. for 16 hours. Two peaks with product mass detected via HPLC-MS. The reaction mixture was extracted with aqueous NaHCO3 solution and DCM. The organic phase was dried and evaporated to dryness. The crude product was purified by using reversed phase chromatography under acid conditions.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([NH2:22])[CH3:21])=[CH:16][CH:15]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.CCOC(C)=O>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:22][CH:20]([C:17]1[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=1)[CH3:21])=[O:4]
Reactant: CC(N)c1ccc(Cl)cc1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)c1ccccc1N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 13.6 %

Procedure:
To a mixture of isatoic anhydride (500 mg, 3.07 mmol) and 1-(4-chloro-phenyl)-ethylamine (530 mg, 3.68 mmol) in CH2Cl2 (20 mL) is added diisopropyl ethyl amine (1.2 mL, 6.89 mmol). The mixture is stirred at room temperature for 16 hours. The reaction mixture is diluted with EtOAc (100 mL) and is washed with H2O (50 mL×3). The organic layer is dried over sodium sulfate, concentrated and the resulting residue is purified by flash chromatography with 25% EtOAc in Hexane as the eluent to afford the desired to afford the desired 2-amino-N-[1-(4-chloro-phenyl)-ethyl]-benzamide (115 mg, 14%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.CCOC(C)=O>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(N2CCCC2)nc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirring mixture of 2-chloro-5-nitropyridine (5.0 g, 31.5 mmol), potassium carbonate (7.0 g, 50.4 mmol), in 65 ml of DMF add pyrrolidine (6.7 g, 95 mmol) and stir at room temperature for 72 h. Dilute reaction mixture with 100 ml EtOAc and wash 2 times with 100 ml saturated NaHCO3, and 2 times with 100 ml of brine. Dry organics over Na2SO4, and evaporate in vacuo to obtain 5-nitro-2-pyrrolidin-1-yl-pyridine. Mass spec.: m+1=194 (AP+).
Reaction SMILES: [CH3:1][C:2]1[O:17][C:11]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:5]2[CH:6]=[C:7](Br)[CH:8]=[CH:9][C:4]=2[N:3]=1.Br[C:19]1[CH:20]=[C:21]([C:24]#[N:25])[S:22][CH:23]=1>>[CH3:1][CH:2]1[O:17][C:11]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:5]2[CH:6]=[C:7]([C:19]3[CH:20]=[C:21]([C:24]#[N:25])[S:22][CH:23]=3)[CH:8]=[CH:9][C:4]=2[NH:3]1
Reactant: N#Cc1cc(Br)cs1
Reactant: CC1=Nc2ccc(Br)cc2C2(CCCCC2)O1
Product: CC1Nc2ccc(-c3csc(C#N)c3)cc2C2(CCCCC2)O1

Procedure:
Prepared according to the procedure for Example 13 from 2-methyl-6-bromospiro[4H-3,1-benzoxazine-4,1′-cyclohexane] and 4-bromo-2-thiophenecarbonitrile. A brown solid: mp 111-112° C.; 1H-NMR (DMSO-d6) δ 8.42 (s, 1H), 8.14 (s, 1H), 7.47 (s, 1H), 7.35 (dd, 1H, J=8.3, 1.1 Hz), 6.58 (d, 1H, J=8.4 Hz), 6.38 (s, 1H), 4.72 (m, 1H), 1.92-2.16 (m, 2H), 1.35-1.75 (m, 8H), 1.31 (d, 3H, J=5.3 Hz); MS (ESI) m/z 325 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]2[CH3:17])=[CH:4][CH:3]=1.[C:18](O)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1.C(Cl)CCl>C(#N)C.O>[CH3:17][C:9]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:18]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[O:25])=[CH:3][CH:4]=2)[C:16]2[C:11]([CH:10]=1)=[CH:12][CH:13]=[CH:14][CH:15]=2
Reactant: Cc1cc2ccccc2n1-c1ccc(N)cc1
Reactant: O=C(O)c1cccnc1
Solvent: CC#N
Solvent: ClCCCl
Solvent: O
Product: Cc1cc2ccccc2n1-c1ccc(NC(=O)c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.9 %

Procedure:
A mixture of the above amine (0.08 g, 0.36 mmol), nicotinic acid (114 mg, 0.59 mmol) and EDC (66 mg, 0.54 mmol) was dissolved in 2 mL acetonitrile and the reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with water, extracted with EtOAc, washed with water and dried (MgSO4). The residue obtained on concentration was flash chromatographed on silica gel, eluting with a gradient of 2% MeOH in dichloromethane to give the title compound (40 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].O>ClC(Cl)C.ClCCl>[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:21]=[CH:22][C:23]([CH2:24][NH:1][C:2]2[CH:3]=[CH:4][C:5]([C@@H:8]3[CH2:10][C@H:9]3[C:11]([OH:13])=[O:12])=[CH:6][CH:7]=2)=[CH:26][CH:27]=1
Reactant: O=Cc1ccc(-c2ccccn2)cc1
Reactant: Nc1ccc([C@@H]2C[C@H]2C(=O)O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC(Cl)Cl
Product: O=C(O)[C@@H]1C[C@H]1c1ccc(NCc2ccc(-c3ccccn3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.3 %

Procedure:
A suspension of racemic-(trans)-2-(4-aminophenyl)cyclopropanecarboxylic acid (I-1) (0.30 g, 1.69 mmol) and 4-(2-pyridinyl)benzaldehyde (0.37 g, 2.03 mmol) in dichloroethane (10 mL) were heated to reflux until a clear solution formed. The solution was cooled to RT then NaB(OAc)3H (0.54 g, 2.54 mmol) was added and stirred for 2 h. Water (50 mL) and dichloromethane (50 mL) were added and the organic layer was separated, dried over Na2SO4, filtered and concentrated. The crude material was purified on silica gel eluting with an increasing gradient from 20% ethyl acetate/hexanes to 100% ethyl acetate to give the title compound as a white solid (0.13 g, 22%). 1H NMR (400 MHz, DMSO) δ 12.15 (s, 1H), 8.65 (d, J=4.1 Hz, 1H), 8.02 (d, J=8.3 Hz, 2H), 7.92 (d, J=8.2 Hz, 1H), 7.86 (t, J=8.0 Hz, 1H), 7.44 (d, J=8.1 Hz, 2H), 7.32 (dd, J=5.2, 6.6 Hz, 1H), 6.84 (d, J=8.4 Hz, 2H), 6.50 (d, J=8.4 Hz, 2H), 6.23 (s, 1H), 4.30 (d, J=4.6 Hz, 2H), 2.22-2.17 (m, 1H), 1.61-1.57 (m, 1H), 1.31-1.27 (m, 1H), 1.20-1.16 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=2)([OH:17])[CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:6][CH:5]=1.N1C=CC=CC=1.[Cl:37][C:38]1[CH:39]=[C:40]([CH:44]=[CH:45][C:46]=1[O:47][CH3:48])[C:41](Cl)=[O:42]>O1CCCC1>[Cl:37][C:38]1[CH:39]=[C:40]([C:41]([N:14]2[CH2:15][CH2:16][CH:11]([C:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:29])([F:1])[F:30])=[CH:9][CH:8]=3)([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:26])[F:27])=[CH:20][CH:19]=3)[OH:17])[CH2:12][CH2:13]2)=[O:42])[CH:44]=[CH:45][C:46]=1[O:47][CH3:48]
Reactant: OC(c1ccc(OC(F)(F)F)cc1)(c1ccc(OC(F)(F)F)cc1)C1CCNCC1
Reactant: COc1ccc(C(=O)Cl)cc1Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ccc(C(=O)N2CCC(C(O)(c3ccc(OC(F)(F)F)cc3)c3ccc(OC(F)(F)F)cc3)CC2)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In a separate reaction vessel, a solution of 0.5 gram (0.0012 mole) of 4-[bis(4-trifluoromethoxyphenyl)hydroxymethyl]piperidine (prepared in Step B of Example 7) and 0.09 gram (0.0012 mole) of pyridine in a small amount of tetrahydrofuran was stirred, and the solution of 3-chloro-4-methoxybenzoyl chloride in tetrahydrofuran, prepared above, was added. Upon completion of addition, the reaction mixture was stirred at ambient temperature for about 15 minutes and then filtered to remove a white solid. The filtrate was stirred for about 18 hours and then was partitioned between ethyl acetate and an aqueous solution saturated with sodium chloride. The organic layer was separated and passed through a column of silica gel. Elution was accomplished with 50% ethyl acetate in hexane. The product-containing fractions were combined and concentrated under reduced pressure, yielding 0.62 gram of N-(3-chloro-4-methoxyphenylcarbonyl)-4-[bis(4-trifluoromethoxyphenyl)hydroxymethyl]piperidine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C(O)(=O)C.[C:5]([C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])(=[NH:7])[NH2:6].CCO/[CH:21]=[C:22](/[CH:24]=O)\[CH3:23].C[O-].[Na+]>CO>[CH3:24][C:22]1[CH:21]=[N:7][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])=[N:6][CH:23]=1
Reactant: CCO/C=C(\C)C=O
Reactant: COC(=O)c1cccc(C(=N)N)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cccc(-c2ncc(C)cn2)c1
Temperature: 50 °C
Reaction time: 15 h

Procedure:
2.41 g (10 mmol) of methyl 3-carbamimidoylbenzoate acetate are suspended in 40 ml of methanol, 1.31 ml (11 mmol) of 3-ethoxymethacrolein and 2.04 ml of 30% sodium methoxide in methanol are added, and the mixture is stirred at 50° C. for 15 h. The reaction mixture is evaporated to dryness, and 100 ml of water are added. The precipitate formed is filtered off with suction and dried in vacuo. The crude product is reacted further without further purification; product: 1.65 g; ESI: 229 (M+H).
Reaction SMILES: [Al+3:1].[Cl-].[Cl-].[Cl-].[C:5]1([Mg]Br)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:13]1(C)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(OC(C)C)(C)C>[C:5]1([Al:1]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Br[Mg]c1ccccc1
Reactant: Cc1ccccc1
Reactant: [Al+3]
Agent: [Cl-]
Solvent: CC(C)OC(C)C
Product: c1ccc([Al](c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 18 %

Procedure:
To a suspension of AlCl3 (1.25 g, 9.4 mmol) in diisopropyl ether (20 mL) was added phenylmagnesium bromide (10.8 mL, 27 mmol, 2.5 M in Et2O) at 0-5° C. The mixture was stirred at room temperature for 3-4 hours. The solvent was removed using a high-vacuum pump affording a white solid. To the solid was added PhMe (15 mL) and the mixture was stirred for 15 min, and then the resulting slurry was filtered under an atmosphere of nitrogen. The clear filtrate was evaporated to about ⅓rd of the original volume and the resulting solid was filtered affording 1.36 g of crude product. A slurry of the crude product and PhMe (15 mL) was stirred, and was then filtered. The filtrate was evaporated to about ⅓rd of the original volume and the resulting solid was filtered affording the desired product (0.56 g, 18%).
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][C:9]([OH:11])=O)[O:4][N:3]=1.CCN(C(C)C)C(C)C.[C:21]([N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][NH2:35])[CH2:30][CH2:29]1)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>CN(C=O)C>[OH:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][C:9]([NH:35][CH2:34][CH:31]2[CH2:32][CH2:33][N:28]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:29][CH2:30]2)=[O:11])[O:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: O=C(O)CCc1cc(O)no1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)CCc2cc(O)no2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To 3-(3-hydroxyisoxazol-5-yl)propanoic acid (300 mg, 1.909 mmol) in DMF (7 mL) was added DIPEA (0.667 mL, 3.82 mmol) followed by 1-[(1-(cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholino)]uronium hexafluorophosphate (COMU) (981 mg, 2.291 mmol). The resulting brown solution was stirred at RT for 5 mins and then treated with 1-BOC-4-(aminomethyl)piperidine (409 mg, 1.909 mmol). After stirring at RT for 2 hrs, the solution was concentrated under reduced pressure and the residue suspended in 0.2M aqueous HCl (200 ml). The mixture was extracted with EtOAc (2×100 ml) and the combined extracts were dried (MgSO4) and concentrated under reduced pressure. The crude residue was dissolved in DCM (100 ml) and treated with 2M NaOH (50 ml). The mixture was stirred vigorously at ambient temperature for 16 hrs. The mixture was then acidified with citric acid and the organics removed, dried (MgSO4) and concentrated under reduced pressure. The residue was applied to a 24 g silica cartridge and eluted with 0-100% EtOAc/iso-hexane. The product fractions were combined and concentrated to give a tert-butyl 4-((3-(3-hydroxyisoxazol-5-yl)propanamido)methyl)piperidine-1-carboxylate as a gum.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([CH3:30])[C:7]([N:10]3[CH2:15][CH2:14][N:13]([C:16]([C:18]4[N:23]=[CH:22][C:21]([N:24]5[CH2:28][CH2:27][NH:26][C:25]5=[O:29])=[CH:20][CH:19]=4)=[O:17])[CH2:12][CH2:11]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[CH3:31]I>>[CH:1]1([C:4]2[CH:5]=[C:6]([CH3:30])[C:7]([N:10]3[CH2:11][CH2:12][N:13]([C:16]([C:18]4[N:23]=[CH:22][C:21]([N:24]5[CH2:28][CH2:27][N:26]([CH3:31])[C:25]5=[O:29])=[CH:20][CH:19]=4)=[O:17])[CH2:14][CH2:15]3)=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCNC3=O)cn2)CC1
Reactant: CI
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCN(C)C3=O)cn2)CC1

Procedure:
Using 1-{6-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]pyridin-3-yl}imidazolidin-2-one (280 mg) described in Example 393 and methyl iodide (51 μL) and by the reaction and treatment in the same manner as in Example 36, the title compound (211 mg) was obtained.
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[Cl:14][C:15]1[C:20]([NH:21][C:22]([CH3:26])([CH3:25])[CH2:23][OH:24])=[C:19]([N+:27]([O-:29])=[O:28])[CH:18]=[CH:17][CH:16]=1.CC(C)=O>C(O)(C)C>[Cl:14][C:15]1[C:20]([NH:21][C:22]([CH3:26])([C:23]([OH:3])=[O:24])[CH3:25])=[C:19]([N+:27]([O-:29])=[O:28])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(CO)Nc1c(Cl)cccc1[N+](=O)[O-]
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: CC(C)(Nc1c(Cl)cccc1[N+](=O)[O-])C(=O)O

Procedure:
Jones reagent (2.67M) is added in aliquots (30 ml, 15 ml, 10 ml, 5 ml) every 15 min to a solution of 2-[N-(6-Chloro-2-nitrophenyl)]amino-2-methyl-1-propanol (IX, EXAMPLE 13, 21.6 g) and acetone (1.65 l) at 0° until the reaction is done as measured by TLC analysis. After 1 hr total time, isopropanol (90 ml) is added and the mixture is allowed to warm to 20°-25°. The mixture is filtered and the solids washed with acetone several times. The combined filtrates are concentrated and partitioned between ether (1.0 l) and potassium hydroxide (10%, 3×100 ml). The basic layer is acidified (3N hydrochloric acid) and extracted with methylene chloride (3×200 ml). The methylene chloride phase is dried over magnesium sulfate, filtered, and concentrated to give the title compound sufficient pure to be used in the next step without additional purification, mp 107°-109°; IR (mineral oil) 3358, 2953, 2924, 1715, 1597, 1496, 1330, 1280, 1231, 1174, 1105 and 747 cm-1 ; NMR (CDCl3) 8.00, 7.61, 7.06, 6.5-7.1 and 1.54 δ; MS (m/z) 258 and 213.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:3]=1[CH2:4][NH:5][CH2:6][CH3:7].C(N(C(C)C)CC)(C)C.[C:25](Cl)(Cl)=[O:26].C(N(CC)CC)C.[CH2:36]([NH2:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)Cl>[CH2:36]([NH:43][C:25](=[O:26])[N:5]([CH2:4][C:3]1[CH:8]=[C:9]([C:12]([F:13])([F:14])[F:15])[CH:10]=[CH:11][C:2]=1[Br:1])[CH2:6][CH3:7])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(Cl)Cl
Reactant: NCc1ccccc1
Reactant: CCNCc1cc(C(F)(F)F)ccc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(Cc1cc(C(F)(F)F)ccc1Br)C(=O)NCc1ccccc1
Reaction time: 2 h

Procedure:
To a solution of (2-bromo-5-trifluoromethyl-benzyl)-ethyl-amine (1.5 g, 5.3 mmol) in CH2Cl2 (20 mL) at 0° C. was added diisopropylethylamine (1.7 mL, 13.3 mmol). Phosgene (1.9M in toluene; 4.2 mL, 8.0 mmol) was then added dropwise, and the reaction was stirred for 2 hours. Triethylamine (1.48 mL, 10.6 mmol) was added, followed by benzylamine (0.87 mL, 8.0 mmol), and the reaction was stirred at room temperature for 2.5 hours. After work-up with CH2Cl2 and H2O, the crude material was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [CH:1]1([C:5]2[N:9]3[CH:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]3=[C:7]([I:15])[N:6]=2)[CH2:4][CH2:3][CH2:2]1.ClC1[C:18]2[N:19](C(C3CC(N(C)C)C3)=NC=2I)[CH:20]=CN=1>>[CH3:18][N:19]([CH3:20])[CH:3]1[CH2:2][CH:1]([C:5]2[N:9]3[CH:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]3=[C:7]([I:15])[N:6]=2)[CH2:4]1
Reactant: Nc1nccn2c(C3CCC3)nc(I)c12
Reactant: CN(C)C1CC(c2nc(I)c3c(Cl)nccn23)C1
Product: CN(C)C1CC(c2nc(I)c3c(N)nccn23)C1

Procedure:
Prepared according to the procedure described above for 3-cyclobutyl-1-iodoimidazo[1,5-a]pyrazin-8-amine, except using [3-(8-Chloro-1-iodo-imidazo[1,5-a]pyrazin-3-yl)-cyclobutyl]-dimethyl-amine. 1H NMR (400 MHz, CDCl3): δ 2.25 (br.s, 6H), 2.47 (br.s, 2H), 2.63 (q, J=8.17 Hz, 2H), 2.93 (br.s, 1H), 3.30-3.41 (m, 1H), 5.64 (br.s, 2H), 7.03 (d, J=4.80 Hz, 1H), 7.22 (d, J=4.80 Hz, 1H). HPLC: tR=0.36 min. (Open Lynx polar—5 min.). MS (ES+): m/z 357.73 (100) [MH+].
Reaction SMILES: CO[CH:3](OC)[C:4](=[N:7][OH:8])[C:5]#[N:6].Cl.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][NH2:21])=[CH:16][CH:15]=1.Cl.N>CO.O>[NH2:6][C:5]1[N:20]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[N:21]=[CH:3][C:4]=1[N:7]=[O:8]
Reactant: COc1ccc(NN)cc1
Reactant: COC(OC)C(C#N)=NO
Agent: Cl
Agent: N
Solvent: O
Solvent: CO
Product: COc1ccc(-n2ncc(N=O)c2N)cc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 70.3 %

Procedure:
To a flask having an inner volume of 25 ml and equipped with a stirring device, a thermometer and a reflux condenser were charged, 2.97 g (20 mmol) of 3,3-dimethoxy-2-hydroxyiminopropionitrile with a purity of 96.9% by weight synthesized in the same manner as in Example 1, 3.74 g (21 mmol) of 4-methoxyphenylhydrazine hydrochloride with a purity of 98% by weight, 1.4 ml of water, 10 ml of methanol and 1.3 ml (15 mmol) of conc. hydrochloric acid, and the mixture was reacted at 50 to 52° C. for one hour. After completion of the reaction, 25 ml of water and 5 ml of methanol were added to the mixture to cool the same up to 10° C., and 2.3 ml (37.9 mmol) of 28% by weight aqueous ammonia was gradually added dropwise to the mixture and the resulting mixture was stirred for 30 minutes while maintaining the liquid temperature to 5° C. or lower. Precipitated crystals were collected by filtration, and then, the crystals were washed with 10 ml of cold water and dried under reduced pressure to obtain 3.07 g of 5-amino-1-(4-methoxyphenyl)-4-nitrosopyrazole (Isolation yield: 55.3%) as a yellowish solid with a purity of 78.6% by weight (absolute calibration curve method by high performance liquid chromatography).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[NH:21][C:20]4=[O:28])[CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[CH2:31]([OH:33])[CH3:32].Cl>CC(O)C>[CH2:31]([O-:33])[CH3:32].[ClH:1].[Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[NH:21][C:20]4=[O:28])[CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: CCO
Agent: Cl
Agent: O=c1[nH]c2ccccc2n1CCCN1CCC(n2c(=O)[nH]c3cc(Cl)ccc32)CC1
Solvent: CC(C)O
Product: CC[O-]

Procedure:
A solution of 1 part of 5-chloro-1-{1-[3-(1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)propyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-one in 40 parts of ethanol is acidified with 2-propanol, previously saturated with gaseous hydrogen chloride. While cooling, the formed hydrochloride salt is allowed to crystallize, yielding 1 part (83%) of 5-chloro-1-{1-[3-(1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)propyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-one hydrochloride ethanolate; mp. 213.7° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH:12](OC)O)[N:6]=[CH:5]2.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>C(Cl)Cl.CO.CC(O)=O>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[N:6]=[CH:5]2
Reactant: COC(O)Cn1ncc2cc(I)ccc21
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: Ic1ccc2c(cnn2CCN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 40.6 %

Procedure:
To a solution of 2-(5-iodo-1H-indazol-1-yl)-1-methoxyethanol (360 mg, 1.13 mmol) in CH2Cl2 (10.0 mL), MeOH (10.0 mL) and AcOH (4.0 mL) was added morpholine (295 mg, 3.39 mmol) and picoline-borane complex (120 mg, 1.13 mmol). The solution was stirred at ambient temperature for 1.5 h. The reaction mixture was concentrated, diluted with 1 N HCl (10.0 mL) and stirred at ambient temperature for 30 minutes. The mixture was made basic with 1N NaOH (10.0 mL) and extracted with EtOAc (3×50 mL). The organics were dried (Na2SO4), filtered, and concentrated. Purification by flash chromatography (12 g ISCO column, eluting with methylene chloride and a methanol/ammonia mixture (10:1); gradient 100% methylene chloride to 90% methylene chloride over 30 min at 20 mL/min) gave the title compound (164 mg, 41%) as an off-white powder. 1H NMR (300 MHz, CDCl3) 8.08 (d, J=1.0 1H), 7.90 (s, 1H), 7.7.62-7.56 (dd, J=8.8, 1.6 Hz, 1H), 7.23 (d, J=8.8 Hz, 1H), 4.47 (t, J=6.9 Hz, 2H), 3.64 (t, J=4.7 Hz, 4H), 2.85 (t, J=6.9, 2H), 2.48 (d, J=4.7 Hz, 4H).
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[C:15]1[N:20]=[CH:19][CH:18]=[CH:17][N:16]=1.O>CN(C=O)C>[N:16]1[CH:17]=[CH:18][CH:19]=[N:20][C:15]=1[CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: Brc1ncccn1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C(=O)OCC)c1ncccn1
Temperature: 100 °C
Yield: 49.5 %

Procedure:
To a solution of sodium hydride (4.4 g of a 60% dispersion in oil, 0.11 mol) in DMF (200 ml) was added diethyl malonate (16 ml, 0.11 mol) in DMF (50 ml) dropwise at room temperature. After 30 min 2-bromopyrimidine (8.0 g, 0.05 mol) was added portionwise and the solution heated at 100° C. for 3 h. The solution was cooled to room temperature, water (100 ml) was added and the mixture extracted with EtOAc (3×60 ml). The combined organic layers were dried (MgSO4) and evaporated. The residue was chromatographed on silica, using hexane:EtOAc (3:1) as the eluant, to afford the ester (5.9 g, 49%) as a pale yellow oil which solidified on standing at 0° C. 1H NMR (360 MHz, CDCl3) δ 1.29 (6H, t, J=7.1 Hz), 4.29 (4H, q, J=7.1 Hz), 5.10 (1H, s), 7.26 (1H, t, J=4.9 Hz), 8.74 (2H, d, J=4.9 Hz).
Reaction SMILES: [OH-].[Na+].C1C[O:6]CC1.[Br:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([Cl:19])[N:15]=[C:14]2Cl>CC(O)=O>[Br:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([Cl:19])[N:15]=[C:14]2[OH:6]
Reactant: C1CCOC1
Reactant: Clc1nc(Cl)c2cccc(Br)c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Oc1nc(Cl)nc2c(Br)cccc12
Reaction time: 0.33 h
Yield: 79 %

Procedure:
To a biphasic mixture of NaOH 1 N aq. (10.79 mL, 10.79 mmol) and 11 mL THF was added 8-bromo-2,4-dichloroquinazoline (407b, 1.50 g, 5.40 mmol) in one portion. The reaction became dark red. After 20 min the reaction was checked by LC/MS and judged complete. The reaction was cooled in an ice/water bath and acidified with AcOH. The reaction was concentrated to ½ volume on rotovap (precipitate observed) and cooled in an ice/water bath. The slurry was filtered and the solid rinsed with 2× water. The orange solid was collected and dried in vacuo to give 8-bromo-2-chloroquinazolin-4-ol (1.10 g, 4.24 mmol, 79% yield) as an orange solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.49 (1H, br. s.), 8.15 (1H, dd, J=7.8, 1.4 Hz), 8.09 (1H, dd, J=7.9, 1.5 Hz), 7.45 (1H, t, J=7.8 Hz). m/z (ESI, +ve ion) 258.9/260.9 (M+H)+.