Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Si](C)(C)[O:6][C@@H:7]([CH3:35])[C@@H:8]([NH:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([C:31]([F:34])([F:33])[F:32])[CH:24]=1)[C:9]1[O:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)=[N:12][N:13]=1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:20]([C:17]1[CH:16]=[CH:15][C:14]([C:11]2[O:10][C:9]([C@H:8]([NH:22][C:23]3[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([C:31]([F:32])([F:34])[F:33])[CH:24]=3)[C@@H:7]([OH:6])[CH3:35])=[N:13][N:12]=2)=[CH:19][CH:18]=1)#[N:21]
Reactant: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](Nc1ccc(C#N)c(C(F)(F)F)c1)c1nnc(-c2ccc(C#N)cc2)o1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@H](O)[C@@H](Nc1ccc(C#N)c(C(F)(F)F)c1)c1nnc(-c2ccc(C#N)cc2)o1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.8 %

Procedure:
To a pre-cooled (−55° C.) solution of 4-((1R,2S)-2-(tert-butyldimethyl-silyloxy)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)propylamino)-2-(trifluoromethyl)benzonitrile (900 mg, 1.17 mmol) in THF (120 mL) was added TBAF (2.05 mL, 2.05 mmol, 1 M solution in THF) over 10 min. Upon complete addition the reaction mixture was allowed to warm to 0° C. over 1 h, then stirred at 0° C. for a further 30 min and quenched with sat. aq. NH4Cl (150 mL). The resulting mixture was partitioned between H2O (150 mL) and EtOAc (250 mL). The aqueous layer was extracted with EtOAc (100 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to provide a yellow oil, which was purified by flash chromatography over silica gel (30-50% EtOAc in hexanes) to provided the title compound as a colourless oil (420 mg, 66%): 1H NMR (400 MHz, acetone-d6, δ in ppm) 8.20 (dm, J=8.8 Hz, 2H), 8.01 (dm, J=8.8 Hz, 2H), 7.73 (d, J=8.6 Hz, 1H), 7.46 (d, J=2.4 Hz, 1H), 7.20 (dd, J=2.5, 8.8 Hz, 1H), 6.84 (d, J=8.8 Hz, 1H), 5.23 (dd, J=3.5, 8.8 Hz, 1H), 4.62 (dq, J=3.5, 6.5 Hz, 1H), 1.40 (d, J=6.3 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([S:11](Cl)(=[O:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.C(N(CC)CC)C.[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH2:26]>C1COCC1>[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH:26][S:11]([C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([CH3:1])[S:3][C:4]=2[CH:10]=1)(=[O:13])=[O:12]
Reactant: Cc1nc2ccc(S(=O)(=O)Cl)cc2s1
Reactant: CN(C)CCN
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nc2ccc(S(=O)(=O)NCCN(C)C)cc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
To a solution of Compound 8 (7.0 g, 28.26 mmol) in THF (70 mL), a mixture of triethylamine (7.9 mL, 56.52 mmol) and N,N-dimethylethylene-diamine (4.67 mL, 42.38 mmol) in 20 mL THF was added dropwise. The combined mixture was stirred at room temperature for 2 hours during which time TLC showed complete disappearance of Compound 8. Solvents were removed in the rotary evaporator and the residue thus obtained was partitioned between chloroform (100 mL) and water (100 mL). The organic layer was washed with water (2×100 mL), brine (1×100 mL), dried (sodium sulfate) and evaporated to provide Compound 9 as a sticky oily solid (7.1 g, 84% yield). It was used further in the synthesis without any purification. The structure of Compound 9 is given below:
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[H-].[Na+].Cl[C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([C:18]([F:21])([F:20])[F:19])=[CH:11][N:10]=1.O>O1CCCC1>[N+:15]([C:14]1[C:9]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[N:10][CH:11]=[C:12]([C:18]([F:21])([F:19])[F:20])[CH:13]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Cl
Reactant: CS(N)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Yield: 65.8 %

Procedure:
4.4 g of methanesulfonamide was dissolved in 70 ml of dry tetrahydrofuran, and 1.9 g of 60% sodium hydride was added thereto under cooling with ice. After completion of the addition, the mixture was reacted for one hour under reflux. After cooling, 7.0 g of 2-chloro-3-nitro-5-trifluoromethylpyridine was added thereto, and the mixture was reacted for 6 hours under reflux. After completion of the reaction, the reaction product was poured into 300 ml of water and washed with ethyl ether. Then, the aqueous layer was weakly acidified with dilute hydrochloric acid. Precipitated crystals were collected by filtration and dried to obtain 5.8 g of N-(3-nitro-5-trifluoromethyl-2-pyridyl)methanesulfonamide having a melting point of from 138° to 139° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[CH2:9]([O:11][C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1)[CH3:10].CCN(C(C)C)C(C)C.[CH2:30]([CH2:32][NH2:33])[OH:31]>CCCCO>[OH:31][CH2:30][CH2:32][NH:33][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:19][C:16]2[CH:17]=[CH:18][C:13]([C:12]([O:11][CH2:9][CH3:10])=[O:20])=[CH:14][CH:15]=2)[CH:7]=1
Reactant: NCCO
Reactant: Clc1cc(Cl)ncn1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1ccc(Nc2cc(NCCO)ncn2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 67 %

Procedure:
100 mg of 4,6-dichloropyrimidine, 122 mg of ethyl-4-aminobenzoate and 103 mg of DIPEA were dissolved in 1 mL of n-BuOH and the mixture obtained was charged into a microwave vial and the vial obtained was kept in a heating block at 120° C. for 6 hours. The reaction was monitored by TLC and was completed within 6 hours. The mixture obtained was cooled to r.t., 61 mg of ethanolamine and 139 mg of DIPEA were added and the mixture obtained was heated under microwave irradiation for an hour at 200° C. The reaction was finished and crude product was obtained by evaporating n-BuOH. Purification was carried out by column chromatography using EtOAc: MeOH 20:1. Ethyl 4-(6-(2-hydroxyethylamino)pyrimidin-4-ylamino)benzoate in the form of a colorless solid was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:16][CH2:15][N:14]([C:17](=[O:22])[CH2:18][N:19]([CH3:21])[CH3:20])[CH2:13]3)[N:9]=[C:10](I)[C:3]=12.CC1(C)C(C)(C)OB([C:31]2[CH:36]=[CH:35][C:34]([NH:37][C:38]3[O:39][C:40]4[C:46]([CH3:47])=[CH:45][C:44]([CH3:48])=[CH:43][C:41]=4[N:42]=3)=[CH:33][CH:32]=2)O1.NC1N=CN=C2N([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)N=C(C3C=CC(NC4OC5C=CC=CC=5N=4)=C(F)C=3)C=12>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:16][CH2:15][N:14]([C:17](=[O:22])[CH2:18][N:19]([CH3:21])[CH3:20])[CH2:13]3)[N:9]=[C:10]([C:31]3[CH:32]=[CH:33][C:34]([NH:37][C:38]4[O:39][C:40]5[C:46]([CH3:47])=[CH:45][C:44]([CH3:48])=[CH:43][C:41]=5[N:42]=4)=[CH:35][CH:36]=3)[C:3]=12
Reactant: Cc1cc(C)c2oc(Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)nc2c1
Reactant: CN(C)CC(=O)N1CCC(n2nc(I)c3c(N)ncnc32)C1
Agent: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Nc5nc6ccccc6o5)c(F)c4)c4c(N)ncnc43)CC2)CC1
Product: Cc1cc(C)c2oc(Nc3ccc(-c4nn(C5CCN(C(=O)CN(C)C)C5)c5ncnc(N)c45)cc3)nc2c1

Procedure:
rac-1-[3-(4-Amino-3-{4-[(5,7-dimethyl-1,3-benzoxazol-2-yl)amino]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-1-yl)tetrahydro-1H-1-pyrrolyl]-2-(dimethylamino)-1-ethanone was prepared from rac-1-[3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)tetrahydro-1H-1-pyrrolyl]-2-(dimethylamino)-1-ethanone (0.278 g, 0.669 mmol) and N2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5,7-dimethyl-1,3-benzoxazol-2-amine (0.305 g, 0.837 mmol) in a manner similar to that used for the preparation of cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-fluorophenyl)-1,3-benzoxazol-2-amine. The compound was formed as a white powder (0.219 g, 62%). 1H NMR (DMSO-d6, 400 MHz) 2.17 (s, 3H), 2.23 (s, 3H), 2.3-2.50 (m, 4H), 2.34 (s, 3H), 2.40 (s, 3H), 2.99-4.26 (m, 4H), 5.44-5.49 (m, 1H), 6.80 (s, 1H), 7.11 (s, 1H), 7.65 (d, 2H), 7.92 (d, 2H), 8.26 (s, 1H), 10.86 (s, 1H); RP-HPLC Rt 10.765 min, 96% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150×3.9 mm column); m/z 526 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[O:9])[N:3]=1.[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([Cl:24])=[O:23])=[CH:20][CH:19]=1.C(N(CC)CC)C.[OH-].[Na+]>ClCCl>[ClH:24].[ClH:24].[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH:10]3[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)=[O:9])[N:3]=2)=[O:23])=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CN1CCC(C(=O)c2cccc(N)n2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3ccc(F)cc3)n2)CC1
Product: Cl

Procedure:
Stir a mixture of 2-Amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine (0.150 g), 4-fluorobenzoyl chloride (0.218 g), triethylamine (0.192 mL) and dichloromethane at room temperature for 4 hours. Add 1N aqueous NaOH to basify the reaction mixture. Extract the mixture with dichloromethane, dry the organic phase with anhydrous sodium sulfate, evaporate the solvent, and purify the residue by HPLC to provide the free base of the title compound. Re-dissolve the free base in diethyl ether and add excess 1 M HCl. Evaporate the solvent and dry the residue under vacuum to obtain 80 mg of the title compound. M.p. 75-80° C.; HRMS: 342.1605 (obs.) (Cal. 342.1618).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH:3]1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]([CH3:27])[C:22](=[O:28])[CH:21]=[CH:20]3)[CH:10]=1.[CH3:29]I>>[CH3:29][O:8][CH:5]1[CH2:6][CH2:7][CH:2]([CH3:1])[CH:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[N:23]([CH3:27])[C:22](=[O:28])[CH:21]=[CH:20]4)[CH:10]=2)[CH2:4]1
Reactant: CI
Reactant: CC1CCC(O)CC1c1cccc(OCc2ccc3c(ccc(=O)n3C)c2)c1
Product: COC1CCC(C)C(c2cccc(OCc3ccc4c(ccc(=O)n4C)c3)c2)C1
Yield: 60 %

Procedure:
Using an analogous procedure to that described in Example 2, (1RS,3RS,4SR)-4-methyl-3-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]cyclohexan-1-ol was reacted with methyl iodide to give (1RS,3RS,4SR)-1-methoxy-4-methyl-3-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]cyclohexane as a foam in 60% yield.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].[NH3:9].C([O-])(=O)/C=C\C([O-])=O.[NH4+].[NH4+]>O>[NH2:9][C@H:2]([C:1]([O-:8])=[O:7])[CH2:3][C:4]([O-:6])=[O:5].[NH4+:9].[NH4+:9]
Reactant: O=C(O)/C=C\C(=O)O
Reactant: N
Agent: O=C([O-])/C=C\C(=O)[O-]
Agent: [NH4+]
Solvent: O
Product: N[C@@H](CC(=O)[O-])C(=O)[O-]
Temperature: 30 °C
Reaction time: 72 h
Yield: 98.8 %

Procedure:
According to the same procedure of Example 1, 600 g maleic acid was dissolved in deionized water, and 705 g of 25 wt % aqueous ammonia solution (molar ratio to maleic acid was about 2.0) was added thereon. The cells of Alcaligenes faecalis ATCC 8750 were added to 2 L of an ammonium maleate substrate solution (pH 8.4) containing 600 g maleic acid, and the substrate solution were gently stirred at 30° C. for 72 hours. After the reaction, ammonium L-aspartate was formed with a molar yield of 98.8% based on maleic acid. To the reaction solution from which the cells had been removed by centrifugation, was added 610 g maleic acid at 30° C. After the addition, a temperature of the solution was 37.0° C., and pH value thereof was 3.8. L-aspartic acid crystals were separated by filtration, so as to recover 1.5 L of mother liquors. The crude crystals was 769 g (excluding water) (88.0 wt % aspartic acid, 11.4 wt % maleic acid, 250 μm average crystal size). The crystals were washed with about 600 ml of water and dried so as to obtain 675 g of L-aspartic acid crystals (98.8 wt % aspartic acid, 0.77 wt % maleic acid, 100 μm average crystal size).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:15][CH:16]1[CH2:21][C:20](=[O:22])[O:19][C:17]1=[O:18].[Cl-:23].[Al+3].[Cl-].[Cl-].Cl>O.C(=S)=S>[Cl:23][C:9]1[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:8]=1[C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=1[C:20](=[O:22])[CH2:21][CH:16]([CH3:15])[C:17]([OH:19])=[O:18]
Reactant: [Cl-]
Reactant: Clc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CC1CC(=O)OC1=O
Agent: Cl
Agent: [Al+3]
Solvent: S=C=S
Solvent: O
Product: CC(CC(=O)c1ccccc1-c1ccc(Cl)cc1Cl)C(=O)O
Temperature: 10 °C
Reaction time: 4 h

Procedure:
A solution is prepared by adding 33.4 g dichlorobiphenyl (0.15 moles) and 18.0 g methylsuccinic acid anhydride (0.15 moles) to 100 ml carbon disulfide. The solution is cooled to 10° C. and is treated portionwise, under stirring, with 24.0 g anhydrous aluminum chloride (0.18 moles) at a rate such that the temperature of the reaction mixture does not exceed 15° C. The mixture is stirred for an additional 4 hours at 20° C. and is then decomposed by pouring into a mixture of 350 ml water and 175 ml concentrated hydrochloric acid. Carbon disulfide is distilled off and the residue is washed with 1,2-dichloroethane (2×100 ml and 1×100 ml). The extracts are combined and washed with a 5% aqueous sodium hydroxide solution (5×75 ml) and water (1×75 ml). The alkaline extracts and aqueous washings are combined, filtered with active carbon, and the clear filtrate is acidified to a strong acid with 50% sulfuric acid. The precipitate is separated, washed with water, and purified by crystallization from 95 ml of 65% acetic acid. The yield is 19.3 g (38.0% of theoretical yield) of the title compound with a melting point of 155°-157° C.
Reaction SMILES: [CH2:1]([S:5](Cl)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].Cl.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1>>[O:23]=[C:20]1[CH2:21][CH2:22][N:17]([C:14]2[CH:15]=[CH:16][C:11]([NH:10][S:5]([CH2:1][CH2:2][CH2:3][CH3:4])(=[O:7])=[O:6])=[CH:12][CH:13]=2)[CH2:18][CH2:19]1
Reactant: Nc1ccc(N2CCC(=O)CC2)cc1
Reactant: CCCCS(=O)(=O)Cl
Agent: Cl
Product: CCCCS(=O)(=O)Nc1ccc(N2CCC(=O)CC2)cc1

Procedure:
The title compound was prepared from 1-butanesulfonyl chloride and 1-(4-amino-phenyl)-piperidine-4-one hydrochloride (which was obtained in Example 224) according to the procedure B of Example 225 as a crystalline solid; 1H NMR (300 MHz, DMSO-d6) δ 0.83 (t, J=7.3 Hz, 3H), 1.25-1.40 (m, 2H), 1.55-1.70 (m, 2H), 2.40 (t, J=5.9 Hz, 4H), 2.94 (t, J=7.6 Hz, 2H), 3.54 (t, J=5.9 Hz, 4H), 7.00 (d, J=9.0 Hz, 2H), 7.09 (d, J=9.0 Hz, 2H), 9.34 (s, 1H); MS (ES) m/z: 311.0 (MH+); HRMS Calcd. for C15H22N2O2S(M+): 310.1351. Found: 310.1375. Anal. Calcd. for C15H22N2O2S: C, 58.04; H, 7.14; N, 9.02. Found: C, 57.78; H, 6.95; N, 8.83.
Reaction SMILES: Cl.[C:2]([NH:5][C:6]1[C:7](=[CH:16][NH:17][NH:18][CH:19]=[N:20][NH2:21])[CH2:8][C:9](=[CH:14][CH:15]=1)[C:10]([O:12]C)=[O:11])(=[O:4])[CH3:3].[OH-:22].[Na+]>>[OH2:4].[OH2:22].[C:2]([NH:5][C:6]1[C:7](=[CH:16][NH:17][NH:18][CH:19]=[N:20][NH2:21])[CH2:8][C:9](=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11])(=[O:4])[CH3:3]
Reactant: COC(=O)C1=CC=C(NC(C)=O)C(=CNNC=NN)C1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: CC(=O)NC1=CC=C(C(=O)O)CC1=CNNC=NN
Product: O
Temperature: 25 °C
Reaction time: 24 h
Yield: 160.1 %

Procedure:
A mixture of methyl 4-acetylamino-3-{[(aminoiminomethyl)hydrazino]methylene}benzoate hydrochloride (0.54 g, 0.0017 mol) and 1N sodium hydroxide (5.0 mL, 0.005 mol) was stirred at room temperature for 24 h. After filtration, the mixture was neutralized with concentrated hydrochloric acid. The precipitate was collected by filtration, washed with water, and dried over toluene under vacuum to give 0.41 g (80%) of the title compound as a white powder, mp 326°-327° C.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[N:4]1.[C:8]([NH:10][C:11](S(C)=O)=[N:12][CH3:13])#[N:9]>C1COCC1>[C:8]([NH:10][C:11]([N:3]1[CH:7]=[CH:6][CH:5]=[N:4]1)=[N:12][CH3:13])#[N:9]
Reactant: CN=C(NC#N)S(C)=O
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN=C(NC#N)n1cccn1
Reaction time: 1 h

Procedure:
To a stirred suspension of NaH (50% oil suspension, 3.58 g) in THF (160 ml) was added pyrazole (5.84 g) at a temperature below room temperature and stirred for 1 hr. To the mixture was added N-cyano-N'-methyl-methylsulfinylformamidine (8.32 g, obtained by the same procedure as in Example 3 (1)) and stirred for 3 hrs. at room temperature. After evaporation under a reduced pressure, the residue was dissolved in water and washed with ether. The aqueous layer was acidified (pH 4) with 10% HCl under ice-cooling. The precipitate was filtered, washed with water and dried to give 1-(N-cyano-N'-methylamidino)pyrazole (7.52 g). An additional amount (0.2 g) of the same product was further obtained from the filtrate. The crude products were combined and recrystallized from ethyl acetate to give the purified product (6.12 g). Yield 71.7%, m.p. 166.5°-168° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1)C=O.[C:24](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>CN(C=O)C>[CH3:23][O:22][C:20]1[CH:21]=[C:14]([O:13][CH3:12])[CH:15]=[CH:16][C:19]=1[CH2:24][NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Nc1ccc2c(c1)CC(=O)N2
Reactant: COc1cc(C=O)cc(OC)c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COc1ccc(CNc2ccc3c(c2)CC(=O)N3)c(OC)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 50.7 %

Procedure:
A mixture of 5-aminooxindole (1.0 g, 6.75 mmol), 3,5-dimethoxybenzaldehyde (1.35 g, 8.12 mmol), sodium triacetoxyborohydride (4.3 g, 20.3 mmol), and AcOH (0.5 ml) in DMF (15 ml) was stirred at room temperature for 3.5 hours. The mixture was partitioned between saturated NaHCO3 solution (50 ml) and CHCl3 (50 ml). The aqueous layer was extracted again with CHCl3 (2×50 ml). The organic layers were combined, washed with saturated NaHCO3 solution (50 ml), water (2×75 ml), dried over Na2SO4, and poured into Et2O (100 ml) with stirring. The resulting solid was filtered, washed with Et2O and dried to give 5-(2,4-dimethoxy-benzylamino)-1,3-dihydro-indol-2-one as a brown solid (1.02 g, 51%).
Reaction SMILES: FC(F)(F)C(O)=O.COC1C=CC(C[NH:15][C:16]2[CH:25]=[C:24]3[C:19]([CH:20]=[C:21]([C:28]4[CH:33]=[C:32]([NH2:34])[C:31]([F:35])=[CH:30][C:29]=4[CH3:36])[C:22](=[O:27])[N:23]3[CH3:26])=[CH:18][N:17]=2)=CC=1>C(Cl)Cl>[NH2:15][C:16]1[CH:25]=[C:24]2[C:19]([CH:20]=[C:21]([C:28]3[CH:33]=[C:32]([NH2:34])[C:31]([F:35])=[CH:30][C:29]=3[CH3:36])[C:22](=[O:27])[N:23]2[CH3:26])=[CH:18][N:17]=1
Reactant: COc1ccc(CNc2cc3c(cn2)cc(-c2cc(N)c(F)cc2C)c(=O)n3C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(F)c(N)cc1-c1cc2cnc(N)cc2n(C)c1=O
Temperature: 50 °C
Yield: 52.9 %

Procedure:
Trifluoroacetic acid (2 mL, 26.9 mmol) was added to a solution of 7-(4-methoxybenzylamino)-3-(5-amino-4-fluoro-2-methylphenyl)-1-methyl-1,6-naphthyridin-2(1H)-one (0.8 g, 1.9 mmol) in DCM (10 mL) and the reaction mixture was refluxed at 50° C. for 2 hour. After cooling to RT, the reaction mixture was washed with water and the combined aqueous layers were neutralized with saturated aq NaHCO3 to pH 7-8. Then the aqueous layer was extracted with EtOAc (3×50 mL), the extracts were dried (Na2SO4) and concentrated to give 7-amino-3-(5-amino-4-fluoro-2-methylphenyl)-1-methyl-1,6-naphthyridin-2(1H)-one (0.3 g, 53% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.29 (s, 1H), 7.57 (s, 1 H), 6.83 (d, J=12.4 Hz, 1 H), 6.56 (d, J=9.6 Hz, 1 H), 6.48 (s, 2 H), 6.24 (s, 1 H), 4.87 (s, 2 H), 3.45 (s, 3 H), 1.94 (s, 3 H); MS (ESI) m/z: 299.0 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[Cl:13][C:14]1[N:19]=[C:18](Cl)[CH:17]=[CH:16][N:15]=1.C([O-])([O-])=O.[Na+].[Na+].C(COC)OC>O>[Cl:13][C:14]1[N:19]=[C:18]([C:6]2[CH:7]=[CH:8][C:3]([N:2]([CH3:12])[CH3:1])=[CH:4][CH:5]=2)[CH:17]=[CH:16][N:15]=1
Reactant: CN(C)c1ccc(B(O)O)cc1
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CN(C)c1ccc(-c2ccnc(Cl)n2)cc1
Temperature: 80 °C
Yield: 78.6 %

Procedure:
A mixture of 4-dimethylaminophenyl boronic acid (10 g, 60.6 mM), 2,4-dichloropyrimidine (9 g, 60.4 mM), Na2CO3 (12 g, 114.2 mM), tetrakistriphenylphosphine palladium (2.5 g, 2.1 mM), dimethoxyethane (120 ml) and water (35 ml) was heated at 80° C. under a nitrogen atmosphere for 16 hr. The reaction was cooled in an ice bath and the resulting yellow suspension was filtered and the solid washed with water (3×50 ml) then ethyl acetate (2×50 ml). The solid was dried in vaccuo to afford [4-(2-Chloro-pyrimidin-4-yl)-phenyl]-dimethyl-amine (11.1 g, 78% yield) as an orange solid. ES-MS MH+234, 236, 1H NMR (300 MHz, ppm, DMSO-d6): 8.57 (d, 1H), 8.05 (d, 2H), 7.92 (d, 1H), 6.80 (d, 1H), 3.03 (s, 6H)
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][N:19]([C:24]#[N:25])[C:20](=[NH:23])SC)[CH2:14][CH2:13]1.[CH:26]([NH2:30])([CH2:28][CH3:29])[CH3:27]>N1C=CC=CC=1>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][N:19]([C:24]#[N:25])[C:20]([NH:30][CH:26]([CH3:27])[CH2:28][CH3:29])=[NH:23])[CH2:14][CH2:13]1
Reactant: CSC(=N)N(C#N)CC1CCN(CC2COc3ccccc3O2)CC1
Reactant: CCC(C)N
Solvent: c1ccncc1
Product: CCC(C)NC(=N)N(C#N)CC1CCN(CC2COc3ccccc3O2)CC1

Procedure:
A mixture of 3 g 1-[(2,3-dihydro[4H]1,4-benzodioxin-2-yl)methyl]4-[(N-cyano S-methyl isothioureido)methyl]piperidine, 10 ml pyridine and 30 g sec butylamine are heated to the reflux. After evaporation to dryness the resulting oily product is taken up in isopropyl ethyl allowing the recovery of a solid as colourless crystalls. They are recrystallized from isopropanol.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[C:32]([O:36][C:37]([N:39]1[CH2:42][CH2:41][C@H:40]1[CH2:43][OH:44])=[O:38])([CH3:35])([CH3:34])[CH3:33].[Br:45][C:46]1[CH:47]=[N:48][CH:49]=[C:50](O)[CH:51]=1>C1COCC1>[Br:45][C:46]1[CH:51]=[C:50]([O:44][CH2:43][C@@H:40]2[CH2:41][CH2:42][N:39]2[C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:38])[CH:49]=[N:48][CH:47]=1
Reactant: Oc1cncc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(Br)c1
Reaction time: 0.17 h

Procedure:
Triphenylphosphine (4.01 g, 15.3 mmol) and DEAD (2.43 mL, 15.3 mnol) were dissolved in 30 mL of THF at 0° C., and the mixture was stirred for 10 minutes. Samples of 1-t-butyloxycarbonyl-2-(S)-azetidinemethanol (2.86 g, 15.3 mmol, Step 7c above) and 3-bromo-5-hydroxypyridine.(1.51 g, 10.2 mmol, Step 10c above) were added, and the mixture was stirred for 40 hours at room temperature. The volatile components were removed under vacuum, and the residue was triturated with hexane. The separated hexane fraction was concentrated, and the residue was chromatographed (silica gel; hexane/ether, 10:1 to 10:2) to afford 5-bromo-3-((1-t-butyloxycarbonyl-(2S)-azetidinyl)methoxy)pyridine as a colorless oil (1.669 g): 1H NMR (CDCl3, 300 MHz) δ 1.42 (s, 9H), 2.31 (m, 2H), 3.89 (m, 2H), 4.12 (m, 1H), 4.322 (m, 1H), 4.52 (m, 1H), 7.43 (m, 1H), 8.29 (m, 2H); MS (CI/NH3) m/z 344 (M+H)+. The 5-bromo-3-(2-(1-BOC-2-(S)-azetidinyl)methoxy)pyridine was treated with with 4 M HCl in dioxane to give the free base of the title compound. This was converted to the dihydrochloride salt and recrystallized from methanol/ether to provide the title compound: mp 163-165° C.; [α]25D -5.1 (c 0.57, methanol); 1H NMR (D2O, 300 MHz) δ 8.36 (d, J=1.8 Hz, 1H), 8.32 (d, J=2.6 Hz, 1H), 7.84 (dd, J=1.8, 2.6 Hz, 1H), 4.98-4.90 (m, 1H), 4.43 (d, J=4.0 Hz, 2H), 4.20-4.02 (m, 2H), 2.67 (q, J=8.5 Hz, 2H); MS (CI/NH3) m/z 243/246 (M+H)+, 260/262 (M+NH4)+. Anal. calcd for C9H13N2OBrCl2 : C, 34.21; H, 4.15; N, 8.86. Found: C, 34.18; H, 4.17; N, 8.89.