Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([O:19][CH3:20])[N:12]=2)=[CH:6][CH:5]=1.[CH3:21]I>>[I:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]([CH3:21])[C:11]2[N:12]=[C:13]([O:19][CH3:20])[CH:14]=[C:15]([O:17][CH3:18])[N:16]=2)=[CH:8][CH:9]=1
Reactant: COc1cc(OC)nc(Nc2ccc(I)cc2)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: COc1cc(OC)nc(N(C)c2ccc(I)cc2)n1

Procedure:
In the same manner as in Reference Example 24-(1), 4-iodoaniline (220 mg) and 2-chloro-4,6-dimethoxypyrimidine (200 mg) were reacted in the presence of sodium hydride to obtain N-(4-iodophenyl)-4,6-dimethoxypyrimidin-2-amine (141 mg). (2) In the same manner as in Reference Example 24-(2), sodium hydride (16 mg), N-(4-iodophenyl)-4,6-dimethoxypyrimidin-2-amine (140 mg) and methyl iodide (0.024 ml) were reacted to obtain N-(4-iodophenyl)-4,6-dimethoxy-N-methylpyrimidin-2-amine (118 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:14][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[NH:13][CH2:12][CH2:11][S:10]1.[CH3:20][CH2:21]CCCC.C([Li])CCC.C(I)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:14][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[N:13]([CH2:20][CH3:21])[CH2:12][CH2:11][S:10]1
Reactant: Clc1ccc(C2(Cn3cncn3)NCCS2)c(Cl)c1
Reactant: CCCCCC
Agent: [Li]CCCC
Solvent: CCI
Solvent: C1CCOC1
Product: CCN1CCSC1(Cn1cncn1)c1ccc(Cl)cc1Cl
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
2.0 g of 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazole-1-yl methyl) thiazolidine used in Working Example 7 was dissolved in anhydrous tetrahydrofuran. After cooling the solution to -50° C., 4.5 ml of a n-hexane solution containing 15% of n-butyl lithium was added and the mixture was stirred for 30 minutes at the same temperature. Then, 2.2 g of ethyl iodide was added and the mixture was reacted for 1 hour at the same temperature. Then, the temperature was gradually raised to room temperature. After distilling off tetrahydrofuran under reduced pressure, the reaction product was purified by silica gel column chromatography using a solvent mixture of chloroform and ethyl acetate as the developer, whereby 1.0 g of 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazole-1-yl methyl)-3-ethyl thiazolidine (Compound No. 56 in Table 1) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Cl[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Reactant: ClCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(OCCN2CCOCC2)ccc1Cl
Temperature: 80 °C
Reaction time: 20 h

Procedure:
4-chloro-3-nitrophenol (5 g, 28.8 mmol, 1 eq.) was placed in dimethylformamide (96 mL) with 4-(2-chloro-ethyl)morpholine (16 g, 86.4 mmol, 3 eq.), Cs2CO3 (65 g, 0.20 mmol, 7 eq.), KI (10.5 g, 63.4 mmol, 2.2 eq.). The reaction mixture was heated at 80° C. and stirred for 20 hours. The reaction mixture was then concentrated under reduced pressure and the resulting residue was diluted with ethyl acetate. The organic phase was washed with a 1% NaOH aqueous solution, dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to afford 4-(2-(4-chloro-3-nitrophenoxy)ethyl)morpholine. (7.5 g, 96%).
Reaction SMILES: Cl[C:2]([O:4][CH:5]1[CH2:10][C:9]([CH3:12])([CH3:11])[N:8]([O:13][CH3:14])[C:7]([CH3:16])([CH3:15])[CH2:6]1)=[O:3].[CH3:17][NH:18][NH2:19]>CO>[CH3:17][NH:18][NH:19][C:2]([O:4][CH:5]1[CH2:10][C:9]([CH3:12])([CH3:11])[N:8]([O:13][CH3:14])[C:7]([CH3:16])([CH3:15])[CH2:6]1)=[O:3]
Reactant: CON1C(C)(C)CC(OC(=O)Cl)CC1(C)C
Reactant: CNN
Solvent: CO
Product: CNNC(=O)OC1CC(C)(C)N(OC)C(C)(C)C1

Procedure:
The title compound is prepared by reacting the compound of Example 27 (1 mole) with methylhydrazine (1.1 mole) in methanol.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C@:5]([C@@H:14]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]1)([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=1)[CH3:6].CCN(C(C)C)C(C)C.Cl[C:37]([O:39][CH3:40])=[O:38]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:13][C:9]1[CH:8]=[C:7]([C@@:5]([C@@H:14]2[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]2)([O:4][CH2:3][CH2:2][NH:1][C:37]([O:39][CH3:40])=[O:38])[CH3:6])[CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@](C)(OCCN)c2cccc(Cl)c2)C1
Reactant: COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)NCCO[C@@](C)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of (R)-tert-butyl 3-((R)-1-(2-aminoethoxy)-1-(3-chlorophenyl)ethyl)piperidine-1-carboxylate (0.410 g, 1.07 mmol), DMAP (0.380 g), DIPEA (4 mL), and methyl chloroformate (0.960 g) in CH2Cl2 was stirred at rt for 20 h. After the reaction mixture was evaporated under reduced pressure, the crude product was purified by reversed-phase HPLC to afford (R)-tert-butyl 3-((R)-1-(3-chlorophenyl)-1-(2-(methoxycarbonylamino)ethoxy)ethyl)piperidine-1-carboxylate. MS ESI +ve m/z 465 (M+Na).
Reaction SMILES: [Cl:1][C:2]1[CH2:6][CH:5]([CH:7]([N:11]2C(=O)C3=CC=CC=C3C2=O)[C:8]([OH:10])=[O:9])[O:4][N:3]=1.O.NN.C(O)(=O)C>O>[NH2:11][C@@H:7]([C@H:5]1[O:4][N:3]=[C:2]([Cl:1])[CH2:6]1)[C:8]([OH:10])=[O:9]
Reactant: O=C(O)C(C1CC(Cl)=NO1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CC(=O)O
Product: N[C@H](C(=O)O)[C@@H]1CC(Cl)=NO1
Reaction time: 7 h
Yield: 58.4 %

Procedure:
To 710 mg (2.3 mmole) of 3-chloro-4,5-dihydro-α-phthalimido-5-isoxazole acetic acid in 15 ml of water is added 260 μl of hydrazine hydrate and the solution stirred at 50° for 7 hours. After cooling, the solution is adjusted to pH 5.5 with acetic acid (80 μl), filtered, and the precipitate washed with 13 ml water. The filtrate is diluted with 200 ml of 2-butanol and allowed to crystallized in the refrigerator for 18 hours. Filtration yielded 240 mg of (αS,5S)-α-amino-3-chloro-4,5-dihydro-5-isoxazole acetic acid; concentrating the mother liquors approximately 15% afforded 50 mg of a second crop of (αS,5S)-α-amino-3-chloro-4,5-dihydro-5-isoxazole acetic acid (71%).
Reaction SMILES: C(N(CC)CC)C.[CH:8]1[C:13](N=C=S)=[CH:12][C:11]2[C:17]([O:19][C:20]3([C:30]4[CH:31]=[CH:32][C:33]([OH:35])=[CH:34][C:29]=4[O:28][C:22]4[CH:23]=[C:24]([OH:27])[CH:25]=[CH:26][C:21]3=4)[C:10]=2[CH:9]=1)=[O:18]>CN(C=O)C>[CH:8]1[CH:13]=[CH:12][C:11]([C:17]([OH:19])=[O:18])=[C:10]([C:20]2[C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=3[O:28][C:29]3[C:30]=2[CH:31]=[CH:32][C:33]([CH:34]=3)=[O:35])[CH:9]=1
Reactant: O=C1OC2(c3ccc(O)cc3Oc3cc(O)ccc32)c2ccc(N=C=S)cc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12
Reaction time: 17 h
Yield: 81.5 %

Procedure:
Under argon atmosphere, to a solution of the crude 21 obtain as above in DMF (3 mL) were successively added triethylamine (29.0 μL, 208 μmol) and fluorescein isothiocyanate isomer I (FITC, 17, commercial product) (90%, HPLC) (45.0 mg, 104 μmol) at room temperature. After stirring for 17 hours at the same temperature, the reaction solution was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica-gel 8 g, dichloromethane/methanol=12/1) to give 1-[2-{(11,12-didehydro-5,6-dihydrodibenzo[a,e]cycloocten-5-yl)oxycarbonylamino}ethyl]-3-(5-fluoresceinyl)thiourea (22) (59.0 mg, 84.8 μmol, 80.7% based on 17) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Br[CH2:6][C:7]([CH:9]1[CH2:12][CH2:11][CH2:10]1)=O.C(=O)([O-])O.[Na+]>C(O)C>[CH:9]1([C:7]2[N:1]=[C:2]([NH2:4])[S:3][CH:6]=2)[CH2:12][CH2:11][CH2:10]1
Reactant: NC(N)=S
Reactant: O=C(CBr)C1CCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1nc(C2CCC2)cs1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Thiourea (2.3 g, 30.0 mmol) was dissolved in ethanol (100 ml), added with 2-bromo-1-cyclobutyl-1-ethanone synthesized in the same manner as in Example 1, (E), and then heated to 100° C. The reaction solution was stirred for 1 hour, then returned to room temperature, neutralized with saturated sodium hydrogencarbonate and extracted with chloroform. The collected organic layer was washed with saturated brine, dried over magnesium sulfate and then concentrated under reduced pressure. The title compound was obtained as the residue without purification as a brown oily substance (5.4 g, 100%).
Reaction SMILES: C([O:3][C:4](=[O:13])[C:5]([C:7]1[S:8][C:9]([Cl:12])=[CH:10][CH:11]=1)=[O:6])C.[OH-].[Na+].Cl>O.CO>[Cl:12][C:9]1[S:8][C:7]([C:5](=[O:6])[C:4]([OH:13])=[O:3])=[CH:11][CH:10]=1
Reactant: CCOC(=O)C(=O)c1ccc(Cl)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C(=O)c1ccc(Cl)s1

Procedure:
(5-Chlorothiophen-2-yl)-oxo-acetic acid ethyl ester (8.62 g, 39.4 mmol) was dissolved in a mixture of 100 ml water and 100 ml methanol, then treated with 10 N NaOH (5.9 ml, 59 mmol) at room temperature for 20 hours. The reaction was then poured into 200 ml 3N HCl, and extracted with ethyl acetate (2×100 ml). The combined ethyl acetate extracts were dried over Na2SO4 and concentrated under vacuum to provide Preparation 1b (6.89 g, 92%). The product was then recrystallized from hexane/ether. MS (M−H)−: 189.10; 1H NMR (300 MHz, CDCl3) δ9.07 (1H, br s), 8.32 (1H, d, J=4.2 Hz), 7.10 (1H, d, J=4.2 Hz). IR (KBr) 3270, 3099, 1765, 1744, 1675, 1514, 1411, 1325 cm−1.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:22]=[C:21]([N:23]4[CH2:27][CH2:26][C@@H:25]([CH2:28][NH2:29])[CH2:24]4)[C:20]4[C:15](=[N:16][CH:17]=[CH:18][N:19]=4)[CH:14]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[Si]([N:43]=[C:44]=[O:45])(C)(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:22]=[C:21]([N:23]4[CH2:27][CH2:26][C@@H:25]([CH2:28][NH:29][C:44]([NH2:43])=[O:45])[CH2:24]4)[C:20]4[C:15](=[N:16][CH:17]=[CH:18][N:19]=4)[CH:14]=3)=[CH:9][CH:8]=2)[CH2:5][CH2:6]1
Reactant: C[Si](C)(C)N=C=O
Reactant: NC[C@@H]1CCN(c2nc(-c3ccc(N4CCOCC4)cc3)cc3nccnc23)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)NC[C@@H]1CCN(c2nc(-c3ccc(N4CCOCC4)cc3)cc3nccnc23)C1

Procedure:
A solution of (S)-(1-(7-(4-morpholinophenyl)pyrido[4,3-b]pyrazin-5-yl)pyrrolidin-3-yl)methanamine (Compound 77, 0.16 mmol), DIPEA (207 mg, 1.6 mmol) and TMSNCO (184 mg, 1.6 mmol) in anhydrous CH2Cl2 (5 mL) was stirred at room temperature for 70 hours. The reaction mixture was poured into saturated NaHCO3 aqueous and extracted with CH2Cl2. The combined extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography to afford the title compound. MS (m/z): 434 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[F:36][CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][CH:42]([C:45]2[CH:51]=[CH:50][C:48]([NH2:49])=[C:47]([O:52][CH3:53])[CH:46]=2)[CH2:41][CH2:40]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:49][C:48]3[CH:50]=[CH:51][C:45]([CH:42]4[CH2:41][CH2:40][N:39]([CH2:38][CH2:37][F:36])[CH2:44][CH2:43]4)=[CH:46][C:47]=3[O:52][CH3:53])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: COc1cc(C2CCN(CCF)CC2)ccc1N
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: COc1cc(C2CCN(CCF)CC2)ccc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 175 °C
Reaction time: 72 h

Procedure:
To 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (238 mg, 0.50 mmol) and 4-[1-(2-fluoroethyl)-4-piperidinyl]-2-(methyloxy)aniline (140 mg, 0.50 mmol) in iPrOH (1 mL) in a microwave vial was added p-toluenesulfonic acid monohydrate (190 mg, 1.0 mmol). The reaction was heated in a microwave at 175° C. for 1000 seconds. After cooling to rt the material was transferred to another flask, rinsing with a solution of DCM/MeOH. Silica gel was added and the solvent removed on the rotovap. The preabsorbed solids were purified by flash chromatography. The desired fractions were combined and the solvent removed on the rotovap to give product contaminated with an impurity. The material was placed under vacuum for 3 days then triturated with diethyl ether. The desired product was obtained as a white solid (23 mg, 0.033 mmol, 6.6% yield). 1H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 9.35 (d, J=6.2 Hz, 1H), 8.47 (s, 1H), 8.22 (d, J=5.1 Hz, 1H), 8.08, (s, 1H), 7.75 (d, J=8.8 Hz, 1H), 7.71-7.60 (m, 2H), 7.42 (dd, J=8.4, 7.3 Hz, 1H), 7.35 (dd, J=7.1, 6.6 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 7.15 (dd, J=8.1, 7.9 Hz, 2H), 6.97-6.90 (m, 2H), 6.77 (d, J=8.2 Hz, 1H), 6.56 (d, J=5.1 Hz, 1H), 4.51 (dt, J=48.0, 4.8 Hz, 2H), 3.95, (s, 3H), 3.80 (s, 3H), 2.97 (d, J=11.0 Hz, 2H), 2.60 (dt, J=28.2, 4.8 Hz, 2H), 2.08 (dd, J=11.5, 8.8 Hz, 2H), 1.77-1.59 (m, 4H). MS (ESI) m/z=708 [M+1].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O-:10])=[O:9].[CH2:17]([OH:19])C.[C:20]1([CH3:26])C=CC=CC=1.Cl>>[C:2]1([NH:1][C:17](=[O:19])[O:9][CH2:20][CH3:26])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:8][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[N+:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: CCO
Reactant: Cc1ccccc1
Agent: Cl
Solvent: O=[N+]([O-])c1ccccc1
Solvent: Nc1ccccc1
Product: CCOC(=O)Nc1ccccc1
Temperature: 25 °C

Procedure:
Into a 100 ml capacity SUS 316 stainless autoclave were fed the above catalyst (61.9 mg) (0.020 mmol in terms of Pd), aniline (0.931 g, 0.010 mol), nitrobenzene (1.23 g, 0.010 mol), ethanol (4.61 g, 0.10 mol), toluene (10.6 g, 0.11 mol) and 35% hydrochloric acid aqueous solution (0.071 g, HCl=0.68 mmol, H2O=0.067 mmol), followed by introducing CO gas up to 28 Kg/cm2 at room temperature without purging the air inside the system, reacting them at a reaction temperature of 190° C. for 3 hours, cooling the reaction mixture down to room temperature after the reaction, returning the pressure inside the system to the atmospheric pressure and analyzing the reaction product according to gas chromatography. As a result, ethyl N-phenylcarbamate (NPU) (2.97 g) was formed (NPU yield: 90%), and aniline (0.093 g, 0.001 mol) and nitrobenzene (0.123 g, 0.001 mol) remained unreacted.
Reaction SMILES: [OH:1][PH:2]([CH2:4][CH:5]([CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[O:3].[C:22](O)([CH3:25])([CH3:24])[CH3:23].C(N=C=NCCCN(C)C)C.O>ClCCl.CN(C)C1C=CN=CC=1>[C:22]([O:3][PH:2]([CH2:4][CH:5]([CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7])=[O:1])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)O
Reactant: CC(C)(C)OC(=O)CCC(C[PH](=O)O)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)CCC(C[PH](=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
To a solution of di-tert-butyl 2-[(hydroxyphosphinyl)methyl]pentane-1,5-dioate (315 g, 0.977 mol) in dichloromethane (1000 ml) cooled in an ice bath and under nitrogen were added tert-butanol (123.1 g, 1.66 mol), 4-dimethylaminopyridine (1 g, 8.2 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (281 g, 1.47 mol). The reaction was allowed to stir overnight. Water was added to the reaction mixture and the dichloromethane layer was retained and dried, and the solvent was removed under reduced pressure. The resulting residue was purified by column chromatography and the desired product was eluted with 1:1 to 2:3 hexane/ethyl acetate. The fractions containing product were concentrated under reduced pressure leaving a clear oil (260 g, 70%). 1H NMR (CDCl3): δ1.4 (m, 27H), 1.8 (m, 1H), 1.9 (m, 2H), 2.1 (m, 1H), 2.3 (m, 2H), 2.7-2.8 (m, 1H), 6.7 & 8.0 (d, 1H, the P—H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7]([CH2:11][CH2:12][CH3:13])=[N:8]2)=[C:4]([CH3:14])[N:3]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[CH3:14][C:4]1[N:3]=[C:2]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:10]=[C:9]2[C:5]=1[NH:6][C:7]([CH2:11][CH2:12][CH3:13])=[N:8]2
Reactant: CCCc1nc2nc(Cl)nc(C)c2[nH]1
Reactant: C1COCCN1
Product: CCCc1nc2nc(N3CCOCC3)nc(C)c2[nH]1
Temperature: 122 °C

Procedure:
A solution of 2-Chloro-6-methyl-8-propylpurine (from Step 1 of Example 32) (0.1 g, 0.47 mmol) in morpholine (2 ml) was placed in a steel-bomb, and the mixture was heated at 122° C. for 18 hours. The reaction was cooled, and the mixture was concentrated in vacuo. The residue was dissolved in CHCl3 (2 ml) and was purified by flash-chromatography on silica-gel using 5% MeOH in CHCl3 giving the titled compound as an amorphous solid (0.1 g, 87%).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH:10]1([NH2:15])[CH2:14][CH2:13][CH2:12][CH2:11]1>>[CH:10]1([NH:15][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: NC1CCCC1
Reactant: N#Cc1ccccc1F
Product: N#Cc1ccccc1NC1CCCC1

Procedure:
According to a similar manner to that in Reference Example 12, the title compound was synthesized from 2-fluorobenzonitrile and cyclopentylamine.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([S:21][CH3:22])[C:10]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])=[C:6]2[N:5]=[C:4]([CH3:23])[CH:3]=1.[NH3:24]>CO>[CH3:23][C:4]1[CH:3]=[C:2]([NH2:24])[N:7]2[N:8]=[C:9]([S:21][CH3:22])[C:10]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])=[C:6]2[N:5]=1
Reactant: N
Reactant: CSc1nn2c(Cl)cc(C)nc2c1S(=O)(=O)c1ccc(C)cc1
Solvent: CO
Product: CSc1nn2c(N)cc(C)nc2c1S(=O)(=O)c1ccc(C)cc1

Procedure:
In an analogous manner to that described in Example 4, from 7-chloro-5-methyl-2-methylsulphanyl-3-(toluene-4-sulphonyl)-pyrazolo[1,5-a]pyrimidine and NH3 in MeOH there was obtained 5-methyl-2-methylsulphanyl-3-(toluene-4-sulphonyl)-pyrazolo[1,5-a]-pyrimidin-7-ylamine as colorless crystals, m.p. >230°.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[C:8](=O)[NH:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=2.C1(C)C=CC=CC=1.S(Cl)([Cl:31])=O>CN(C)C=O>[Cl:31][C:8]1[C:7]([N:3]2[CH2:4][CH2:5][CH2:6][C@@H:2]2[CH3:1])=[N:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=2)[N:9]=1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1ccc2[nH]c(=O)c(N3CCC[C@@H]3C)nc2c1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2nc(Cl)c(N3CCC[C@@H]3C)nc2c1

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of (S)-methyl 3-(2-methylpyrrolidin-1-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (900 mg, 3.14 mmol, 1.00 equiv), toluene (20 mL), thionyl chloride (11.2 g, 94.12 mmol, 30.00 equiv), N,N-dimethylformamide (4 mL). The resulting solution was heated to reflux for 3 hr in an oil bath. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:50). This resulted in 143 mg (13%) of (S)-methyl 2-chloro-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylate as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6]([NH:12][C:13]([O:15]C3C=CC=CC=3)=O)=[CH:7][CH:8]=2)[N:3]=1.[NH:22]1[CH2:27][CH2:26][CH:25]=[CH:24][CH2:23]1>O1CCCC1.C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]2[C:9]([CH:8]=[CH:7][C:6]([NH:12][C:13]([N:22]3[CH2:27][CH2:26][CH:25]=[CH:24][CH2:23]3)=[O:15])=[N:5]2)=[CH:10][CH:11]=1
Reactant: O=C(Nc1ccc2ccc(Cl)nc2n1)Oc1ccccc1
Reactant: C1=CCNCC1
Solvent: C1CCOC1
Solvent: CC#N
Product: O=C(Nc1ccc2ccc(Cl)nc2n1)N1CC=CCC1
Temperature: 4 °C
Yield: 72.7 %

Procedure:
To a solution of 2-chloro-7-phenoxycarbonylamino-1,8-naphthyridine (15 g) in anhydrous tetrahydrofuran (500 cc), anhydrous acetonitrile (500 cc) and 1,2,5,6-tetrahydropyridine (4.2 g) are added. The mixture is heated under reflux for 45 minutes. The solution is concentrated under reduced pressure (4 kPa) to a volume of 100 cc. After 2 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with acetonitrile (3×15 cc) and dried at 40° C. under reduced pressure (0.067 kPa). N-(7-Chloro-1,8-naphthyridin-2-yl)-1,2,5,6-tetrahydropyridine-1-carboxamide (10.5 g) is produced, m.p. 173° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[N:15]=[CH:14][NH:13][N:12]=1)([O-:3])=[O:2].[CH2:16]([N:18]([CH2:22][CH3:23])[C:19](Cl)=[O:20])[CH3:17].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH2:16]([N:18]([CH2:22][CH3:23])[C:19]([N:13]1[CH:14]=[N:15][C:11]([S:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])=[N:12]1)=[O:20])[CH3:17]
Reactant: CCN(CC)C(=O)Cl
Reactant: O=[N+]([O-])c1ccccc1Sc1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCN(CC)C(=O)n1cnc(Sc2ccccc2[N+](=O)[O-])n1

Procedure:
3-(2-Nitrophenylthio)-1,2,4-triazole (4 g) and diethyl carbamoyl chloride (2.71 g) are dissolved in acetone (50 ml) and potassium carbonate (5.5 g) is added, followed by reaction for 5 h under reflux with stirring. After cooling, water (100 ml) is added to the reaction solution, whereupon the crystal of the end product precipitates. After drying, the crystal is recrystallized from ethyl acetate/n-hexane to produce the titled compound, 1-(diethylcarbamoyl)-3-(2-nitrophenylthio)-1,2,4-triazole, in an amount of 5.08 g; yield, 87.8%; m.p. 101°-103° C.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[N+:9]([O-:11])=[O:10].[I-:12].[Na+]>CC(CC)=O>[I:12][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[N+:9]([O-:11])=[O:10]
Reactant: [I-]
Reactant: O=[N+]([O-])c1nccn1CCCl
Agent: [Na+]
Solvent: CCC(C)=O
Product: O=[N+]([O-])c1nccn1CCI
Yield: 82.9 %

Procedure:
163.4 g of 1-(2-chloroethyl)-2-nitroimidazole and 200.4 g of sodium iodide were heated under reflux for 4.5 hours in a 1 liter of ethyl methyl ketone. After cooling, the mixture was filtered, the solvent was evaporated off, the residue was partitioned between 2 liters of dichloromethane and 1 liter of water and the organic phase was washed twice with 1 liter of water each time and evaporated. Crystallization from 1 liter of of isopropanol yielded 206 g 1-(2-iodoethyl)-2-nitroimidazole, m.p. 79°-82° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH:18]1[CH:23]=[CH:22][C:21]([CH2:24]Br)=[CH:20][CH:19]=1>CN(C=O)C.CCOC(C)=O>[CH2:24]([O:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1)[C:21]1[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=1
Reactant: O=C1CCc2ccc(O)cc21
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1CCc2ccc(OCc3ccccc3)cc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 92 %

Procedure:
To a stirred solution of 6-hydroxy-2,3-dihydroinden-1-one (30 g, 0.203 mol) in 300 mL DMF was added K2CO3 (70 g, 0.507 mol), followed by addition of BnBr (38.2 g, 0.225 mol) dropwise at 0° C. The mixture was allowed to warm to ambient temperature and stirred for 20 h. The mixture was diluted with EtOAc (500 mL), then filtered to remove the solid. The filtrate was washed with brine (200 mL×5), dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulted solid was recrystallized in ether to give the title compound (44.5 g, 92%) as a white solid. 1H-NMR (600 MHz, CDCl3) δ 7.47-7.46 (m, 2H), 7.44-7.39 (m, 3H), 7.38-7.35 (m, 1H), 7.31-7.30 (m, 2H), 5.12 (s, 2H), 3.11-3.09 (m, 2H), 2.76-2.74 (m, 2H) ppm.