Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([I:13])=[C:7]2[C:3]=1[CH:4](O)[N:5](C(C)(C1C=CC=CC=1)C)[C:6]2=[O:14].FC(F)(F)C(O)=O.C([SiH](CC)CC)C.O>[N+](C)([O-])=O.CCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([I:13])=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:14]
Reactant: COc1cc(I)c2c(c1Cl)C(O)N(C(C)(C)c1ccccc1)C2=O
Agent: CC[SiH](CC)CC
Solvent: CCCCCC
Solvent: C[N+](=O)[O-]
Solvent: O
Product: COc1cc(I)c2c(c1Cl)CNC2=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 64.2 %

Procedure:
In a similar manner to Step 4 of Example 16, 4-chloro-5-methoxy-3-hydroxy-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (300 mg, 0.655 mmol) was dissolved in nitromethane (5 mL), and the solution was treated with trifluoroacetic acid (0.505 mL, 6.55 mmol) and triethylsilane (0.212 mL, 1.31 mmol), followed by stirring at room temperature for 24 hours. The reaction mixture was added with water, ethyl acetate and hexane. The precipitated solid was collected by filtration and washed with hexane and water, followed by drying under reduced pressure to obtain 4-chloro-5-methoxy-7-iodoisoindolinone (136 mg, yield 64%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9](O)=[N:8][C:6]=2[N:7]=1.ClCCl.S(Cl)(Cl)=O>CN(C)C=O>[CH2:4]([NH:3][C:9]1[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:11][C:5]2[CH:4]=[N:3][C:2]([NH2:1])=[N:7][C:6]=2[N:8]=1)[CH2:5][CH2:11][CH3:10]
Reactant: Nc1ncc2cc(-c3ccccc3)c(O)nc2n1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCCCNc1nc2nc(N)ncc2cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 44.4 %

Procedure:
To a mixture of 23.8 g of 2-amino-6-phenyl-pyrido-[2,3-d]pyrimidin-7-ol prepared above in Example 8, 250 mL of dichloromethane, and 77.5 mL of dimethylformamide was added dropwise with cooling 36 mL of thionyl chloride keeping the temperature below 15° C. Following complete addition, the suspension was heated to reflux with stirring for 5 hours. The solvents were removed in vacuo maintaining the temperature below 60° C. The resulting solid was added with cooling to 250 mL of n-butylamine and the suspension refluxed for 6 hours with stirring. The reaction mixture was allowed to cool to room temperature, filtered, and the volatile components of the filtrate removed on a rotary evaporator in vacuo. The viscous oil was partitioned between diethyl ether and water, the layers were separated, and the ethereal layer was washed with water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and evaporated. The residue was partitioned between diethyl ether and dilute 1N HCl. The aqueous layer was washed three times with diethylether and made alkaline to pH 12 by addition of sodium hydroxide. The solid product was collected by filtration and dried in vacuo to afford 6.5 g of the title compound N7 -butyl-6-phenyl-pyrido[2,3-d]pyrimidine-2,7-diamine, mp 174°-181° C. dec.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[F:12][C:13]([F:44])([F:43])[C:14]1[CH:15]=[C:16]([CH:40]=[CH:41][CH:42]=1)[CH2:17][NH:18][C:19](=[O:39])[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([C:26]2[CH:31]=[C:30]([N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[CH:29]=[CH:28][C:27]=2[NH2:38])[CH:21]=1.ClCC1C=C(C=CC=1)C(NC1C=CC(N2CCCCC2)=CC=1C1C=C(C=CN=1)C(NCC1C=CC=C(C(F)(F)F)C=1)=O)=O>>[Br:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:38][C:27]1[CH:28]=[CH:29][C:30]([N:32]2[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]2)=[CH:31][C:26]=1[C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][N:23]=1)[C:19]([NH:18][CH2:17][C:16]1[CH:40]=[CH:41][CH:42]=[C:14]([C:13]([F:44])([F:12])[F:43])[CH:15]=1)=[O:39])=[O:7]
Reactant: Nc1ccc(N2CCCCC2)cc1-c1cc(C(=O)NCc2cccc(C(F)(F)F)c2)ccn1
Reactant: O=C(Cl)c1cccc(CBr)c1
Agent: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(CCl)c2)c1
Product: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(CBr)c2)c1

Procedure:
This compound was prepared from 3-(bromomethyl)benzoyl chloride and Intermediate 4.1c using the procedure described for the synthesis of 2-(2-(3-(chloromethyl)benzamido)-5-(piperidin-1-yl)phenyl)-N-(3-(trifluoromethyl)benzyl)isonicotinamide 8.1a.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:26])[N:5]([CH2:12][CH:13]([C:20]1([CH3:25])OCC[O:21]1)[C:14]([O:16][CH2:17][CH:18]=[CH2:19])=[O:15])[C:6]2=[O:11].C1(C)C=CC(S(OS(C2C=CC(C)=CC=2)(=O)=O)(=O)=O)=CC=1>CC(C)=O.O>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:26])[N:5]([CH2:12][CH:13]([C:20](=[O:21])[CH3:25])[C:14]([O:16][CH2:17][CH:18]=[CH2:19])=[O:15])[C:6]2=[O:11]
Reactant: C=CCOC(=O)C(CN1C(=O)c2cccc(F)c2C1=O)C1(C)OCCO1
Agent: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: O
Solvent: CC(C)=O
Product: C=CCOC(=O)C(CN1C(=O)c2cccc(F)c2C1=O)C(C)=O
Temperature: 80 °C

Procedure:
Allyl 3-(4-fluoro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (331 mg, 0.91 mmol) was dissolved in a a solvent mixture of acetone/water (v/v=5/1), and catalyst amount of p-toluenesulfonic acid anhydride was added to the obtained solution. The resulting mixture was refluxed at 80° C. for 18 hours. After the reaction was completed, the reaction mixture was washed with water, and then acetone was removed by distilling under a reduced pressure. The residue was extracted with dichloromethane. The combined organic layer was dried with anhydrous sulfate and distilled under a reduced pressure. The desired product was obtained (131.2 mg, 31%) by performing column chromatography (eluent: n-hexane/ethyl acetate=2/1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[CH:10]([CH3:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][O:24][CH:25]([CH3:29])[C:26](Cl)=[O:27]>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[C:26](=[O:27])[CH:25]([O:24][CH3:23])[CH3:29])[CH:10]([CH3:22])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1CN(Cc2ccccc2)CCC1Nc1ccccc1F
Reactant: COC(C)C(=O)Cl
Solvent: C1CCOC1
Product: COC(C)C(=O)N(c1ccccc1F)C1CCN(Cc2ccccc2)CC1C
Yield: 77.6 %

Procedure:
Ten grams of 1-benzyl-3-methyl-4-(2-fluoroanilino)piperidine of Example XXIII and 4.57 g of 2-methoxypropionyl chloride are mixed in dry tetrahydrofuran. After two weeks the solid product is filtered from the mixture and converted with 10% NaOH to the free base; 10 g of 1-benzyl-3-methyl-4-[N-(2-fluorophenyl)-2-methoxypropionamido]piperidine is obtained (90% yield).
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([CH2:25][C:26]#[N:27])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28]I.[H-].[Na+]>C1COCC1>[C:1]([N:20]1[CH:24]=[C:23]([CH:25]([CH3:28])[C:26]#[N:27])[N:22]=[CH:21]1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C#N)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: -5 °C
Reaction time: 12 h

Procedure:
9.2 g (1-trityl-1H-imidazol-4-yl)-acetonitrile are dissolved in 120 mL THF, the solution is cooled to −5° C. and 1.8 mL methyl iodide and 1.08 g sodium hydride (60%) are added. The suspension is stirred for 12 h at RT and then applied directly to RP gel and purified by RP chromatography (C18, 10/90 to 90/10 acetonitrile/water in 15 min-0.2% formic acid is added to both solvents).
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[NH2:6][CH2:4][C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:2]=1[NH2:1]
Reactant: Cc1cccc(C(N)=O)c1N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(CN)c1N
Temperature: 0 °C
Yield: 3.1 %

Procedure:
Under an atmosphere of argon, a solution 2-amino-3-methylbenzamide (1.2 g, 80 mmol) in THF (25 ml) was added to a suspension of LiAlH4 (1.52 g, 40 mmol) in THF (25 ml) over 20 min. The suspension was heated to reflux (4 h). For workup, the mixture was cooled to 0° C., and 1.5 ml H2O, 3 ml 4n NaOH, and 3 ml H2O were added subsequently. The suspension was dried (Na2SO4), and evaporated under reduced pressure. The title compound (338 mg, 31%) was isolated from the residue by chromatographic purification (silica gel, CH2Cl2/MeOH (2M NH3)=9:1).
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=O)=[CH:5][CH:4]=1)#[CH:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:35][CH2:36][C:37]1[N:38]=[CH:39][N:40]([C:42]2[CH:47]=[CH:46][C:45]([N:48]3[CH:53]=[CH:52][CH:51]=[CH:50][C:49]3=[O:54])=[CH:44][CH:43]=2)[CH:41]=1>CN(C=O)C>[C:1]([C:3]1[S:7][C:6]([C:8]([NH:35][CH2:36][C:37]2[N:38]=[CH:39][N:40]([C:42]3[CH:43]=[CH:44][C:45]([N:48]4[CH:53]=[CH:52][CH:51]=[CH:50][C:49]4=[O:54])=[CH:46][CH:47]=3)[CH:41]=2)=[O:10])=[CH:5][CH:4]=1)#[CH:2]
Reactant: NCc1cn(-c2ccc(-n3ccccc3=O)cc2)cn1
Reactant: C#Cc1ccc(C(=O)O)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: C#Cc1ccc(C(=O)NCc2cn(-c3ccc(-n4ccccc4=O)cc3)cn2)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-ethynyl-thiophene-2-carboxylic acid (83 mg, 0.54 mmol) and TEA (0.15 mL, 1.1 mmol) in DMF (4 mL), HATU (228 mg, 0.60 mmol) was added. After being stirred at room temperature for 30 min, a solution of 1-(4-(4-(aminomethyl)-1H-imidazol-1-yl)phenyl)pyridin-2(1H)-one prepared above (145 mg, 0.54 mmol) and TEA (0.15 mL, 1.1 mmol) in DMF (8 mL) was added. The mixture was stirred at room temperature overnight. It was then purified by HPLC to give the title compound (65 mg). MS 401 (M+H).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12>>[C:14]1(=[O:24])[N:18]([CH2:2][C:3]([NH:5][CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:4])[C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C(CCl)NCCc1ccccc1
Product: O=C(CN1C(=O)c2ccccc2C1=O)NCCc1ccccc1

Procedure:
KR2002076486 describes a process for preparation of praziquantel by reacting phenylethylamine with chloroacetyl chloride to obtain 2-chloro-N-phenethylacetamide. The compound 2-chloro-N-phenethylacetamide is then reacted with pthalimide to give 2-pthalimido-N-phenethylacetamide, which is then treated with hydrazine monohydrate to give 2-amino-N-phenylethylacetamide. On further treatment with bromoacetal, 2-amino-N-phenylethylacetamide gives 2-[2,2-dimethoxyethyl)amino]-N-(2-phenylethyl)acetamide. This compound on further cyclization and acylation using cyclohexanoylchloride forms praziquantel.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.[Cl:14][C:15]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:16]=1[CH2:17][S:18][CH2:19][CH2:20][NH2:21]>>[Cl:14][C:15]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:16]=1[CH:17]=[SH:18][CH2:19][CH2:20][NH:21][C:11]([C:9]1[NH:8][C:5]2=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[CH:10]=1)=[O:13]
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Reactant: NCCSCc1c(F)cccc1Cl
Product: O=C(NCC[SH]=Cc1c(F)cccc1Cl)c1cc2cc(Cl)ncc2[nH]1

Procedure:
The title compound was prepared as outlined in EXAMPLE 1 from 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18) and 2-(2-chloro-6-fluorobenzylsulfanyl)ethylamine. The product was purified by mass directed purification to give the title compound as a yellow solid. δH (CD3OD): 2.82 (2H, t), 3.64 (2H, t), 3.95 (2H, s), 7.04–7.09 (2H, m), 7.20–7.25 (2H, m), 7.67 (1H, s), 8.58 (1H, s); m/z (ES+)=398 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.[N:16]1[N:17]=[C:18]([C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[C:28](O)[CH:29]=[C:30]([F:35])[CH:31]=3)[N:26]=2)[N:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=12>>[N:16]1[N:17]=[C:18]([C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[C:28]([O:1][CH2:2][C@H:3]4[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]4)[CH:29]=[C:30]([F:35])[CH:31]=3)[N:26]=2)[N:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=12
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](CO)C1
Reactant: Oc1cc(F)cc2ccc(-c3nnc4ccccn34)nc12
Product: Fc1cc(OC[C@H]2CCCNC2)c2nc(-c3nnc4ccccn34)ccc2c1

Procedure:
Prepared as described in Example 16 using (S)-tert-butyl 3-(hydroxymethyl)piperidine-1-carboxylate in place of tert-butyl 3-(hydroxymethyl)piperidine-1-carboxylate, and 2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-ol in place of 2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-quinolin-8-ol. MS ESI (+) m/z 378.2 (M+1) detected.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:18]2[CH:19]=[CH:20][N:21]=[CH:22][C:17]=2[C:16]2[C:11](=[CH:12][CH:13]=[N:14][C:15]=2[O:23]CCCC)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>Br>[CH2:1]([NH:8][C:9]1[C:18]2[CH:19]=[CH:20][N:21]=[CH:22][C:17]=2[C:16]2[C:15](=[O:23])[NH:14][CH:13]=[CH:12][C:11]=2[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCOc1nccc2nc(NCc3ccccc3)c3ccncc3c12
Agent: Br
Product: O=c1[nH]ccc2nc(NCc3ccccc3)c3ccncc3c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-benzyl-1-butoxypyrido[4,3-c]-1,6-naphthyridin-6-amine (90 mg, 0.251 mmol) was dissolved in hydrobromic acid (2.5 mL, 33% in acetic acid). The reaction mixture was left to stir overnight at room temperature. The reaction mixture was quenched with aqueous sodium hydrogen carbonate. The aqueous mixture was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC Reverse phase (C-18), eluting with Acetonitrile/Water+0.05% TFA, to afford 6-(benzylamino)pyrido[4,3-c]-1,6-naphthyridin-1(2H)-one as a red solid. 1H NMR (500 MHz, C2D6SO) δ 11.39 (d, 1H), 11.00 (s, 1H), 8.94 (t, 1H), 8.72 (d, 1H), 8.24 (d, 1H), 7.40 (t, 3H), 7.30 (t, 2H), 7.22 (t, 1H), 6.39 (d, 1H), 4.82 (d, 2H). LRMS (APCI) calc'd for (C18H15N4O) [M+H]+, 303.1; found 303.1.
Reaction SMILES: CC1(C)N(CCCCCCCCCS(CCCC(F)(F)C(F)(F)F)=[O:17])C(=O)N(C2C=CC([N+]([O-])=O)=C(C(F)(F)F)C=2)C1=O.[CH3:44][C:45]1([CH3:86])[N:49]([CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][S:60][CH2:61][CH2:62][CH2:63][C:64]([F:70])([F:69])[C:65]([F:68])([F:67])[F:66])[C:48](=[O:71])[N:47]([C:72]2[CH:77]=[CH:76][C:75]([N+:78]([O-:80])=[O:79])=[C:74]([C:81]([F:84])([F:83])[F:82])[CH:73]=2)[C:46]1=[O:85]>>[CH3:44][C:45]1([CH3:86])[N:49]([CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][S:60]([CH2:61][CH2:62][CH2:63][C:64]([F:69])([F:70])[C:65]([F:68])([F:67])[F:66])=[O:17])[C:48](=[O:71])[N:47]([C:72]2[CH:77]=[CH:76][C:75]([N+:78]([O-:80])=[O:79])=[C:74]([C:81]([F:83])([F:84])[F:82])[CH:73]=2)[C:46]1=[O:85]
Reactant: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCCCCCCSCCCC(F)(F)C(F)(F)F
Reactant: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F
Product: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F
Yield: 74 %

Procedure:
The experimental protocol used is the same as that described for the synthesis of the compound of Example 2, the compound of Example 8 replacing the compound of Example 1. The expected compound is obtained in the form of a pale yellow oil with a yield of 74% (71 mg).
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([S:38](Cl)(=[O:40])=[O:39])[CH:33]=1.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:38]([C:34]1[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=1)(=[O:40])=[O:39]
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1cccnc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. pyridin-3-sulfonyl chloride (12 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that the target compound was obtained.
Reaction SMILES: [NH:1]([C:3]1[CH2:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[N:4]=1)[NH2:2].[Cl:21][CH2:22][C:23](=O)[CH3:24]>>[Cl:21][CH2:22][C:23](=[N:2][NH:1][C:3]1[CH2:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[N:4]=1)[CH3:24]
Reactant: CC(=O)CCl
Reactant: NNC1=Nc2ccccc2C(c2ccccc2Cl)=NC1
Product: CC(CCl)=NNC1=Nc2ccccc2C(c2ccccc2Cl)=NC1

Procedure:
In the manner given in Example 1, 2-hydrazino-5-(o-chlorophenyl)-3H-1,4-benzodiazepine can be reacted with chloropropanone to give 2-[(2-chloro-1-methylethylidene)hydrazino]-5-(o-chlorophenyl)-3H-1,4-benzodiazepine.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([SiH2][O:24][C:25](C)(C)[C:26]1[CH:31]=[CH:30][C:29]([CH:32]([O:42][CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][O:44]2)[C:33]2[CH:34]=[CH:35][C:36]([F:41])=[C:37]([CH:40]=2)[C:38]#[N:39])=[CH:28][CH:27]=1)(C)(C)C>ClCCl>[F:41][C:36]1[CH:35]=[CH:34][C:33]([CH:32]([C:29]2[CH:28]=[CH:27][C:26]([CH2:25][OH:24])=[CH:31][CH:30]=2)[O:42][CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][O:44]2)=[CH:40][C:37]=1[C:38]#[N:39]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccc(C(OC2CCCCO2)c2ccc(F)c(C#N)c2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Product: N#Cc1cc(C(OC2CCCCO2)c2ccc(CO)cc2)ccc1F
Reaction time: 8 h
Yield: 98.5 %

Procedure:
Add tetrabutylammonium fluoride (1.0M in tetrahydrofuran, 5.27 mL, 5.27 mmol) to 5-[[4-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-2-fluoro-benzonitrile (1.20 g, 2.64 mmol) and stir the solution overnight. Dilute with dichloromethane and wash with water and brine. Dry the organic layer and concentrate the solution to afford the title compound (0.890 g, 2.60 mmol, 99%, mixture of diastereomers): 1H NMR (400 MHz, CDCl3) δ 1.55 (m, 2H), 1.68 (m, 2H), 1.74 (m, 2H), 3.46 (m, 1H), 3.77 (m, 1H), 4.60 (m, 1H), 4.67 (s, 2H), 5.78 (s, 1H), 7.10 (m, 1H), 7.27 (m, 4H), 7.55 (m, 1H), 7.64 (m, 1H).
Reaction SMILES: Cl[CH:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])=[CH:6][CH:5]=1)[CH3:3].[C-:15]#[N:16].[Na+]>>[CH2:10]([C:7]1[CH:8]=[CH:9][C:4]([CH:2]([CH3:3])[C:15]#[N:16])=[CH:5][CH:6]=1)[CH:11]=[C:12]([CH3:14])[CH3:13]
Reactant: CC(C)=CCc1ccc(C(C)Cl)cc1
Reactant: [C-]#N
Agent: [Na+]
Product: CC(C)=CCc1ccc(C(C)C#N)cc1
Temperature: 0 °C
Reaction time: 7 h
Yield: 81.8 %

Procedure:
A mixture of 21.0 g of 1-chloro-1-(p-prenylphenyl)ethane, 11.3 g of sodium cyanide and 140 ml of dimethylsufoxide was stirred at 60°-65° C. for 7 hours. After cooling, 400 g of ice-water was added and the resulting solution was extracted with n-hexane. The extract was washed with water, concentrated and distilled to give 16.4 g of 2-(p-prenylphenyl)propionitrile, b.p. 108-110 °C/0.28 mmHg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]1[C:26](=[O:27])[N:25]([O:28][CH3:29])[C:14]2[N:15]=[C:16]([NH:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])[N:17]=[CH:18][C:13]=2[CH:12]=1.Cl>CCO.[Fe]>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:11]2[C:26](=[O:27])[N:25]([O:28][CH3:29])[C:14]3[N:15]=[C:16]([NH:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])[N:17]=[CH:18][C:13]=3[CH:12]=2)[CH:4]=1
Reactant: COn1c(=O)c(-c2cc([N+](=O)[O-])ccc2Cl)cc2cnc(NCCN(C)C)nc21
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: COn1c(=O)c(-c2cc(N)ccc2Cl)cc2cnc(NCCN(C)C)nc21
Temperature: 80 °C
Reaction time: 6 h
Yield: 32 %

Procedure:
To an solution of 6-(2-chloro-5-nitrophenyl)-2-(2-(dimethylamino)ethylamino)-8-methoxypyrido[2,3-d]pyrimidin-7(8H)-one (73.2 mmol) in EtOH (700 mL) were added conc. aq. hydrochloric acid (170 mL) and iron powder (732 mmol), and the mixture was stirred at 80° C. for 6 h. The mixture was allowed to cool to room temperature and filtered through a pad of Celite. The filtrate was diluted with EtOAc (700 mL) and washed with sat. aq. NaHCO3 (700 mL). The aqueous layer was backextracted with EtOAc (8×300 mL). The organic layers were combined and washed with sat. aq. NaCl (1×700 mL). Drying of the organic layer over Na2SO4, followed by evaporation of the solvent gave crude product that was purified by column chromatography on silica gel (dichloromethane/triethylamine 95:5, followed by dichloromethane/MeOH/triethylamine 90:5:5). The collected fractions were dissolved in dichloromethane and washed with water to remove triethylamine salts. The aqueous layer was backextracted with dichloromethane, the organic layers were combined, dried over Na2SO4, filtered and evaporated to give 6-(5-amino-2-chlorophenyl)-2-(2-(dimethylamino)ethylamino)-8-methoxypyrido[2,3-d]pyrimidin-7(8H)-one as a solid (32%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])=[O:9].C([Li])CCC.I[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[OH-].[NH4+]>O1CCCC1.C(OCC)(=O)C.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:3]=1[S:8]([NH:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:9])=[O:10]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1Cl
Reactant: Ic1ccccc1
Agent: [Li]CCCC
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)NS(=O)(=O)c1c(Cl)cccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
A solution of 21.5 g (0.087 mol) 2-chloro-N-t-butylbenzenesulfonamide in anhydrous tetrahydrofuran was cooled to -30° under a nitrogen atmosphere while 121 ml of 1.6M n-butyllithium in hexanes was added over ten minutes. The mixture was then stirred for one hour at room temperature then recooled to below 0° and 16.6 g (0.087 mol) cuprous iodide (Alfa ultrapure grade) was added. After ten minutes at 0°, 10 ml (0.089 mol) iodobenzene was added and the mixture heated to reflux for 18 hours. The suspension was subsequently cooled to below 15° and 20 ml of acetic acid was added followed by 400 ml each of ethyl acetate and concentrated ammonium hydroxide. After stirring vigorously in air for 15 minutes the mixture was filtered, rinsed with water and ethyl acetate and the filtrate separated. The blue aqueous phase was extracted with 200 ml ethyl acetate and the combined organic phase washed successively with 200 ml concentrated ammonium hydroxide, water and brine, then dried and evaporated in vacuo. The solid residue was triturated with ether and collected by filtration to afford 23.5 g (84%) of the title compound, m.p. 168°-170°. An NMR spectrum (90 MHz) in CDCl3 had resonances at 1.10 (s, 9H), 5.08 (s, br, NH), 7.35-7.65 (m, ArH, 8H) ppm.