Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24][OH:25])[CH2:19]4)[C:14]([F:26])=[CH:13][N:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[O:37]=[C:38]=[N:39][C:40](Cl)=[O:41].C(Cl)Cl.C[O-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@H:20]([N:24]5[C:40](=[O:41])[NH:39][C:38](=[O:37])[O:25]5)[CH2:19]4)[C:14]([F:26])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C=NC(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@@H](NO)C4)n3)c3cc(Cl)cnc32)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=c1[nH]c(=O)n([C@@H]2CCC[C@H](Nc3nc(-c4c[nH]c5ncc(Cl)cc45)ncc3F)C2)o1
Reaction time: 2.25 h

Procedure:
To a solution of 2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-((1S,3R)-3-(hydroxyamino)cyclohexyl)pyrimidin-4-amine, 55b, (0.072 g, 0.136 mmol) in THF (2 mL) at 0° C. was added N-(oxomethylene)carbamoyl chloride (0.014 mL, 0.176 mmol). A white solid formed immediately. The slurry was shaken and sonicated to make an even suspension/slurry. Then, —CH2Cl2 (1 mL)) was added to help solvate the slurry. After 135 min, the mixture was treated with NaOMe (2 mL, 25% w/v). After 2 min, the mixture was quenched with saturated NH4Cl and acidified with 1M HCl. The mixture was extracted with EtOAc (3×) and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Preparative HPLC provided the desired product (25 mg).
Reaction SMILES: [NH:1]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[C@H:2]([C:11]([O:13]C(C)(C)C)=[O:12])[CH2:3][O:4][C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6].C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[NH:1]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][O:4][C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6]
Reactant: C=CCOC(=O)OC[C@H](NN1CCOCC1)C(=O)OC(C)(C)C
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: C=CCOC(=O)OC[C@H](NN1CCOCC1)C(=O)O

Procedure:
Morpholino-Ser(OAloc) was prepared from Ser(OtBu)-OtBu. Reaction of Ser(OtBu)-OtBu with 4-morpholinecarbonyl chloride in pyridine yielded morpholino-Ser(OtBu)-OtBu. Morpholino-Ser(OtBu)-OtBu was hydrolyzed with TFA to yield morpholino-Ser. Esterification of morpholino-Ser with isobutylene in the presence of a catalytic amount of H2SO4 afforded morpholino-Ser-OtBu. Reaction of morpholino-Ser-OtBu with allyl 1-benzotriazolyl carbonate yielded morpholino-Ser(OAloc)-OtBu. Morpholino-Ser(OAloc)-OtBu was hydrolyzed with TFA in CHCl3 (1:1) to yield morpholino-Ser(OAloc).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([O:19][CH3:20])([CH3:18])[CH3:17])[N:11]=1)(C(C)(C)C)(C)C>CC(O)=O.C1COCC1.O>[OH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([O:19][CH3:20])([CH3:17])[CH3:18])[N:11]=1
Reactant: COC(C)(C)c1cccc(CO[Si](C)(C)C(C)(C)C)n1
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(C)(C)c1cccc(CO)n1
Yield: 100.1 %

Procedure:
A solution of 2-tert-butyldimethylsilyloxymethyl-6-(1-methoxy-1-methylethyl)pyridine (1.20 g, 4.08 mmol) in AcOH (45 mL), THF (15 mL) and H2O (15 mL) was stirred for 48 h at room temperature. The solvent was removed in vacuo, the residue was partitioned between DCM and sat aq NaHCO3, the organic portion was separated, dried (MgSO4), filtered and evaporated to give the title compound (740 mg, 100%) as a colourless oil; NMR δH (400 MHz, CDCl3) 7.70-7.66 (1H, m), 7.48-7.45 (1H, m), 7.07-7.04 (1H, m), 4.74 (2H, d, J 5.0 Hz), 4.14 (1H, t, J 5.0 Hz), 3.18 (3H, s), 1.57 (6H, s).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].[C:19]1([CH3:27])[CH:24]=[CH:23][C:22]([C:25]#[CH:26])=[CH:21][CH:20]=1>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:26]#[C:25][C:22]2[CH:23]=[CH:24][C:19]([CH3:27])=[CH:20][CH:21]=2)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1ccc(C)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Product: Cc1ccc(C#Cc2ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c2)cc1
Yield: 89.7 %

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1) (728 mg, 2.0 mmol) and 4-tolylacetylene (349 mg, 3.0 mmol) according to the general procedure F. Obtained as a yellow solid (632 mg).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([NH:11]C(=O)OC(C)(C)C)[CH2:2]1.[ClH:19]>C(OCC)(=O)C.O1CCOCC1>[ClH:19].[ClH:19].[NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([NH2:11])[CH2:2]1
Reactant: CC(C)(C)OC(=O)NC1CNc2ccccc2C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: NC1CNc2ccccc2C1

Procedure:
To a stirred room temperature solution of tert-butyl 1,2,3,4-tetrahydroquinolin-3-ylcarbamate (1.0 g) in ethyl acetate (20 mL) was added 4 M HCl in dioxane (10 mL). After 6 hours the mixture was evaporated to dryness to obtain 1,2,3,4-tetrahydroquinolin-3-amine bis HCl salt as a cream colored solid (925 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=1.Br[CH2:23][CH:24]=[CH:25][C:26](Cl)=[O:27].[CH3:29][N:30]1CCC[C:31]1=O.CNC>O1CCCC1>[Br:21][C:17]1[CH:16]=[C:15]([NH:14][C:5]2[C:6]([C:12]#[N:13])=[CH:7][N:8]=[C:9]3[C:4]=2[CH:3]=[C:2]([NH:1][C:26](=[O:27])[CH:25]=[CH:24][CH2:23][N:30]([CH3:31])[CH3:29])[CH:11]=[N:10]3)[CH:20]=[CH:19][CH:18]=1
Reactant: CN1CCCC1=O
Reactant: O=C(Cl)C=CCBr
Reactant: N#Cc1cnc2ncc(N)cc2c1Nc1cccc(Br)c1
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)CC=CC(=O)Nc1cnc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Reaction time: 1 h

Procedure:
To a suspension of 2.5 g (7.35 mmol) of 6-amino-4-(3-bromo-phenylamino)-[1.8]naphthyridine-3-carbonitrile and 0.95 g (7.35 mmol) of disopropylethyl amine in 40 ml tetrahydrofuran at 0° C., with stirring, was added 1.42 g (7.72 mmol) of 4-bromo-2-butenoyl chloride followed by 5 ml of N-methyl pyrrolidone. After 1 hr, 55 ml of 2M dimethylamine in tetrahydrofuran was added. After 30 min, the solvents were removed. The mixture was mixed with ethyl acetate and saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate and the solvent was removed. The product was purified by chromatography on silica gel eluting first with ethyl acetate-methanol 9:1 to remove less polar impurities and then with acetate-methanol-triethyl amine 40:10:1 to elute 0.49 g of the product which was obtained as and orange powder: mass spectrum (electrospray, m/e): M+H 450.9,453.0; (M+2H)+2 226.7, 225.8.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14]([NH:16][C:17]1[C:22]([CH:23]([CH3:25])[CH3:24])=[CH:21][CH:20]=[CH:19][C:18]=1[CH:26]([CH3:28])[CH3:27])=[NH:15])([CH3:3])[CH3:2].[Cl:29][CH:30](Cl)[C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C(C)=CC=CC=1>[CH:23]([C:22]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:26]([CH3:28])[CH3:27])[C:17]=1[NH:16][C:14]([NH:13][C:5]1[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=[CH:7][C:6]=1[CH:10]([CH3:12])[CH3:11])=[N:15][CH2:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][Cl:29])=[CH:32][CH:33]=1)([CH3:25])[CH3:24]
Reactant: Cc1ccc(C(Cl)Cl)cc1
Reactant: CC(C)c1cccc(C(C)C)c1NC(=N)Nc1c(C(C)C)cccc1C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: CC(C)c1cccc(C(C)C)c1NC(=NCc1ccc(CCl)cc1)Nc1c(C(C)C)cccc1C(C)C
Yield: 40.5 %

Procedure:
11.4 g (0.03 mole) of N,N'-bis-(2,6-diisopropylphenyl) guanidine, 5.7 g (0.033 mole) of α,α-dichloro-p-xylene and 2.1 g (0.015 mole) of anhydrous potassium carbonate were added to 50 ml of xylene. The thus-formed mixture was then refluxed under heating for 10 hours. After the mixture had been allowed to cool, the insoluble substance was removed by filtration. The thus-obtained filtrate was washed with water and then concentrated for the purpose of recovering the solvent and unreacted raw materials to obtain a slightly yellow crystal. The crystal was then recrystallized from benzene to obtain 6.3 g of white powder.
Reaction SMILES: [N:1]1[C:10]2[C@H:9]([NH2:11])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:12][C:13]1[C:14]([CH:20]=O)=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:12][C:13]1[C:14]([CH2:20][NH:11][C@H:9]2[C:10]3[N:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH2:6][CH2:7][CH2:8]2)=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=1
Reactant: Cc1cnc(C=O)c(C)c1
Reactant: N[C@@H]1CCCc2cccnc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cnc(CN[C@@H]2CCCc3cccnc32)c(C)c1

Procedure:
Using General Procedure B: Reaction of (R)-5,6,7,8-tetrahydro-quinolin-8-ylamine in CH2Cl2 (4 ml) with 3,5-dimethyl-pyridine-2-carbaldehyde and NaBH(OAc)3 gave (R)-(3,5-dimethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine as a brown oil. 1H NMR (CDCl3) δ 1.78 (m, 1H), 2.03 (m, 1H), 2.10 (m, 1H), 2.26 (s+m, 4H), 2.33 (s, 3H), 2.81 (m, 2H), 3.96 (t, 1H, J=6.0 Hz), 4.02 (d, 1H, J=12.0 Hz), 4.17 (d, 1H, J=12.0 Hz), 5.41 (br s, 2H), 7.06 (dd, 1H, J=7.5, 3.0 Hz), 7.25 (s, 1H), 7.37 (d, 1H, J=9.0 Hz), 8.24 (s, 1H), 8.40 (d, 1H, J=3.0 Hz).
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:18]3[C@H:21]([S:22][CH2:23][C:24]=2[CH2:25][S:26][C:27]2[N:32]4[N:33]=[C:34]([C:36]([O:38]C(C5C=CC=CC=5)C5C=CC=CC=5)=[O:37])[N:35]=[C:31]4[N:30]=[C:29]([CH3:52])[CH:28]=2)[C@H:20]([NH:53][C:54](=[O:95])/[C:55](/[C:89]2[N:90]=[C:91]([NH2:94])[S:92][CH:93]=2)=[N:56]\[O:57][CH:58]([C:73]([O:75]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:74])[C:59]2[CH:64]=[CH:63][C:62]([O:65][C:66](=[O:68])[CH3:67])=[C:61]([O:69][C:70](=[O:72])[CH3:71])[CH:60]=2)[C:19]3=[O:96])=[O:16])C2C=CC=CC=2)C=CC=CC=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClC(Cl)C>[NH2:94][C:91]1[S:92][CH:93]=[C:89](/[C:55](=[N:56]/[O:57][CH:58]([C:73]([OH:75])=[O:74])[C:59]2[CH:64]=[CH:63][C:62]([O:65][C:66](=[O:68])[CH3:67])=[C:61]([O:69][C:70](=[O:72])[CH3:71])[CH:60]=2)/[C:54]([NH:53][C@@H:20]2[C:19](=[O:96])[N:18]3[C@@H:21]2[S:22][CH2:23][C:24]([CH2:25][S:26][C:27]2[N:32]4[N:33]=[C:34]([C:36]([OH:38])=[O:37])[N:35]=[C:31]4[N:30]=[C:29]([CH3:52])[CH:28]=2)=[C:17]3[C:15]([OH:16])=[O:14])=[O:95])[N:90]=1
Reactant: CC(=O)Oc1ccc(C(O/N=C(\C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CSc4cc(C)nc5nc(C(=O)OC(c6ccccc6)c6ccccc6)nn45)CS[C@H]23)c2csc(N)n2)C(=O)OC(c2ccccc2)c2ccccc2)cc1OC(C)=O
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(=O)Oc1ccc(C(O/N=C(\C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(CSc4cc(C)nc5nc(C(=O)O)nn45)CS[C@H]23)c2csc(N)n2)C(=O)O)cc1OC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 109.8 %

Procedure:
To a solution of the product obtained in Step 2 (0.87 g) in dichloroethane (1.6 ml) were added anisole (0.8 ml) and trifluoroacetic acid (2.4 ml) under ice cooling, and the resulting solution was stirred at room temperature for two hours. After removing the solvent by decantation, the residue was washed with dichloroethane and crystallized with ether, giving 0.6 g of the objective compound (as trifluoroacetic acid salt).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[OH:12].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][O:12][C:4]1[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]=1[C:2]([F:13])([F:14])[F:1])[CH3:21]
Reactant: O=[N+]([O-])c1ccc(O)c(C(F)(F)F)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)COc1ccc([N+](=O)[O-])cc1C(F)(F)F
Reaction time: 10 h
Yield: 94.2 %

Procedure:
A mixture of 2-trifluoromethyl-4-nitrophenol (73.4 g, 0.354 mol), ethyl bromoacetate (65.2 g, 0.39 mol), potassium carbonate (58.7 g, 0.425 mol) and 2-butanone (400 mL) was refluxed under stirring for 10 h. The solid was filtered off, the filtrate was evaporated and the residue was fractionated yielding 97.8 g (95%) of 2-trifluromethyl-4-nitrophenoxyacetic acid ethyl ester, b.p. 126° C./40 Pa.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([F:20])[C:18]=1O)[CH2:13][C:14]#[N:15].[C:21]([O-:24])([O-])=O.[K+].[K+]>>[CH2:1]([O:9][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([F:20])[C:18]=1[O:24][CH2:21][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:13][C:14]#[N:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: N#CCc1cc(O)c(O)c(F)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Product: N#CCc1cc(F)c(OCc2ccccc2)c(OCc2ccccc2)c1
Yield: 80 %

Procedure:
Benzyl chloride (0.54 mL), 4.5 mmol) was added to a solution of 3,4-dihydroxy-5-fluorobenzylcyanide 16 (330 mg, 2 mmol), K2CO3 (620 mg, 4.5 mmol) and KI (50 mg) in DMK (10 mL). The mixture was heated at reflux for 4 h, cooled and concentrated under reduced pressure. The residue was dissolved in H2O (10 mL), and EtOAc (10 mL). The organic layer was washed with brine (2×10 mL), H2O (2×10 mL), dried with anhydrous MgSO4 and concentrated under reduced pressure to an oil. The oil was purified by flash chromatography (20% EtOAc/hexanes) to give an oil which solidified on standing. The solid was crystallized from CH2Cl2 /hexanes to give 555 mg (80%) of 12 as white needles: mp 120°-121° C.; IR (KBr) 2400 cm-1 ; 1H NMR (CDCl3) δ 7.47-7.25 (m, 10H, ArH), 6.76-6.61 (m, 2H, ArH), 5.11 (s, 4H, ArCH2), 3.63 (s, 2H, ArCH2CN); analysis calc. for C22H18FNO2 ; C, H, N.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]3[CH:17]=[C:16]([O:18]C)[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][C:4]=1[I:20].B(Br)(Br)Br.O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]3[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][C:4]=1[I:20]
Reactant: CNc1ccc(-c2nc3ccc(OC)cc3s2)cc1I
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CNc1ccc(-c2nc3ccc(O)cc3s2)cc1I
Temperature: 25 °C
Reaction time: 18 h
Yield: 43.6 %

Procedure:
To a solution of 2-(4′-methylamino-3′-iodophenyl)-6-methoxy benzothiazole (12 mg, 0.03 mmol) dissolved in CH2Cl2 (4 mL) was added BBr3 (400 μl, 0.4 mmol, 1M in CH2Cl2) under N2. The reaction was allowed to stir at room temperature for 18 hr. Water was then added to quench the reaction and the solution was neutralized with NaHCO3, extracted with ethyl acetate (3×5 mL). The organic layers were combined, dried over MgSO4 and evaporated. The residue was purified with preparative TLC (Hexane:EA=7:3) to give 2-(4′-methylamino-3′-iodophenyl)-6-hydroxy benzothiazole (5 mg, 43%) as brown solid. 1HNMR (300 MHz, CDCl3) δ (ppm): 8.37 (d, H=2.0 Hz, 1H), 7.88 (dd, J1=2.0 Hz, J2=8.4 Hz, 1H), 7.83 (d, J=8.8 Hz, 1H), 7.28 (d, J=2.4 Hz, 1H), 6.96 (dd, J1=2.5 Hz, J2=8.8 Hz, 1H), 6.58 (d, J=8.5 Hz, 1H), 2.96 (s, 3H, CH3).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:22]C)[N:12]2[CH2:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[C:8]([NH2:24])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>>[NH2:24][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:22])[N:12]2[CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:18][CH2:17]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CC3CCNCC3)c2n1
Reactant: IC1CCCC1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CC3CCN(C4CCCC4)CC3)c2n1

Procedure:
Prepared similarly to Example 24 from 2-(butyloxy)-8-(methyloxy)-9-(4-piperidinylmethyl)-9H-purin-6-amine and iodocyclopentane.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:28]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][C:26]2[N:25]3[CH2:33][CH2:34][N:35]=[C:36]([CH:37]([CH3:39])[CH3:38])[C:24]3=[CH:23][C:22]=2[CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([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.[H][H]>[Pd].CO>[Si:1]([O:18][CH2:19][C:20]1[C:28]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][C:26]2[N:25]3[CH2:33][CH2:34][NH:35][CH:36]([CH:37]([CH3:39])[CH3:38])[C:24]3=[CH:23][C:22]=2[CH:21]=1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)C1=NCCn2c1cc1cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c(S(C)(=O)=O)cc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)C1NCCn2c1cc1cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c(S(C)(=O)=O)cc12

Procedure:
A solution of 8-(((tert-butyldiphenylsilyl)oxy)methyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indole (140 mg, 0.25 mmol), 10% palladium on charcoal (37 mg, 0.025 mmol), and methanol (5 mL) was stirred at rt under 1 atmosphere of hydrogen for 3 h. The mixture was filtered through Celite® and the Celite® was washed thoroughly with methanol. Combined solvent was removed under reduced pressure to afford 8-(((tert-butyldiphenylsilyl)oxy)methyl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydropyrazino[1,2-a]indole. It was used directly without further purification. A small portion of product was purified by chromatography for characterization. LC-MS m/z 561 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 8.00 (s, 1H), 7.73-7.70 (m, 5H), 7.47-7.40 (m, 6H), 6.36 (s, 1H), 5.20 (d, J=2.0 Hz, 2H), 4.24-4.19 (m, 1H), 4.11-4.00 (m, 2H), 3.52-3.47 (m, 1H), 3.20-3.13 (m, 1H), 3.03 (s, 3H), 2.47-2.39 (m, 1H), 1.18 (d, J=6.8 Hz, 3H), 1.09 (s, 9H), 0.96 (d, J=6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 143.06, 135.68, 134.04, 133.31, 131.52, 130.26, 129.79, 129.51, 127.77, 121.39, 111.22, 97.14, 63.76, 59.28, 45.00, 42.94, 42.47, 31.55, 26.94, 19.72, 19.31, 16.49.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH:16]=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]1([NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH2:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.CN(C=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][NH:24][C:19]2[C:18]([NH2:25])=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1N
Reactant: O=CCCC1CCN(Cc2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Nc1ccccc1NCCCC1CCN(Cc2ccccc2)CC1

Procedure:
The title compound was prepared from 300 mg 3-(1-benzyl-piperidin-4-yl)-propionaldehyde (from Step D), 300 mg of 1,2-phenylenediamine and 200 mg sodium triacetoxyborohydride in THF and DMF using a procedure analogous to that described in Example 1, Step J.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH2:8][CH:9]1[O:11][CH2:10]1)[CH:2]=[CH2:3].[NH2:16][CH2:17][CH2:18][C:19]1[NH:20][C:21]2[CH:27]=[C:26]([C:28]3[CH2:29][CH2:30][C:31](=[O:34])[NH:32][N:33]=3)[CH:25]=[CH:24][C:22]=2[N:23]=1>>[CH2:1]([O:4][C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH2:8][CH:9]([OH:11])[CH2:10][NH:16][CH2:17][CH2:18][C:19]1[NH:20][C:21]2[CH:27]=[C:26]([C:28]3[CH2:29][CH2:30][C:31](=[O:34])[NH:32][N:33]=3)[CH:25]=[CH:24][C:22]=2[N:23]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccccc1OCC1CO1
Reactant: NCCc1nc2ccc(C3=NNC(=O)CC3)cc2[nH]1
Product: C=CCOc1ccccc1OCC(O)CNCCc1nc2ccc(C3=NNC(=O)CC3)cc2[nH]1

Procedure:
Prepared analogously to Example 1 from 1-(2-allyloxy-phenoxy)-2,3-epoxypropane and 6-[2-(2-aminoethyl)benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:17]([O:21][C:22]([N:24]1[CH2:31][C@@H:30]2[C@@H:26]([CH2:27][NH:28][CH2:29]2)[CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>CN1CCCC1=O>[C:17]([O:21][C:22]([N:24]1[CH2:25][C@@H:26]2[C@@H:30]([CH2:29][N:28]([C:2]3[NH:3][C:4]4[CH:10]=[C:9]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)[CH:8]=[CH:7][C:5]=4[N:6]=3)[CH2:27]2)[CH2:31]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CNC[C@H]2C1
Reactant: Clc1nc2ccc(-c3ccccc3)cc2[nH]1
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3nc4ccc(-c5ccccc5)cc4[nH]3)C[C@@H]2C1
Temperature: 150 °C
Reaction time: 4 h
Yield: 48.2 %

Procedure:
2-Chloro-5-phenylbenzimidazole (34 mg) was added to the N-methylpyrrolidone solution (0.2 mL) containing 3-tert-butoxycarbonyl-cis-3,7-diazabicyclo[3.3.0]octane (62 mg), followed by stirring at 150° C. for 4 hrs. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was separated and purified on a silica-gel column chromatograph (C-300, chloroform:THF=4:1) to give the title compound (29 mg).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH2:4][CH2:5][N:6]=1.Br[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:15])=[N:13][CH:14]=1>C(#N)C>[Cl:15][C:12]1[N:13]=[CH:14][C:9]([CH2:8][N:6]2[CH2:5][CH2:4][S:3][C:2]2=[NH:1])=[CH:10][CH:11]=1.[Cl:15][C:12]1[N:13]=[CH:14][C:9]([CH2:8][N:6]2[CH2:5][CH2:4][S:3][C:2]2=[N:1][CH2:8][C:9]2[CH:14]=[N:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:10][CH:11]=1
Reactant: NC1=NCCS1
Reactant: Clc1ccc(CBr)cn1
Solvent: CC#N
Product: Clc1ccc(CN=C2SCCN2Cc2ccc(Cl)nc2)cn1
Product: N=C1SCCN1Cc1ccc(Cl)nc1
Temperature: 90 °C
Yield: 7.4 %
Yield: 54.7 %

Procedure:
A mixture of 511 mg (5 mmol) of 2-amino-2-thiazoline and 1.03 g (5 mmol) of 5-bromomethyl-2-chloropyridine in 50 ml of acetonitrile was heated for 6 hours at 90° C. under refluxing. Then, the reaction mixture was cooled to the room temperature, and the solvent was removed under reduced pressure. The resulting residue was mixed with dichloromethane and saturated sodium hydrogen-carbonate aqueous solution, and the organic layer was separated. The water layer was extracted with dichloromethane, and combined organic layer was dried over magnesium sulfate. The solvent was removed under reduced pressure and the resulting residue was purified by aminopropyl-coated silica gel (Chromatorex NH-type; Fuji Silysia Chemical Ltd.) column chromatography (eluent; hexane:ethyl acetate=2:1) to give 623 mg (yield; 54.7%) of 3-(6-chloro-3-pyridyl)methyl-2-iminothiazolidine as yellow oil and 173 mg (yield; 7.4%) of 3-(6-chloro-3-pyridyl)methyl-2-[(6-chloro-3-pyridyl)methyl]iminothiazolidine as yellow oil.
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)([O:3][CH3:4])=[O:2].[OH:30][CH2:31][CH:32]([CH2:34]O)[OH:33].B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([O:27][CH2:34][CH:32]([OH:33])[CH2:31][OH:30])=[O:26])=[CH:28][CH:29]=1)([O:3][CH3:4])=[O:2]
Reactant: OCC(O)CO
Reactant: COC(=O)CCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Agent: FB(F)F
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COC(=O)CCCCCCCCCCCCCCCNc1ccc(C(=O)OCC(O)CO)cc1
Reaction time: 120 h

Procedure:
A solution of 11.8 g. of 4-(15-carbomethoxypentadecylamino)benzoic acid, 1.00 g. of glycerol, and 5.35 ml. of boron trifluoride etherate in 200 ml. of toluene is stirred under reflux for 4 hours. The solution is treated with an additional 5.35 ml. of boron trifluoride etherate and refluxing is continued for 120 hours. Dilution with water and methylene chloride followed by filtration affords 2,3-dihydroxypropyl 4-(15-carbomethoxypentadecylamino)benzoate as a white solid.