Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH:5]=[CH:6][C:7](Cl)=[O:8].[CH2:13]([NH2:17])[CH:14]([CH3:16])[CH3:15]>C1(C)C=CC=CC=1.C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)/[CH:5]=[CH:6]/[C:7]([NH:17][CH2:13][CH:14]([CH3:16])[CH3:15])=[O:8]
Reactant: O=C(Cl)C=Cc1cccc(Cl)c1
Reactant: CC(C)CN
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: CC(C)CNC(=O)/C=C/c1cccc(Cl)c1
Reaction time: 24 h

Procedure:
A solution of 3-chlorocinnamoyl chloride (4g) in dry toluene (75 ml) was added with stirring to a solution of isobutylamine (12 ml) in dry benzene (200 ml). The reaction mixture was allowed to stand for 24 hours. The solvent was evaporated under reduced pressure and the residue thoroughly triturated with water, washed with dilute hydrochloric acid and then with water. The resulting crude product was recrystallized from ethanol-water (1:10) to give trans 3-chloro-N-isobutylcinnamamide (3.9 g), m.p. 111.5°-112.5° C. Elemental analysis, nmr and ir data were all consistent with the assigned structure. TLC gave one spot run on silica gel with 5:1 and 3:1 hexane:ethanol.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.F[C:17]1[C:18]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[C:19]([CH3:34])[C:20]([C:32]#[N:33])=[C:21]2[C:25]=1[O:24][C:23]([CH2:26][C:27]1[O:28][CH:29]=[CH:30][CH:31]=1)=[N:22]2>CS(C)=O>[CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][N:5]([C:17]2[C:18]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[C:19]([CH3:34])[C:20]([C:32]#[N:33])=[C:21]3[C:25]=2[O:24][C:23]([CH2:26][C:27]2[O:28][CH:29]=[CH:30][CH:31]=2)=[N:22]3)[CH2:4]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cc3ccco3)nc2c1C#N
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(Cc3ccco3)nc2c1C#N
Temperature: 95 °C
Reaction time: 1 h
Yield: 13.7 %

Procedure:
(3S)-3-(Dimethylamino)pyrrolidine (88 μl, 0.695 mmol) and triethylamine (97 μl, 0.695 mmol) were added to a dimethyl sulfoxide (4 ml) solution of 7-fluoro-2-(2-furylmethyl)-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-271) (154 mg, 0.463 mmol), followed by stirring in an oil bath at 95° C. for 1 hour. The reaction liquid was concentrated under reduced pressure, then the residue was dissolved in ethyl acetate, and washed with water and saturated brine. After drying over anhydrous sodium sulfate, the insoluble matter was separated by filtration, and the residue obtained by concentration was purified by silica gel column chromatography and preparative TLC (eluent, chloroform:methanol=20:1, v/v) to obtain the entitled compound (27 mg, 14%) as a pale brown foamy substance.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1S(C)(=O)=O.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1>O>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:3]2[N:2]([CH3:1])[C:6]3=[N:7][CH:8]=[CH:9][CH:10]=[C:5]3[N:4]=2)=[CH:18][CH:17]=1
Reactant: Oc1ccc(Br)cc1
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Solvent: O
Product: Cn1c(Oc2ccc(Br)cc2)nc2cccnc21
Temperature: 120 °C
Reaction time: 3 h
Yield: 59 %

Procedure:
A mixture of 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (2.0 g), 4-bromophenol (4.9 g) and TEA (4.0 ml) was stirred at 120° C. for 3 h. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with 1 M NaOH aqueous solution, dried over Na2SO4, filtered and concentrated under reduced pressure. The residual crystals were recrystallized from AcOEt to give the title compound (1.7 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C([Sn](CCCC)(CCCC)[C:17]1[O:18][CH:19]=[CH:20][CH:21]=1)CCC>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: Clc1nc(Cl)c2sccc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: Clc1nc(-c2ccco2)c2sccc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.5 %

Procedure:
A solution of 2,4-dichlorothieno[3,2-d]pyrimidine (205 mg, 1 mmol) in DMF (4 mL) was treated with PdCl2(PPh3)2 (35 mg, 0.05 mmol) and 2-(tributylstannyl)-furan (315 μL, 1 mmol), stirred at room temperature for 16 h, the reaction mixture purified directly by chromatography (SiO2:EtOAc:Heptane, 1:9) and the resulting cream solid recrystallised (EtOAc/Heptane) to give the title compound (122 mg, 52%) as a cream solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[NH:16][CH:10]([CH2:11][O:12][CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:26][O:27][C:28]([C:30]1[C@H:31]([C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:44]=2[Cl:50])[N:32]=[C:33]([C:38]2[S:39][CH:40]=[CH:41][N:42]=2)[NH:34][C:35]=1[CH2:36]Br)=[O:29]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]2[N:16]([CH2:36][C:35]3[NH:34][C:33]([C:38]4[S:39][CH:40]=[CH:41][N:42]=4)=[N:32][C@@H:31]([C:43]4[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:44]=4[Cl:50])[C:30]=3[C:28]([O:27][CH3:26])=[O:29])[CH:14]([CH2:13][O:12][CH2:11]2)[CH2:15]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CC2COCC(C1)N2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1=C(CN2C3COCC2CN(C(=O)OC(C)(C)C)C3)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.6 %

Procedure:
To a mixture of 3-oxa-7,9-diaza-bicyclo[3.3.1]nonane-7-carboxylic acid tert-butyl ester (171 mg, 0.75 mmol) and DIPEA (0.45 mL, 2.5 mmol) in CH2Cl2 (10 mL) was added (R)-6-bromomethyl-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester (222 mg, 0.5 mmol). The mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo. The residue was purified by flash column chromatography to afford 9-[(R)-6-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-3-oxa-7,9-diaza-bicyclo[3.3.1]nonane-7-carboxylic acid tert-butyl ester as yellow oil (0.28 g, 94%). MS: calc'd (MH+) 592, measured (MH+) 592.
Reaction SMILES: [C:1]([C:4]1[CH:41]=[CH:40][C:7]([CH2:8][O:9][C:10]([NH:12][C:13]2[C:14](=[O:39])[N:15]([CH2:25][C:26]([NH:28][CH:29]([CH:36]([CH3:38])[CH3:37])[C:30](=[O:35])[C:31]([F:34])([F:33])[F:32])=[O:27])[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:17][CH:18]=2)=[O:11])=[CH:6][CH:5]=1)(O)=[O:2].Cl.CN(C)CCCN=C=NCC.[CH3:54][S:55]([NH2:58])(=[O:57])=[O:56]>CN(C)C1C=CN=CC=1.ClCCl.C(OCC)(=O)C>[CH3:54][S:55]([NH:58][C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([NH:12][C:13]2[C:14](=[O:39])[N:15]([CH2:25][C:26]([NH:28][CH:29]([CH:36]([CH3:37])[CH3:38])[C:30](=[O:35])[C:31]([F:33])([F:34])[F:32])=[O:27])[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:17][CH:18]=2)=[O:11])=[CH:40][CH:41]=1)=[O:2])(=[O:57])=[O:56]
Reactant: CS(N)(=O)=O
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(NC(=O)OCc2ccc(C(=O)O)cc2)c1=O)C(=O)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(NC(=O)OCc2ccc(C(=O)NS(C)(=O)=O)cc2)c1=O)C(=O)C(F)(F)F
Reaction time: 120 h

Procedure:
To a solution of 2-[3-(4-carboxybenzyloxycarbonylamino)-2-oxo-6-phenyl-1,2-dihydro-1-pyridyl]-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide (0.387 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.43 g) and 4-dimethylaminopyridine (0.27 g) in dry dichloromethane was added methanesulfonamide; and the reaction mixture was stirred for 5 days. The mixture was diluted with ethyl acetate, washed (three times with 10% aqueous hydrochloric acid, then brine), dried and evaporated before purification by chromatography, eluting with dichloromethane:ethyl acetate:methanol:acetic acid (50:48.9:1.0:0.1), to give the title compound; TLC: Rf =0.38, dichloromethane:ethyl acetate:methanol:acetic acid (50:48.9:1.0:0.1); HPLC: tR =5.38, FR=2, column A, water:acetonitrile (7:3); MS: m/z=651(M+1).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:13][C@@H:12]([CH3:14])[CH2:11][N:10]([C:15](=[O:17])[CH3:16])[CH2:9]1)(C)(C)C.[ClH:19].O1CCOCC1>C(Cl)Cl>[ClH:19].[NH2:7][C@@H:8]1[CH2:13][C@@H:12]([CH3:14])[CH2:11][N:10]([C:15](=[O:17])[CH3:16])[CH2:9]1
Reactant: CC(=O)N1C[C@H](C)C[C@@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=O)N1C[C@H](C)C[C@@H](N)C1
Temperature: 25 °C
Yield: 95 %

Procedure:
((3R,5R)-1-Acetyl-5-methyl-piperidin-3-yl)-carbamic acid tert-butyl ester (0.5 g, 1.971 mmol) was dissolved in DCM (15) and HCl 4M in dioxane (2.5 mL, 10 mmol) was added. The resulting colorless solution was stirred at RT until precipitation of a solid was observed. The solvent was evaporated and the residue was dried under high vacuum to give 0.45 g of 1-((3R,5R)-3-amino-5-methyl-piperidin-1-yl)-ethanone hydrochloride as an off-white solid (>95% yield).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11]2[CH2:16][CH2:15][CH:14]([CH:17]3[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24][CH2:25]O)[CH2:19][CH2:18]3)[CH2:13][CH2:12]2)=[CH:5][CH:4]=1.C(N(S(F)(F)[F:35])CC)C>C(COC)OC>[F:35][CH2:25][CH2:24][CH2:23][CH:20]1[CH2:21][CH2:22][CH:17]([CH:14]2[CH2:15][CH2:16][CH:11]([CH2:10][CH2:9][C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:28])([F:27])[F:1])=[CH:4][CH:5]=3)[CH2:12][CH2:13]2)[CH2:18][CH2:19]1
Reactant: OCCCC1CCC(C2CCC(CCc3ccc(C(F)(F)F)cc3)CC2)CC1
Reactant: CCN(CC)S(F)(F)F
Solvent: COCCOC
Product: FCCCC1CCC(C2CCC(CCc3ccc(C(F)(F)F)cc3)CC2)CC1
Yield: 49.5 %

Procedure:
Dimethoxyethane (10 ml) was added to the above 3-(4-(4-(2-(4-trifluoromethylphenyl)ethyl)cyclohexyl)cyclohexyl)propanol (1.20 g, 3.03 mmol), followed by dropwise adding thereto diethylaminosulfur trifluoride (DAST) (1.13 g, 7.01 mmol), refluxing the mixture for 5 hours, extracting the resulting product with toluene, washing the organic layer successively with a saturated, aqueous solution of sodium bicarbonate and water, drying over magnesium sulfate, distilling off the solvent, purifying the residue according to column chromatography treatment using heptane as a developing solvent, on silica gel, distilling off the solvent, and recrystallizing the residue from ethanol/heptane (9/1), to isolate only trans-form of 1-(2-(4-(4-(3-fluoropropyl)cyclohexyl)cyclohexyl)ethyl)-4-trifluoromethylbenzene (0.60 g, 1.5 mmol). Yield: 49.5%. SB -I point: 118.9° C.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([N:15]2[C:19]([C:20]3[S:21][C:22]4[CH2:23][CH2:24][O:25][C:26]5[CH:33]=[C:32]([C:34]6[CH:35]=[N:36][N:37]([CH2:39][C:40]([CH3:43])([OH:42])[CH3:41])[CH:38]=6)[CH:31]=[CH:30][C:27]=5[C:28]=4[N:29]=3)=[N:18][CH:17]=[N:16]2)[CH2:11][CH2:10]1)(C)(C)C.CO.Cl>>[OH:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([N:15]2[C:19]([C:20]3[S:21][C:22]4[CH2:23][CH2:24][O:25][C:26]5[CH:33]=[C:32]([C:34]6[CH:35]=[N:36][N:37]([CH2:39][C:40]([CH3:43])([OH:42])[CH3:41])[CH:38]=6)[CH:31]=[CH:30][C:27]=5[C:28]=4[N:29]=3)=[N:18][CH:17]=[N:16]2)[CH2:11][CH2:10]1
Reactant: CC(C)(O)Cn1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4C4CCN(CCO[Si](C)(C)C(C)(C)C)CC4)nc2-3)cn1
Agent: Cl
Solvent: CO
Product: CC(C)(O)Cn1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4C4CCN(CCO)CC4)nc2-3)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.1 %

Procedure:
To a solution of 1-{4-[2-(2-{1-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-piperidin-4-yl}-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-2-methyl-propan-2-ol (0.150 g, 0.000231 mol) in methanol (2.0 mL, 0.049 mol) was added hydrogen chloride (4N in dioxane, 1 mL, 0.00025 mol). The reaction was stirred at room temperature overnight. The solvent was removed in vacuo and the crude was purified by reverse-phase HPLC to give 462 (31.1 mg) as a white solid. MS(ESI+) 536.2
Reaction SMILES: [OH:1][CH:2]([CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.[OH-].[K+].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1.C(OCC)(=O)C>CS(C)=O>[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][O:1][CH:2]([CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:3][N:4]2[CH:8]=[CH:7][N:6]=[CH:5]2)=[CH:22][CH:21]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CCCCCOCC(O)Cn1ccnc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCCOCC(Cn1ccnc1)OCc1ccc(OC)cc1
Reaction time: 0.5 h

Procedure:
1-[2-Hydroxy-3-(pentoxy)propyl]-1H-imidazole (Example 29b; 2.12 g, 0.01 mol) was added to a stirred suspension of powdered potassium hydroxide (2.24 g, 0.040 mol) in dimethylsulphoxide (10 ml) at 18° C. and stirred for 0.5 hours. 4-Methoxybenzyl chloride was then added and stirring was continued for 2 hours. Ethyl acetate (350 ml) was added and the solution was washed with water and dried (MgSO4). Ths solvent was evaporated off under reduced pressure and the crude product was purified by column chromatography (silica gel, chloroform) to give 1-[2-[(4-methoxyphenyl)methoxy]-3-(pentoxy)propyl]-1H-imidazole as a pale-yellow oil.
Reaction SMILES: [CH2:1]([N:6]1[CH:10]=[CH:9][N:8]=[N:7]1)[CH2:2][CH2:3][C:4]#[CH:5].[N:11]([CH2:14][C:15]([CH3:23])=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[N+:12]=[N-:13]>>[CH3:23][C:15](=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:14][N:11]1[CH:5]=[C:4]([CH2:3][CH2:2][CH2:1][N:6]2[CH:10]=[CH:9][N:8]=[N:7]2)[N:13]=[N:12]1
Reactant: C#CCCCn1ccnn1
Reactant: CC(=Cc1ccccc1)CN=[N+]=[N-]
Product: CC(=Cc1ccccc1)Cn1cc(CCCn2ccnn2)nn1
Yield: 99.6 %

Procedure:
1-Pent-4-ynyl-1H-[1,2,3]triazole (0.100 g, 0.739 mmol) was reacted with (3-Azido-2-methylpropenyl)-benzene (0.154 g, 0.889 mmol) following the general procedure for click reactions outlined above to produce 1-(2-Methyl-3-phenyl-allyl)-4-(3-[1,2,3]triazol-1-yl-propyl)-1H-[1,2,3]triazole (0.227 g, Quantitative) as a white solid. 1H NMR (300 MHz, DMSO) δ 7.91 (s, 1H), δ 7.77 (s, 2H), δ 7.40-7.25 (m, 5H), δ 6.47 (s, 1H), δ 5.05 (s, 2H), δ 4.48 (t, 2H), δ 2.62 (t, 2H), δ 2.50 (t, 2H), δ 2.21 (m, 2H), δ 1.74 (s, 3H) ppm; 13C (75 MHz, DMSO) δ 146.4, 137.1, 134.8, 133.6, 132.8, 129.4, 129.3, 129.2, 128.9, 127.6, 123.0, 57.9, 54.0, 32.9, 29.6, 22.7, 16.2 ppm; HRMS (ESI) calcd for C17H21N6 (M+) 309.1822. found 309.1821.
Reaction SMILES: [Na].[CH:2]1([N:7]2[C:11]([NH2:12])=[C:10]([C:13]([NH2:15])=[O:14])[C:9]([CH2:16][CH3:17])=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[NH:18]1[C:22]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][C:32](OC)=O)=[CH:27][CH:26]=2)=[N:21][N:20]=[N:19]1>C(O)C>[CH:2]1([N:7]2[C:11]3=[N:12][C:32]([CH2:31][C:28]4[CH:27]=[CH:26][C:25]([O:24][CH2:23][C:22]5[NH:18][N:19]=[N:20][N:21]=5)=[CH:30][CH:29]=4)=[N:15][C:13](=[O:14])[C:10]3=[C:9]([CH2:16][CH3:17])[NH:8]2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Reactant: COC(=O)Cc1ccc(OCc2nnn[nH]2)cc1
Agent: [Na]
Solvent: CCO
Product: CCc1[nH]n(C2CCCC2)c2nc(Cc3ccc(OCc4nnn[nH]4)cc3)nc(=O)c1-2
Yield: 13.5 %

Procedure:
Sodium (0.253 g) was dissolved in ethanol (15 ml) and then 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (0.813 g, 3.7 mmol) and methyl 4-(5-tetrazolylmethoxy)phenylacetate (17 g, 7.3 mmol) were added. The reaction mixture was refluxed for about 2 days, cooled, and then the solvent was removed in vacuo. The residue was treated with water and acetic acid and the precipitate which formed was collected by filtration and dried at 60° C. under vacuum. The product was then dissolved in ethyl acetate, extracted with Na2CO3 (4×200 ml) and the aqueous layer was acidified to pH 2.5 with concentrated HCl. The aqueous layer was then extracted with ethyl acetate (2×300 ml) and the organic layer was dried over MgSO4, filtered and concentrated in vacuo. The solid residue was recrystallized from ethyl acetate to afford 0.21 g of 1-cyclopentyl-3-ethyl-6-[4-(5-tetrazolylmethoxy)phenylmethyl]pyrazolo[3,4-d]pyrimidin-4-one.2/5 hydrate, m.p. 240°-242° C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[C:7]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:8]=2[S:9][CH:10]=1.C(OC(=O)C)(=O)C>C(O)(=O)C>[Br:5][C:6]1[C:7]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:8]=2[S:9][C:10]=1[N+:1]([O-:4])=[O:2]
Reactant: Fc1ccc2scc(Br)c2c1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])c1sc2ccc(F)cc2c1Br
Yield: 26 %

Procedure:
A solution of 5.12 ml of fuming nitric acid and 4.5 ml of acetic acid was added dropwise, with stirring, to a cooled (5°-10° C.) mixture of 3-bromo-5-fluorobenzo[b]thiophene (5.35 g, 23.15 mmol) and 28.5 ml of acetic anhydride. The reaction mixture was stirred for 2 hours and poured onto ice water (350 ml) and extracted with CH2Cl2 (4×50 ml). The organic phases were combined, washed with water and dried over MgSO4. The solvent was evaporated and the residue was recrystallized from 90% ethanol to yield 1.7 g (26%) of 3-bromo-5-fluoro-2-nitrobenzo[b]thiophene. M.p. 129°-130° C. 1H-NMR(CDCl3): δ7.40 (ddd, 1H), 7.68 (ddd, 1H), 7.78 (dd, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C@@H:7]([CH2:13][NH:14][CH3:15])[CH2:6]2.[CH3:16][O:17][C:18]1[C:33]([O:34][CH3:35])=[CH:32][C:21]2[CH2:22][C:23](=[O:31])[N:24]([CH2:27][CH2:28][CH:29]=O)[CH2:25][CH2:26][C:20]=2[CH:19]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C@@H:7]([CH2:13][N:14]([CH3:15])[CH2:29][CH2:28][CH2:27][N:24]1[C:23](=[O:31])[CH2:22][C:21]3[CH:32]=[C:33]([O:34][CH3:35])[C:18]([O:17][CH3:16])=[CH:19][C:20]=3[CH2:26][CH2:25]1)[CH2:6]2
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCC=O)CC2
Reactant: CNC[C@H]1Cc2cc(OC)c(OC)cc21
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)C[C@H]1Cc3cc(OC)c(OC)cc31)CC2
Temperature: 85 °C
Reaction time: 1 h

Procedure:
1 mmol of [(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methylmethanamine and 1 mmol of 3-(7,8-dimethoxy-2-oxo-1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl)propanal are introduced into a clean and dry stainless-steel autoclave under an argon atmosphere. The mixture is degassed by three vacuum/argon cycles and 3 mL of distilled and degassed ethanol are added. The solution is stirred at 85° C. for one hour. The iron complex (5 mol %) is added under argon. The autoclave is then placed under hydrogen pressure (5 bars) and the reaction mixture is stirred at 85° C. for 16 hours and then the autoclave is returned to ambient temperature and decompressed.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:26][CH:27]1[CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28]1>C(#N)C>[CH2:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:35][CH:27]1[NH:26][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:7]=1
Reactant: BrCCCOc1cccc(-c2noc3ccsc23)c1
Reactant: NC1Cc2ccccc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1cc(OCCCNC2Cc3ccccc3C2)cc(-c2noc3ccsc23)c1

Procedure:
The title compound is prepared from 3-[3-(3-bromo-propoxy)-phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, 2-aminoindan, and acetonitrile essentially as described above in example 48. Purity by LC/MS (APCI)=99%, [M+H]+=391.
Reaction SMILES: [BH4-].[Na+].O.[C:4]([O:8][C:9]([N:11]1[CH2:15][CH:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:13][CH:12]1[CH:24]=[CH:25][N+:26]([O-:28])=[O:27])=[O:10])([CH3:7])([CH3:6])[CH3:5]>C1COCC1>[C:4]([O:8][C:9]([N:11]1[CH2:15][CH:14]([O:16][Si:17]([C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:19])[CH3:18])[CH2:13][CH:12]1[CH2:24][CH2:25][N+:26]([O-:28])=[O:27])=[O:10])([CH3:7])([CH3:5])[CH3:6]
Reactant: CC(C)(C)OC(=O)N1CC(O[Si](C)(C)C(C)(C)C)CC1C=C[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(O[Si](C)(C)C(C)(C)C)CC1CC[N+](=O)[O-]
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
A 1 L round-bottomed flask was charged with NaBH4 (3.2 g, 84.5 mmol) in THF (300 mL) and then cooled to −20° C. Water (50 mL) was added to the reaction mixture followed by the dropwise addition of 2 (6.3 g, 16.9 mmol) in THF (50 mL) over 1 h. After an additional 30 min, the cold reaction mixture was quenched by the careful addition of 1M HCl (60 mL). The reaction mixture was then diluted with EtOAc. The organic phase was washed successively with 1M HCl and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was chromatographed by flash silica gel chromatography (4:1 hexanes/EtOAc) to afford 5.9 g (93%) of 3. 1H NMR (CDCl3, 300 MHz), mixture of rotomers: δ4.48 (m, 1H), 4.32 (m, 1H), 4.08 (m, 1H), 3.55 (m, 0.4H), 3.38 (m, 0.6H), 3.28 (app dd, J=11.7, 4.2 Hz, 1H), 2.32 (m, 1H), 2.18 (m, 1H), 2.04 (m, 2H), 1.67 (m, 1H), 1.45 (s, 9H), 0.85 (s, 9H), 0.05 (s, 6H) ppm.
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[Br-:15].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>N1C=CC=CC=1>[Br:15][C:3]1[C:4]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[NH:1][C:2]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: [Br-]
Reactant: CCOC(=O)c1cc2ccncc2[nH]1
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Product: CCOC(=O)c1[nH]c2cnccc2c1Br
Temperature: 20 °C
Reaction time: 16 h
Yield: 99.6 %

Procedure:
To a solution of 2.24 g of ethyl 1H-pyrrolo[2,3-c]pyridine-2-carboxylate in 150 mL of pyridine is added dropwise a solution of 3.53 g of pyridinium tribromide in 30 mL of pyridine, at 5° C. The reaction mixture is then stirred for 16 hours at a temperature in the region of 20° C., and then washed with 500 mL of ice-cold water. The suspension is filtered. The resulting solid is washed with water and then dried in a vacuum oven at 40° C. 1.97 g of ethyl 3-bromo-1H-pyrrolo[2,3-c]pyridine-2-carboxylate are obtained, the characteristics of which are as follows:
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[CH:17]=[C:16](N)[CH:15]=[CH:14][N:13]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[I-:19].[K+].II>COCCOC.[Cu]I>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[CH:17]=[C:16]([I:19])[CH:15]=[CH:14][N:13]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: Nc1ccnc(Nc2ccc3c(c2)OCCO3)c1
Reactant: [I-]
Agent: [Cu]I
Agent: II
Agent: [K+]
Solvent: COCCOC
Product: Ic1ccnc(Nc2ccc3c(c2)OCCO3)c1
Temperature: 62.5 °C

Procedure:
Isopentyl nitrile (Aldrich Chemical Company) (3.9 mL, 29 mmol) was added to a mixture of N2-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-pyridine-2,4-diamine (Example 2(a), 2.4 g, 9.8 mmol), potassium iodide (Aldrich Chemical Company) (1.6 g, 9.8 mmol), iodine (Aldrich Chemical Company) (1.2 g, 4.9 mmol) and copper (I) iodide (Aldrich Chemical Company) (1.9 g, 9.8 mmol) in 1,2-dimethoxyethane (60 mL). The reaction mixture was heated at 60-65° C. for 1 hr.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][NH:6][C:7]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][C:16]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:17])=[O:8])C.[OH-].[Li+]>O1CCCC1>[C:28]([O:27][C:25]([NH:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][O:18][C:16]([NH:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][C:7]([NH:6][CH2:5][C:4]([OH:32])=[O:3])=[O:8])=[O:17])=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: CCOC(=O)CNC(=O)OCCOCCNC(=O)OCCOCCNC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCOCCOC(=O)NCCOCCOC(=O)NCC(=O)O
Yield: 96.7 %

Procedure:
(2-{2-[2-(2-t-Butoxycarbonylaminoethoxy)ethoxycarbonylamino]ethoxy}ethoxycarbonylamino)acetic acid ethyl ester (Compound 5, 12.2 g, 0.026 mol) was dissolved in tetrahydrofuran (THF, 150 mL) and then stirred. After slowly adding 2 N lithium hydroxide (LiOH) aqueous solution (40 mL), the mixture was stirred at room temperature for 40 minutes. After removing THF from the reaction mixture, 1 N HCl was slowly added for acidification. After extracting 3 times with dichloromethane, the organic layer was separated, dried with magnesium sulfate, and then concentrated. The target compound (2-{2-[2-(2-t-butoxycarbonylaminoethoxy)ethoxycarbonylamino]ethoxy}ethoxycarbonylamino)acetic acid (Compound 7, 11 g, 90.1%) was yielded.