Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([N:9]=[C:10]([NH2:12])[N:11]=2)[CH:8]=1.[C:13](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:14]>ClCCl>[N:12]([C:10]1[N:11]=[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][N:7]2[N:9]=1)=[C:13]=[S:14]
Reactant: COc1ccc2nc(N)nn2c1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: ClCCl
Product: COc1ccc2nc(N=C=S)nn2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.4 %

Procedure:
To 6-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-amine (0.3 g, 1.8 mmol) in dichloromethane (15 mL) was added 1,1′-thiocarbonyldi-2(1H)-pyridone (0.51 g, 2.2 mmol). The reaction was stirred at room temperature overnight, concentrated in vacuo and purified via flash chromatography yielding 2-isothiocyanato-6-methoxy-[1,2,4]triazolo[1,5-a]pyridine (166 mg, 0.8 mmol, 44% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 8.03 (1 H, d, J=2.20 Hz), 7.54 (1 H, d, J=9.88 Hz), 7.34 (1 H, dd, J=9.51, 2.56 Hz), 3.88 (3 H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[NH2:13].C[O:15][C:16](=O)[C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([N:24]2[CH:28]=[C:27]([C:29]3[CH:30]=[N:31][N:32]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:33]=3[CH2:34][CH3:35])[N:26]=[CH:25]2)[CH:18]=1>>[CH2:34]([C:33]1[N:32]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:31]=[CH:30][C:29]=1[C:27]1[N:26]=[CH:25][N:24]([C:19]2[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=2[CH3:23])[C:16]([NH:13][C:4]2[CH:5]=[C:6]([C:9]([F:11])([F:10])[F:12])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])=[O:15])[CH:28]=1)[CH3:35]
Reactant: COc1ccc(C(F)(F)F)cc1N
Reactant: CCc1c(-c2cn(-c3cc(C(=O)OC)ccc3C)cn2)cnn1-c1ccccc1
Product: CCc1c(-c2cn(-c3cc(C(=O)Nc4cc(C(F)(F)F)ccc4OC)ccc3C)cn2)cnn1-c1ccccc1

Procedure:
Example 154 was prepared from 2-methoxy-5-trifluoromethyl-phenylamine and 3-[4-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl-benzoic acid methyl ester (Example 151) in the same manner as Example 151. ESI MS m/z 546 [C30H26F3N5O2+H]+.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]1[CH:26]=[CH:25][C:24]([C:27]2[N:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[CH:23][C:12]=1[C:13]([O:15]CC1C=CC=CC=1)=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1(C)C=CC=CC=1>O1CCOCC1.CO>[CH2:3]([O:10][C:11]1[CH:26]=[CH:25][C:24]([C:27]2[N:28]=[CH:29][CH:30]=[CH:31][N:32]=2)=[CH:23][C:12]=1[C:13]([OH:15])=[O:14])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(OCc1ccccc1)c1cc(-c2ncccn2)ccc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Solvent: CO
Product: O=C(O)c1cc(-c2ncccn2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.1 %

Procedure:
A 2 mol/L aqueous solution of sodium hydroxide (8.6 mL) was added to a solution mixture of the obtained benzyl 2-(benzyloxy)-5-(pyrimidin-2-yl)benzoate (1.4 g) in dioxane (10 mL) and methanol (5 mL), followed by stirring at room temperature for 4 hours. Toluene was added to the reaction mixture, and the aqueous layer was separated. After adjusting the pH to 1 with 6 mol/L hydrochloric acid, the solid substance was collected by filtration to obtain 0.65 g of 2-(benzyloxy)-5-(pyrimidin-2-yl)benzoic acid as a white solid.
Reaction SMILES: CN(C(/N=N/C(N(C)C)=O)=O)C.C(OC([N:20]1[CH2:25][CH2:24][N:23]([C:26]2[C:27]([O:32]CCO)=[N:28][CH:29]=[CH:30][N:31]=2)[CH2:22][CH2:21]1)=O)(C)(C)C.[C:36]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:37]=1.[CH3:55][O:56][C:57]1[CH:58]=[C:59]([OH:63])[CH:60]=[CH:61][CH:62]=1>C1COCC1.CN(C=O)C>[CH3:55][O:56][C:57]1[CH:58]=[C:59]([CH:60]=[CH:61][CH:62]=1)[O:63][CH2:36][CH2:37][N:28]1[CH:29]=[CH:30][N:31]=[C:26]([N:23]2[CH2:22][CH2:21][NH:20][CH2:25][CH2:24]2)[C:27]1=[O:32]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCO)CC1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COc1cccc(O)c1
Agent: CN(C)C(=O)/N=N/C(=O)N(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cccc(OCCn2ccnc(N3CCNCC3)c2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.1 %

Procedure:
TMAD (0.060 g, 0.35 mmol) was dissolved in THF (1 mL) and DMF (0.5 mL) and the solution added dropwise to a mixture of 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-pyrazinyloxy]ethanol (0.100 g, 0.310 mmol), triphenylphosphine (0.092 g, 0.35 mmol) and 3-methoxyphenol (0.124 g, 1.00 mmol) in THF (0.5 mL). The reaction mixture was stirred overnight at room temperature, concentrated, and put through a silica column using toluene/EtOAc (7:3) as eluent. Solvents were removed in vacuo and the N-t-BOC derivative of the title compound was treated with dichloromethane/TFA/H2O (50:45:5; 5 mL) for 15 min. The mixture was concentrated and the residue was purified by chromatography on silica gel using EtOAc/HOAc/MeOH/H2O (20:3:3:2) as eluent. The product-containing fractions were concentrated, washed between dichloromethane/5% aqueous NaOH, and put through a silica column using dichloromethane/MeOH (8:2) as eluent to give 40 mg (34%) of the title compound as an oil. HRMS m/z calcd for C17H22N4O3 (M)+ 330.1692, found 330.1677.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8][N:7]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1)=[O:25].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[CH2:14]([O:13][C:11]([C:9]1[CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]([CH2:23][C:24]([N:26]2[CH2:27][CH2:28][N:29]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[CH2:30][CH2:31]2)=[O:25])[N:8]=1)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1cc(C(=O)OCC)[nH]n1
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCOC(=O)c1cc(C(=O)OCC)n(CC(=O)N2CCN(c3ccc(F)cc3)CC2)n1

Procedure:
Protocol T was followed using 1H-Pyrazole-3,5-dicarboxylic acid diethyl ester, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1/1) afforded the title compound as a white solid. 1H NMR (400 MHz, CDCl3): 7.38 (s, 1H), 6.94–7.0 (m, 2H), 6.82–7.90 (dd, 2H), 5.54 (s, 2H), 4.36–4.42 (q, 2H), 4.26–4.32 (q, 2H), 3.60–3.80 (m, 4H), 3.02–3.20 (m, 4H), 1.22–1.42 (m, 6H). 13C NMR (400 MHz, CDCl3): 164.2, 162.2, 158.2, 157.4, 156.2, 148.5, 144.4, 134.2, 118.4, 116.2, 115.8, 114.2, 62, 61.8, 54.2, 50.6, 50.2, 45.2, 42.2, 14.6, 14.2.
Reaction SMILES: [CH3:1][N:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C@H:3]1[CH2:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][CH:10]2[CH:22]=[N:23]O.C(O)C.C(O)(=O)C.[H][H]>O=[Pt]=O.O>[NH2:23][CH2:22][CH:10]1[CH2:9][CH2:8][C@H:7]2[C@H:6]3[C@H:15]([CH2:14][CH2:13][C@:11]12[CH3:12])[C@:16]1([CH3:21])[C@H:3]([N:2]([CH3:1])[C:19](=[O:20])[CH2:18][CH2:17]1)[CH2:4][CH2:5]3
Reactant: CN1C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)C(C=NO)CC[C@H]4[C@@H]3CC[C@@H]12
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CN1C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)C(CN)CC[C@H]4[C@@H]3CC[C@@H]12

Procedure:
A mixture of (46) (0.67 g, 2.0 mM), ethanol (100 mL), glacial acetic acid (8 mL) and water (4 mL) was reduced in a hydrogen atmosphere (40 p.s.i.) at room temperature in the presence of PtO2 until TLC analysis indicated complete reduction. The filtered reaction mixture was concentrated in vacuo, the residue taken up in chloroform, and the chloroform solution washed with fresh dilute sodium hydrogen carbonate solution and dried (Na2SO4). Concentration of the filtered chloroform solution followed by trituration of the residue obtained with hexane containing a small amount of ether yielded (47) as an off-white solid. MS MH+ calcd for C20H34N2O 318.49, observed m/e 319.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:13][C:14]1[CH:15]=[C:16]([C:26]([OH:28])=O)[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:18][CH:19]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>>[CH2:5]([O:13][C:14]1[CH:15]=[C:16]([C:26]([Cl:3])=[O:28])[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:18][CH:19]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCOc1ccc(-c2ccccc2)c(C(=O)O)c1
Reactant: O=S(Cl)Cl
Product: CCCCCCCCOc1ccc(-c2ccccc2)c(C(=O)Cl)c1

Procedure:
With an excess amount of thionyl chloride, 4.0 g of 4-n-octyloxybiphenyl carboxylic acid was heated under refluxing for 6 hours. Unaltered thionyl chloride was distilled off to obtain 4-n-octyloxybiphenyl carboxylic acid chloride.
Reaction SMILES: [N+:1]([CH2:4][CH:5]1[O:9][B:8]([OH:10])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]1=2)([O-])=O.N.[ClH:16]>C(O)C.O.[Ni]>[ClH:16].[NH2:1][CH2:4][CH:5]1[O:9][B:8]([OH:10])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]1=2
Reactant: O=[N+]([O-])CC1OB(O)c2ccccc21
Agent: [Ni]
Agent: Cl
Agent: N
Solvent: CCO
Solvent: O
Product: NCC1OB(O)c2ccccc21
Reaction time: 2 h
Yield: 92 %

Procedure:
To a solution of 3-(nitromethyl)benzo[c][1,2]oxaborol-1(3H)-ol (965 mg, 5 mmol) in ethanol (30 mL) were added ammonia (2M solution in ethanol, 18 mL, 36 mmol) and Raney 2800 Nickel (⅓ teaspoon of a slurry in water). The reaction mixture was subjected to hydrogenation at 45 atmospheres for 2 h at rt. The resulting mixture was filtered through Celite and the filtrate was concentrated in vacuo yielding the crude amine. The amine was dissolved in dioxanes (10 mL) and HCl (4M in dioxanes, 5 mL, 20 mmol) was added. After 1 h, the suspension was concentrated and the resulting solid was washed with hexanes followed by ether yielding 3-(aminomethyl)benzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (917 mg, 4.6 mmol, 92% yield) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:22]([CH3:23])[CH:21]=[N:20][CH:19]=3)[S:17][C:10]=12.[C:25]1([CH2:31][C:32]([N:34]=[C:35]=[O:36])=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[F:1][C:2]1[CH:3]=[C:4]([NH:24][C:35]([NH:34][C:32](=[O:33])[CH2:31][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:36])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:22]([CH3:23])[CH:21]=[N:20][CH:19]=3)[S:17][C:10]=12
Reactant: O=C=NC(=O)Cc1ccccc1
Reactant: Cn1cncc1-c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Product: Cn1cncc1-c1cc2nccc(Oc3ccc(NC(=O)NC(=O)Cc4ccccc4)cc3F)c2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
A mixture of 306 (99 mg, 0.29 mmol) and 2-phenylacetyl isocyanate (97 mg, 0.60 mmol) [A. J. Hill, et al. JACS, 62; 1940; 1595] was stirred for 1 h at room temperature, loaded directly onto a flash chromatography column and gradient eluted with EtOAc, to MeOH/EtOAc (10:90) to afford the title compound 307 (42% yield) as a white solid. 1H NMR (d-DMSO) δ (ppm): 11.11(s, 1H), 10.68(s, 1H, J=5.5 Hz), 8.49(d), 7.85(s, 1H), 7.82(dd, 1H, J1=12.9 Hz, J2=2.4 Hz), 7.76(s, 1H), 7.43(m, 2H), 7.40(s, 1H), 7.32(m, 4H), 7.28(m, 1H), 6.61(d, 1H, J=5.5 Hz), 3.89(s, 3H), 3.74(s, 2H). MS (m/z): 502.4 (M+H) (found).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:15]([O:17]C)=[O:16])[CH2:12][C:11]([F:14])([F:13])[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[Li+].[OH-]>C1COCC1.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:15]([OH:17])=[O:16])[CH2:10][C:11]([F:14])([F:13])[CH2:12]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: COC(=O)C1(c2ccc(C#N)cc2)CC(F)(F)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(C2(C(=O)O)CC(F)(F)C2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.2 %

Procedure:
To a stirred solution of Intermediate 314E (300 mg, 1.194 mmol) in THF (2 mL) and water (2 mL) was added LiOH (57.2 mg, 2.388 mmol) and the reaction mixture was stirred at RT for 12 h. The reaction mixture was concentrated to remove THF and the aq. layer was acidified to a pH of 2 with a 1.5N aq. solution of HCl and extracted with EtOAc (3×15 mL) The combined organic layer was washed with brine, dried over Na2SO4, filtered and the filtrate concentrated to afford Intermediate 314F (230 mg, 81%) as a colorless semi-solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.39 (br. s., 1H), 7.91-7.79 (m, 2H), 7.62-7.49 (m, 2H), 3.50-3.25 (m, 2H), 3.11 (d, J=14.0 Hz, 2H).
Reaction SMILES: [C:1]1([C:7]2([CH2:13][CH:14]=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)([OH:18])N.Cl([O-])=O.[Na+]>C1COCC1.O>[C:1]1([C:7]2([CH2:13][C:14]([OH:18])=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NS(=O)(=O)O
Reactant: O=CCC1(c2ccccc2)CCCCO1
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CC1(c2ccccc2)CCCCO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(2-phenyltetrahydro-2H-pyran-2-yl)acetaldehyde (100 mg, 0.490 mmol) and sulfamic acid (57.0 mg, 0.587 mmol) in THF (1.5 mL) was added a solution of sodium chlorite (53.1 mg, 0.587 mmol) in water (1.5 mL) dropwise, and the mixture was stirred at room temperature for 3 hrs. Then the product was extracted with EtOAc (3×) and the combined extracts were washed with brine, dried over Na2SO4, and evaporated to give 2-(2-phenyltetrahydro-2H-pyran-2-yl)acetic acid as oil. LC/MS: m/e 221.14 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6](=O)[C:7](=[CH:18][N:19](C)[CH3:20])[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1.C(O)(=O)C.C(N)=[NH:30].C[O-].[Na+].CCCCCC>CO>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:30]=[CH:20][N:19]=[CH:18][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1
Reactant: N=CN
Reactant: CN(C)C=C1CN=C(c2ccccc2F)c2cc(Cl)ccc2C1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCCCCC
Solvent: CO
Product: Fc1ccccc1C1=NCc2cncnc2-c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 34.2 g (0.1 mole) of 8-chloro-3,4-dihydro-1-(2-fluorophenyl)-4-[(dimethylamino)methylene]-5H-2-benzazepin-5-one, 62.4 g (0.6 mole) of formamidine acetate, and 35 g (0.63 mole) of sodium methoxide in 700 ml of methanol was stirred at room temperature for 3 hr, while bubbling nitrogen through the solution. The mixture was diluted with water and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to give a red oil. The oil was suspended in boiling hexane and the hexane solution decanted. Upon cooling the end product was collected by filtration. Recrystallization from cyclohexane gave off-white crystals, mp 123°-125° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([CH2:10][CH2:11][OH:12])=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].[Br:16]Br>C(Cl)Cl>[Br:16][CH2:14][C:13]([C:3]1[CH:4]=[C:5]([CH2:10][CH2:11][OH:12])[C:6]([O:8][CH3:9])=[CH:7][C:2]=1[OH:1])=[O:15]
Reactant: BrBr
Reactant: COc1cc(O)c(C(C)=O)cc1CCO
Solvent: ClCCl
Product: COc1cc(O)c(C(=O)CBr)cc1CCO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 100 mL of methylene chloride was dissolved 10.0 g of 1-[2-hydroxy-5-(2-hydroxyethyl)-4-methoxyphenyl]-1-ethanone, and 2.94 mL of bromine was added dropwise to the solution, after which the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water and the organic layer was separated. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 16.4 g of 2-bromo-1-[2-hydroxy-5-(2-hydroxyethyl)-4-methoxyphenyl]-1-ethanone as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]=[CH:9]2)([O-])=O.[NH4+].[Cl-].C(OCC)(=O)C>CCO.O.[Fe]>[NH2:1][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]=[CH:9]2
Reactant: O=[N+]([O-])c1cccc2cnccc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1cccc2cnccc12
Temperature: 80 °C
Reaction time: 10 h
Yield: 54 %

Procedure:
To a solution of 5-nitro-isoquinoline (150 g, 0.861 mol) in EtOH/H2O=4:1 (5 L) was added NH4Cl (92.2 g, 1.723 mol) and Fe (193 g, 3.445 mol) at room temperature. Then the mixture was heated to 80° C. and stirred for 10 hours. TLC (petroleum ether:ethyl acetate=1:1) showed the reaction was complete. The mixture was cooled to room temperature and filtered though a pad of celite. The filter cake was washed with EtOH (2 L×2). The filtrate was concentrated in vacuo to remove most of EtOH. The residue was extracted with EtOAc (500 ml×10). The combined layers were dried over Na2SO4, filtered and then concentrated in vacuo to afford 5-amino-isoquinoline (67 g, 54%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[CH:15]=[C:14]([NH2:16])[N:13]=[CH:12][N:11]=2)=[CH:5][CH:4]=1.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[N:25]=[C:26]=[O:27]>>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[NH:25][C:26]([NH:16][C:14]1[CH:15]=[C:10]([NH:9][C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:11]=[CH:12][N:13]=1)=[O:27]
Reactant: COc1ccc(Nc2cc(N)ncn2)cn1
Reactant: O=C=Nc1c(Cl)cccc1Cl
Product: COc1ccc(Nc2cc(NC(=O)Nc3c(Cl)cccc3Cl)ncn2)cn1

Procedure:
The title compound is prepared analogously as described in Example 105B from N-(6-methoxy-pyridin-3-yl)-pyrimidine-4,6-diamine and 2,6-dichlorophenyl isocyanate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)[C:10]([O:12][C@@H:13]1[CH:18]2[CH2:19][CH2:20][N:15]([CH2:16][CH2:17]2)[CH2:14]1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:28][CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:31]>CCOC(C)=O>[Br-:28].[C:1]([O:5][C:6]([NH:8][CH:9]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)[C:10]([O:12][C@@H:13]1[CH:18]2[CH2:17][CH2:16][N+:15]([CH2:29][C:30](=[O:31])[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([CH2:20][CH2:19]2)[CH2:14]1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(C(NC(=O)OC(C)(C)C)C(=O)O[C@H]2CN3CCC2CC3)cc1
Reactant: O=C(CBr)c1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccc(C(NC(=O)OC(C)(C)C)C(=O)O[C@H]2C[N+]3(CC(=O)c4ccccc4)CCC2CC3)cc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 36 h
Yield: 61 %

Procedure:
To a solution of (R)-quinuclidin-3-yl 2-(tert-butoxycarbonylamino)-2-p-tolylacetate (C41) (100 mg, 0.27 mmol) in EtOAc (3 ml), was added 2-bromo-1-phenylethanone (58.5 mg, 0.29 mmol), and the reaction was stirred at RT for 36 hours. The solvent was evaporated, and the residue was first triturated with i-Pr2O and then purified by flash chromatography (DCM/MeOH=95/5 to 9/1) to obtain (3R)-3-(2-(tert-butoxycarbonylamino)-2-p-tolylacetoxy)-1-(2-oxo-2-phenylethyl)-1-azoniabicyclo[2.2.2]octane bromide (94.4 mg; 62% yield).
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:25])[NH:12][C:13]2[S:14][CH:15]=[C:16]([C:18](=[O:24])[C:19](OCC)=[O:20])[N:17]=2)=[CH:6][CH:5]=1.CO.Cl>O1CCCC1.O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:25])[NH:12][C:13]2[S:14][CH:15]=[C:16]([CH:18]([OH:24])[CH2:19][OH:20])[N:17]=2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(=O)c1csc(NC(=O)Nc2ccc(Br)cc2)n1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccc(Br)cc1)Nc1nc(C(O)CO)cs1

Procedure:
2.4 g of sodium borohydride were added to a suspension of 5 g of ethyl 2-(3-p-bromophenylureido)thiazol-4-ylglyoxylate in 60 ml of tetrahydrofuran, then 20 ml of methanol were added dropwise over a period of 1 hour while heating the reaction mixture under reflux, and the reaction mixture was thereafter heated under reflux for a further 1 hour. The reaction mixture was poured into water and neutralized with 3N hydrochloric acid. The crystals which precipitated out were collected by filtration, washed with water and dried, giving crude 1-[2-(3-p-bromophenyl- ureido)thiazol-4-yl]ethane-1,2-diol.
Reaction SMILES: [CH:1]1([C:7]2([C:10]([NH:12][C:13]3[C:22]([Cl:23])=[CH:21][CH:20]=[C:19]4[C:14]=3[CH:15]=[CH:16][C:17](Cl)=[N:18]4)=[O:11])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[N:26]([CH3:31])[CH2:27][CH2:28][CH2:29][NH2:30].[C:32](#N)C>>[ClH:23].[Cl:23][C:22]1[C:13]([NH:12][C:10]([C:7]2([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH2:9][CH2:8]2)=[O:11])=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([N:30]([CH3:32])[CH2:29][CH2:28][CH2:27][NH:26][CH3:31])[CH:16]=[CH:15]2
Reactant: O=C(Nc1c(Cl)ccc2nc(Cl)ccc12)C1(C2CCCCC2)CC1
Reactant: CC#N
Reactant: CN(C)CCCN
Product: CNCCCN(C)c1ccc2c(NC(=O)C3(C4CCCCC4)CC3)c(Cl)ccc2n1
Product: Cl
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a 10 mL vial was added 1-cyclohexyl-N-(2,6-dichloro-5-quinolinyl)-cyclopropanecarboxamide (example 26 (b)) (0.13 g), N,N-dimethyl-1,3-propanediamine (0.13 mL) and acetonitrile (3 mL). The vial was sealed and heated at 100° C. in a microwave for 20 minutes followed by 30 minutes at 110° C. The solvent was removed from the cooled reaction under reduced pressure, saturated aqueous sodium hydrogen carbonate solution (30 mL) was added and the mixture was extracted with dichloromethane (3×50 mL). The combined organics were washed with water (50 mL) and brine (50 mL) before being dried, filtered and concentrated. Purification (Varian SCX cartridge, using methanol and 10% ammonia in methanol as eluant) gave a crude product which was further purified by chromatography (SiO2, ammonia:methanol:dichloromethane, 1:2.5:96.5 as eluant). The product was converted to its hydrochloride salt by dissolution in dichloromethane and treatment with 4M hydrogen chloride in 1,4 dioxane (5 mL). Removal of volatiles and recrystallisation from methanol/acetonitrile afforded the title compound (0.075 g).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=O.[N+:11]([CH2:14][C:15]#[N:16])([O-])=O.[Si]([N:21]=[N+:22]=[N-])(C)(C)C.[F-]>C1COCC1>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]1[N:21]=[N:22][NH:11][C:14]=1[C:15]#[N:16]
Reactant: N#CC[N+](=O)[O-]
Reactant: O=Cc1c(F)cccc1F
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: [F-]
Solvent: C1CCOC1
Product: N#Cc1[nH]nnc1-c1c(F)cccc1F
Temperature: 25 °C

Procedure:
4-(2,6-difluorophenyl)-1H-1,2,3-triazole-5-carbonitrile (2) was prepared in one step from 2,6-difluorobenzaldehyde (1) and nitroacetonitrile using a modified literature procedure (see Fringuelli et al. Eur. J. Org. Chem. (2008) 3928-3932). A solution of 2,6-difluorobenzaldehyde (1.0 equiv), nitroacetonitrile (1.5 equiv) and TMS-azide (3.0 equiv) in dry THF (0.4 M) under inert atmosphere and at 0° C. was treated with fluoride-bound resin (Aldrich #387789, 1:1 w/w with respect to aldehyde). The resulting mixture was heated to reflux for 2 h (reaction completed according to TLC), cooled to room temperature and concentrated in vacuo to provide (2) as an orange solid which was used directly in the next reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:10]=2[C:11]([OH:13])=O)=[CH:5][N:4]=1.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]2[O:27][C:26]([NH:28][CH2:29][C@@H:30]3[C@H:35]([CH3:36])[CH2:34][CH2:33][CH2:32][NH:31]3)=[N:25][C:24]=2[CH:37]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]2[O:27][C:26]([NH:28][CH2:29][C@@H:30]3[C@H:35]([CH3:36])[CH2:34][CH2:33][CH2:32][N:31]3[C:11]([C:10]3[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:9]=3[C:6]3[CH:7]=[N:8][C:3]([O:2][CH3:1])=[N:4][CH:5]=3)=[O:13])=[N:25][C:24]=2[CH:37]=1
Reactant: C[C@@H]1CCCN[C@@H]1CNc1nc2cc(Cl)ccc2o1
Reactant: COc1ncc(-c2ccc(C)cc2C(=O)O)cn1
Product: COc1ncc(-c2ccc(C)cc2C(=O)N2CCC[C@@H](C)[C@H]2CNc2nc3cc(Cl)ccc3o2)cn1

Procedure:
The title compound was prepared following the same general protocol as described in Example A1, using 2-(2-methoxypyrimidin-5-yl)-5-methylbenzoic acid and 5-chloro-N-(((2S,3R)-3-methylpiperidin-2-yl)methyl)benzo[d]oxazol-2-amine. ESI-MS (m/z): 506 [M+1]+.