Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:16]3[C:11]([CH:12]=[N:13][C:14]([NH:17][C:18]4[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=4)=[N:15]3)=[C:10]([CH3:30])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>ClCCl>[CH3:30][C:10]1[N:9]=[C:8]([C:4]2[CH:3]=[C:2]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[C:32]([F:43])([F:42])[F:31])[CH:7]=[CH:6][CH:5]=2)[N:16]2[C:11]=1[CH:12]=[N:13][C:14]([NH:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=1)=[N:15]2
Reactant: COc1cc(Nc2ncc3c(C)nc(-c4cccc(Br)c4)n3n2)cc(OC)c1OC
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cc(Nc2ncc3c(C)nc(-c4cccc(-c5ccccc5C(F)(F)F)c4)n3n2)cc(OC)c1OC
Temperature: 150 °C
Yield: 27.1 %

Procedure:
To a mixture of 7-(3-bromophenyl)-5-methyl-N-(3,4,5-trimethoxyphenyl)-imidazo[5,1-f][1,2,4]triazin-2-amine (Example 9) (50 mg, 0.106 mmol), 2-trifluoromethylphenyl boronic acid (30.3 mg, 0.159 mmol), potassium carbonate (44.1 mg, 0.318 mmol), and Combiphos catalyst POPd1 ((dihydrogen di-κ-chlorotetrakis(di-tert-butylphosphinito-κP)dipalladate(2-)) (5.0 mg, 0.005 mmol) was added 1,4-dioxane (1.8 mL) and distilled water (0.2 mL). In a sealed reaction vessel, the mixture was heated with microwave radiation at 150° C. for a total time of 1 hour. After cooling to room temperature, poured reaction mixture into dichloromethane (50 mL) and washed with distilled water (3×25 mL) and brine (1×25 mL). Dried over MgSO4, filtered and removed solent under reduced pressure to give a gold oil. Dissolved oil in dichloromethane and added silica gel (200 mg). Following evaporation of the volatiles under reduced pressure, the pre-adsorbed solids were loaded into a solid loading cartridge and subjected to a gradient elution using ethyl acetate:hexanes (20:80 to 70:30) using a RediSep silica gel cartridge (4.2 g; ISCO). The appropriate fractions were combined and concentrated under reduced pressure to give 5-methyl-7-[2′-(trifluoromethyl)-1,1′-biphenyl-3-yl]-N-(3,4,5-trimethoxyphenyl) imidazo[5,1-f][1,2,4]triazin-2-amine (0.0154 g) as a yellow solid. 1H NMR (DMSO-d6): δ9.63 (s, 1H), 9.26 (s, 1H), 8.59 (d, J=7.90 Hz, 1H), 8.14 (s, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.71 (dd, J=7.9, 7.1 Hz, 1H), 7.62 (dd, J=7.3, 7.5 Hz, 1H), 7.54 (dd, J=7.7, 7.9 Hz, 1H), 7.45 (d, J=6.6 Hz, 1H), 7.39 (d, J=7.1 Hz, 1H), 7.05 (s, 2H), 3.67 (s, 6H), 3.61 (s, 3H), 2.51 (s, 3H). MS m/z 536 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[C:17]([C:18](=O)[CH:19]=1)=[CH:16][CH:15]=[C:14]1[C:9]=2[CH:10]=[CH:11][CH:12]=[N:13]1)=[O:5])[CH3:2].[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[CH2:1]([O:3][C:4]([CH:6]1[CH2:19][CH2:18][C:17]2[C:8](=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH2:12][CH2:11][CH2:10]3)[O:7]1)=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)c1cc(=O)c2ccc3ncccc3c2o1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C1CCc2ccc3c(c2O1)CCCN3
Yield: 41.4 %

Procedure:
8-Oxo-8H-5-oxa-1-aza-phenanthrene-6-carboxylic acid ethyl ester (2.0 g, 7.4 mmole) was dissolved in 200 mL of ethanol and 0.50 g of 20% palladium hydroxide on carbon added. The mixture was treated with 60 psi of hydrogen on a Parr apparatus for 48 hours, then filtered through celite and concentrated in vacuum. Thin layer chromatography on silica gel vs. a starting material standard indicated that the reaction was incomplete. The material was redissolved in 150 mL of acetic acid, 0.50 g of 20% palladium hydroxide on carbon added, and the mixture again treated with 60 psi of hydrogen for 48 hours. It was then filtered through celite, concentrated in vacuum and column chromatographed on silica gel with 2% ethanol in chloroform as eluant to give 0.80 g of 1,3,4,6,7,8-hexahydro-2H-5-oxa-1-aza-phenanthrene-6-carboxylic acid ethyl ester. 1H-NMR (CDCl3): doublet 6.65 δ (1 H); doublet 6.1 δ (1 H); multiplet 4.7 δ (1 H); quartet 4.25 δ (2 H); broad singlet 3.65 δ (1 H); multiplet 3.2 δ (2 H); multiplet 2.65 δ (4 H); multiplet 2.2 δ (2 H); multiplet 1.95 δ(2 H); triplet 1.25 δ (3 H).
Reaction SMILES: [CH2:1]([SH:4])[CH:2]=[CH2:3].[C:5](O)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.S(=O)(=O)(O)O>C(O)(=O)C>[CH2:1]([S:4][C:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH:2]=[CH2:3]
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C=CCS
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: C=CCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
48 ml of allylmercaptan and 129.6 g of trityl alcohol were suspended in 500 ml of acetic acid and 2.0 ml of concentrated sulfuric acid was dropwise added thereto at room temperature with stirring. Then, the mixture was further stirred for one hour under the same conditions as above, and the precipitates were recovered therefrom by filtration, washed with 200 ml of methanol and then thoroughly washed with water. The resulting colorless powder was dissolved in benzene, washed with an aqueous 5% sodium hydrogen carbonate solution and then with water, and dried over anhydrous magnesium sulfate, and the solvent was removed therefrom by distillation under reduced pressure. The residue was treated with a small amount of methanol to obtain 130 g of allyl tritylsulfide (melting point: 99°-101° C.).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]1[C:12]#[N:13])=[O:4].[NH2:14][C:15]1([CH3:29])[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[C:25]([C:27]#[N:28])[CH:24]=[CH:23][N:22]=2)[CH2:17][CH2:16]1.C(N(C(C)C)CC)(C)C>C(#N)C>[C:12]([C@@H:6]1[CH2:7][CH2:8][C@H:9]([C:10]#[CH:11])[N:5]1[C:3](=[O:4])[CH2:2][NH:14][C:15]1([CH3:29])[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[C:25]([C:27]#[N:28])[CH:24]=[CH:23][N:22]=2)[CH2:17][CH2:16]1)#[N:13]
Reactant: CC1(N)CCN(c2cc(C#N)ccn2)CC1
Reactant: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CCl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CNC1(C)CCN(c2cc(C#N)ccn2)CC1
Temperature: 55 °C
Reaction time: 48 h
Yield: 5.1 %

Procedure:
To a stirred solution of (2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (170 mg, 0.86 mmol, Example 8D) in acetonitrile (4 mL) at room temperature was added 4amino-4-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4′-carbonitrile (150 mg, 0.78 mmol) and diisopropylethylamine (250 μL, 1.38 mmol). The reaction mixture was stirred at 55° C. for 48 hours, concentrated under reduced pressure and purified by flash chromatography with a gradient from 1% to 6% methanol in methylene chloride buffered with ammonium hydroxide (0.3%). Combined fractions were concentrated under reduced pressure to afford 15 mg of the desired compound. The residue was subjected to 4N HCl in dioxane (2 mL), and after 0.5 h, the volatiles were removed under reduced pressure. Solidification by trituration with diethyl ether provided the titled compound as the HCl salt. MS (CI) m/z 377 (M+H)+; 1H NMR (300 MHz, MeOH-d4) δ 8.21 (d, 1H), 7.09 (m, 1H), 6.79 (d, 1H), 4.75 (m, 1H), 4.61 (m, 1H), 3.94 (m, 2H), 3.77-3.52 (m, 4H), 3.06 (m, 1H), 2.45-2.22 (m, 4H), 1.65 (m, 4H), 1.19 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][C:9](=O)[CH2:8][CH2:7]2.[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([N:25]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1)[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][NH2:34])=[CH:29][CH:28]=1)(=[O:24])=[O:23])([O-:15])=[O:14].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.C(O)(=O)C>[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([N:25]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1)[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][NH:34][CH:9]2[CH2:8][CH2:7][C:6]3[C:11](=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=3)[CH2:10]2)=[CH:29][CH:28]=1)(=[O:23])=[O:24])([O-:15])=[O:14]
Reactant: NCc1ccc(CN(Cc2ccccn2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Reactant: O=C1CCc2cccc(F)c2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)N(Cc1ccc(CNC2CCc3cccc(F)c3C2)cc1)Cc1ccccn1
Yield: 91.9 %

Procedure:
Following General Procedure B: Reaction of 8-fluoro-2-tetralone (159 mg, 0.97 mmol), N-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-1,4-benzenedimethanamine (400 mg, 0.97 mmol) and NaBH(OAc)3 (411 mg, 1.9 mmol) in a mixture of CH2Cl2 (10 mL) and acetic acid (0.2 mL) for 18 hours followed by purification of the crude material by column chromatography on silica gel (CHCl3/MeOH/NH4OH 20:2:1) afforded the title compound (500 mg, 92%) as a yellow foam.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]2[N:9]=[C:10]([NH:12][C:13]3[C:18](=[O:19])[N:17]([CH3:20])[CH:16]=[C:15]([C:21]4[C:26]([CH:27]=[O:28])=[C:25]([N:29]5[CH2:41][CH2:40][C:39]6[N:38]7[C:33]([CH2:34][CH2:35][CH2:36][CH2:37]7)=[CH:32][C:31]=6[C:30]5=[O:42])[N:24]=[CH:23][CH:22]=4)[CH:14]=3)[CH:11]=[C:5]2[CH2:4]1)[CH3:2].[BH4-].[Na+]>CO>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]2[N:9]=[C:10]([NH:12][C:13]3[C:18](=[O:19])[N:17]([CH3:20])[CH:16]=[C:15]([C:21]4[CH:22]=[CH:23][N:24]=[C:25]([N:29]5[CH2:41][CH2:40][C:39]6[N:38]7[C:33]([CH2:34][CH2:35][CH2:36][CH2:37]7)=[CH:32][C:31]=6[C:30]5=[O:42])[C:26]=4[CH2:27][OH:28])[CH:14]=3)[CH:11]=[C:5]2[CH2:4]1)[CH3:2]
Reactant: CCN1CCn2nc(Nc3cc(-c4ccnc(N5CCc6c(cc7n6CCCC7)C5=O)c4C=O)cn(C)c3=O)cc2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCN1CCn2nc(Nc3cc(-c4ccnc(N5CCc6c(cc7n6CCCC7)C5=O)c4CO)cn(C)c3=O)cc2C1
Reaction time: 0.5 h
Yield: 8.8 %

Procedure:
To a mixture of 208e (95 mg, 0.16 mmol) at 0° C. in methanol (10 mL) was added sodium borohydride (19 mg, 0.50 mmol). The reaction mixture was stirred for 30 minutes and quenched with water (2.0 mL). It was then concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 208 (8 mg, 9%) as white solid. MS-ESI: [M+H]+ 569.3. 1H NMR (500 MHz, CDCl3) δ 8.46 (d, J=5.0 Hz, 1H), 7.92 (d, J=2.0 Hz, 1H, 7.70 (d, J=2.0 Hz, 1H), 7.40 (s, 1H), 7.30 (d, J=5.0 Hz, 1H), 6.30 (s, 1H), 5.71 (s, 1H), 4.93-4.96 (m, 1H), 4.63-4.61 (m, 1H), 4.42-4.26 (m, 2H), 4.09 (s, 2H), 3.94-3.81 (m, 3H), 3.69-3.68 (m, overlap, 5H), 3.06-2.90 (m, 4H), 2.81 (d, J=3.0 Hz, 2H), 2.66 (d, J=3.5 Hz, 2H), 2.04-2.00 (m, 2H), 1.88-1.85 (m, 2H), 1.20 (t, J=7.5 Hz, 3H).
Reaction SMILES: [C:1]([O:4][CH2:5]C)(=[O:3])[CH3:2].[Cl:7][CH2:8][CH2:9][Cl:10]>>[C:1]([O:4][CH3:5])(=[O:3])[CH3:2].[Cl:7][CH2:8][CH2:9][Cl:10]
Reactant: CCOC(C)=O
Solvent: ClCCCl
Product: COC(C)=O

Procedure:
Example 17 was repeated using ethyl acetate instead of isopropyl acetate and 1,2-dichloroethane instead of toluene.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([N:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[CH:36]=O)[CH:25]=[CH2:26].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:36][C:28]2[N:27]([CH2:24][CH:25]=[CH2:26])[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[N:29]=2)[CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCn1c(C=O)nc2ccccc21
Reactant: Cc1cnc(CNC2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: C=CCn1c(CN(Cc2ncc(C)cc2C)C2CCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21

Procedure:
Using General Procedure B: Reaction of the 4-[(3,5-dimethyl-pyridin-2-ylmethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester and 1-allyl-1H-benzoimidazole-2-carbaldehyde in CH2Cl2 with NaBH(OAc)3 gave 4-[(1-allyl-1H-benzoimidazol-2-ylmethyl)-(3,5-dimethyl-pyridin-2-ylmethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as white foam. 1H NMR (CDCl3) δ 1.44 (s, 9H), 1.57-1.65 (m, 2H), 1.86-1.89 (m, 2H), 2.25 (s, 3H), 2.27 (s, 3H), 2.57 (t, 2H, J=12.0 Hz), 2.72 (td, 2H, J=10.5, 3.0 Hz), 3.78 (s, 2H), 3.98 (s, 2H), 4.15-4.17 (m, 2H), 4.53 (d, 2H, J=3.0 Hz), 4.65 (d, 1H, J=18.0 Hz), 4.98 (d, 1H, J=9.0 Hz), 5.51-5.63 (m, 1H), 7.20-7.24 (m, 4H), 7.70-7.73 (m, 1H), 8.19 (s, 1H). Deprotection with TFA using General Procedure F gave (1-allyl-1H-benzoimidazol-2-ylmethyl)-(3,5-dimethyl-pyridin-2-ylmethyl)-piperidin-4-yl-amine as a yellow solid. 1H NMR (CDCl3) δ 1.72 (br t, 2H, J=10.5 Hz), 1.93 (d, 2H, J=11.1 Hz), 2.25 (s, 3H), 2.26 (s, 3H), 2.54 (t, 2H, J=12.0 Hz), 2.69 (t, 1H, J=11.4 Hz), 3.17 (d, 2H, J=11.4 Hz), 3.38 (br s, 2H), 3.82 (s, 2H), 3.99 (s, 2H), 4.55 (s, 2H), 4.65 (d, 1H, J=17.4 Hz), 4.97 (d, 1H, J=10.2 Hz), 5.53-5.62 (m, 1H), 7.20-7.23 (m, 4H), 7.71 (d, 1H, J=4.8 Hz), 8.18 (s, 1H).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:8]1[N:15]=[CH:14][C:13]([CH2:16][N:17]2[C:21]([Br:22])=[N:20][C:19]([Br:23])=[N:18]2)=[C:12]([CH3:24])[C:9]=1[C:10]#[N:11].[CH:25]1([NH:28][C:29]2[C:38]([CH3:39])=[CH:37][C:36]([OH:40])=[CH:35][C:30]=2[C:31]([O:33][CH3:34])=[O:32])[CH2:27][CH2:26]1>CN(C=O)C>[C:10]([C:9]1[C:8]([O:40][C:36]2[CH:37]=[C:38]([CH3:39])[C:29]([NH:28][CH:25]3[CH2:27][CH2:26]3)=[C:30]([CH:35]=2)[C:31]([O:33][CH3:34])=[O:32])=[N:15][CH:14]=[C:13]([CH2:16][N:17]2[C:21]([Br:22])=[N:20][C:19]([Br:23])=[N:18]2)[C:12]=1[CH3:24])#[N:11]
Reactant: COC(=O)c1cc(O)cc(C)c1NC1CC1
Reactant: Cc1c(Cn2nc(Br)nc2Br)cnc(Cl)c1C#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Oc2ncc(Cn3nc(Br)nc3Br)c(C)c2C#N)cc(C)c1NC1CC1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
Cs2CO3 (14.9 g, 45.8 mmol) and DMF (25 mL) are added into a 250 mL flask, and the reaction mixture is heated to 80° C. 2-chloro-5-((3,5-dibromo-1H-1,2,4-triazol-1-yl)methyl)-4-methylnicotinonitrile (7.2 g, 18.3 mmol) and hydrochloride salt of methyl 2-(cyclopropylamino)-5-hydroxy-3-methylbenzoate (4.2 g, 18.3 mmol) is dissolved by DMF (25 mL) in a 100 mL flask, and the mixture is added into the 250 ml flask over 30 min. The resulting mixture is stirred at 80° C. for 30 min. A sample of the mixture is taken for HPLC analysis. The reaction mixture is kept stifling until the conversion to product is at least 99%. Then, the reaction mixture is cooled to 20° C., and the reaction is quenched with EtOAc (50 mL) and water (50 mL). The bottom aqueous layer is then removed, and the organic layer is washed with two times of 10% NaCl (40 mL each). The solvent of the organic layer is distilled under vacuum with internal temperature of the solvent as between 30˜45° C. to ⅙ of original volume. Then the resulting solvent is passed through a pad of silica gel (15 g) by 4:1 hexanes/EtOAc (100 mL). The resulting solvent is then distilled under vacuum with internal temperature of the solvent as between 30˜45° C. to ⅛ of original volume. Then MeOH (70 mL) is added into the solvent, and the resulting solvent is distilled under vacuum with internal temperature of the solvent as between 30˜45° C. to ⅛ of original volume. Another 70 ml of MeOH is added into the solvent, and the resulting solvent is distilled under vacuum with internal temperature of the solvent as between 30˜45° C. to ⅛ of original volume. An additional 70 ml of MeOH is added into the solvent, and the resulting solvent is heated to 60° C., then is cooled down to 20° C. in 2 h and stirred at 20° C. for 2 h. The resulting mixture is filtered, and the filter cake is washed with MeOH (15 mL). The filter cake is then dried under vacuum at 20° C. to afford 8 g product with more than 97% purity.
Reaction SMILES: Br[CH2:2][CH:3]1[O:7][CH2:6][CH2:5][O:4]1.[CH2:8]([NH2:11])[CH2:9][CH3:10].[OH-].[Na+]>O>[CH2:8]([NH:11][CH2:2][CH:3]1[O:7][CH2:6][CH2:5][O:4]1)[CH2:9][CH3:10]
Reactant: CCCN
Reactant: BrCC1OCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCNCC1OCCO1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
2-Bromomethyl-1,3-dioxolane (20 grams) and n-propylamine (100 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture was heated at a temperature of about 100° C. for a period of about 3 hours. After this time sodium hydroxide (10 grams) dissolved in water (100 ml) was added and the resulting mixture was stirred for a period of about 30 minutes. The reaction mixture was then extracted with ether and the ether solution separated and dried over magnesium sulfate. The dried solution was filtered and stripped of solvent to yield the desired product N-n-propyl-N-(1,3-dioxolan-2-ylmethyl)amine an an oil.
Reaction SMILES: [Cl:1]C(OCC)=O.[F:7][C:8]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:15][CH2:16][O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=O.C(N(CC)CC)C>ClCCl>[F:7][C:8]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:15][CH2:16][O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([Cl:1])=[O:26]
Reactant: O=C(O)CCCCCCOCCc1cccc(F)c1F
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cl)CCCCCCOCCc1cccc(F)c1F
Yield: 95.4 %

Procedure:
Ethyl chloroformate (414 mg, 3.82 mmol) was added at 0° C. to a solution of 7-[2-(2,3-difluoro-phenyl)-ethoxy]-heptanoic acid (800 mg, 2.94 mmol) and triethylamine (387 mg, 3.82 mmol) in dichloromethane (15 mL), then after 2 h volatile material was removed by distillation, producing 7-[2-(2,3-difluoro-phenyl)-ethoxy]-heptanoyl chloride (855 mg). This was redissolved in acetone (2 mL) and treated at 0° C. with a solution of sodium azide (268 mg, 4.12 mmol) in water (4 mL) under vigorous stirring. The reaction mixture was stirred for 1 h at 10° C., then partitioned between toluene and brine. The organic layer was separated and heated at 65° C. for 90 min, then concentrated in vacuo, affording [6-(2,3-difluoro-benzyloxy)-hexyl]-isocyanate (486 mg, 61%) as a yellow oil.
Reaction SMILES: [C:1]([N:8]1[CH2:11][C:10](=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:13]([O:17][C:18]([NH:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(O)(=O)C>CO.[C].[Pd]>[C:13]([O:17][C:18]([NH:20][CH:21]1[CH2:22][CH2:23][N:24]([CH:10]2[CH2:11][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]2)[CH2:25][CH2:26]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCN(C2CN(C(=O)OC(C)(C)C)C2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 58.3 %

Procedure:
To 1-Boc-azetidin-3-on (1.00 g) and 4-(tert-butoxycarbonylamino)piperidine (1.17 g) dissolved in methanol (50 ml) were added acetic acid (0.368 ml) and 10% palladium carbon (1.0 g), followed by stirring under hydrogen atmosphere at room temperature for 12 hours. The reaction mixture was stirred under hydrogen atmosphere (0.4 MPa) at room temperature for 4 hours. The reaction mixture was filtered to remove the catalyst. The filtrate was concentrated under reduced pressure. Ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate were added thereto, followed by partition. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated. The resultant crystals were suspended in diethyl ether-hexane, collected by filtration, and washed with hexane. There crystals were dried under aeration to provide the title compound (1.21 g) as colorless crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.Cl.CCOCC.[CH3:20][C:21](=[O:24])[CH2:22][CH3:23]>>[OH:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:22]([CH3:23])[C:21](=[O:24])[CH3:20])[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10]
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: CCC(C)=O
Agent: Cl
Solvent: CCOCC
Product: CC(=O)C(C)=Cc1cc(O)c(O)c([N+](=O)[O-])c1

Procedure:
A solution containing 0.5 g of 3,4-dihydroxy-5-nitrobenzaldehyde in 2.0 ml of butanone was saturated with gaseous hydrogen chloride. After standing over night ether was added to the solution and it was filtered. The product was crystallized from isopropanol, yield 0.2 g (30%), m.p. 139°-141° C.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([CH3:7])[S:5][CH:6]=1.[CH2:8]([C:12]1[N:13]=[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]2[CH:20]=1)[CH2:9][C:10]#[CH:11]>C(N(CC)CC)C.[Cu](I)I.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>[CH3:7][C:4]1[S:5][CH:6]=[C:2]([C:11]#[C:10][CH2:9][CH2:8][C:12]2[N:13]=[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]3[CH:20]=2)[N:3]=1
Reactant: Cc1nc(I)cs1
Reactant: C#CCCc1cn2ccccc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: Cc1nc(C#CCCc2cn3ccccc3n2)cs1
Temperature: 25 °C
Yield: 13.8 %

Procedure:
In a dry reaction tube containing in suspension copper iodide (6.5 mg, 0.03 mmol) and triethylamine (2.33 mL, 13.60 mmol), were added 4-iodo-2-methylthiazole (150 mg, 0.68 mmol) and Pd(PPh3)2Cl2 (39 mg, 0.03 mmol) under N2. A yellow suspension is obtained and after a few minutes of stirring at room temperature, was added a solution 2-(but-3-ynyl)-imidazo[1,2-a]pyridine (115 mg, 0.68 mmol) in triethylamine (0.5 mL) under N2. Immediately the color of the reaction turns to black. The mixture was stirred at room temperature for 4 h and 50° C. overnight under N2. Triethylamine was removed under reduce pressure. The crude product was purified by flash chromatography (Prepacked 25 g silicagel column from DCM/MeOH: 100/0 to 97/3 as eluent) to afford 25 mg of 2-(4-(2-methylthiazol-4-yl)but-3-ynyl)-imidazo[1,2-a]pyridine (Yield: 14%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:4][CH:3]=1.[S-:16][C:17]#[N:18].[NH4+].BrBr>C(O)(=O)C>[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:17]([NH2:18])[S:16][C:3]=2[CH:4]=1
Reactant: N#C[S-]
Reactant: Nc1ccc(CCc2ccccn2)cc1
Agent: BrBr
Agent: [NH4+]
Solvent: CC(=O)O
Product: Nc1nc2ccc(CCc3ccccn3)cc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.7 %

Procedure:
A mixture of 2-[2-(4-aminophenyl)ethyl]pyridine (5.94 g) and ammonium thiocyanate (4.56 g) in acetic acid (50 ml) was stirred at ambient temperature for one hour. A solution of bromine (4.8 g) in acetic acid (5 ml) was dropwise added to the above mixture at 18° to 23° C. under stirring and the resultant mixture was stirred at ambient temperature for 3 hours. The reaction mixture was evaporated in vacuo and the residue was dissolved in a mixture of ethyl acetate and water. The solution was acidified to pH 1.0 with hydrochloric acid. The separated aqueous layer was adjusted to pH 7.5 with aqueous 20% potassium carbonate and extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was recrystallized from ethyl acetate to give 6-[2-(2-pyridyl)ethyl]-2-aminobenzothiazole (4.8 g).