Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[C:12](Cl)(=[O:21])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1>[C:15]1([CH2:14][CH2:13][C:12]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)=[O:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: O=C(Cl)CCc1ccccc1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NC(=O)CCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of methyl 4-aminobenzoate (825 mg, 5.46 mmol) in anhydrous pyridine (16 mL) was added dropwise hydrocinnamoyl chloride (990 μL) at 0° C. After 5 min, the temperature was allowed to warm up to rt. After 90 min aminomethyl resin (Polymers Laboratories PL-AMS, 1.93 mmol/g, 1200 mg) was added and the resulting mixture was stirred overnight at rt. After rinsing the resin and filtration, water (200 mL) was added to the filtrate and a white solid precipated out. Filtration and washing with water gave a solid which was dried under vacuo at 60° C. overnight. The title compound (1.40 g) was obtained as a white solid (90%) in 98.2% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [C:1]([C:3]1[C:4]([CH2:11][C:12]([NH:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]3[O:23][N:22]=[C:21]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:20]=3[CH:32]=2)=[O:13])=[N+:5]([O-:10])[C:6](Cl)=[CH:7][CH:8]=1)#[N:2].[F:33][C:34]([F:43])([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1)[CH2:35][NH2:36]>CS(C)=O>[C:1]([C:3]1[C:4]([CH2:11][C:12]([NH:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]3[O:23][N:22]=[C:21]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:20]=3[CH:32]=2)=[O:13])=[N+:5]([O-:10])[C:6]([NH:36][CH2:35][C:34]([F:43])([F:33])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)Nc1noc2ccc(CNC(=O)Cc3c(C#N)ccc(Cl)[n+]3[O-])cc12
Reactant: NCC(F)(F)c1ccccn1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)Nc1noc2ccc(CNC(=O)Cc3c(C#N)ccc(NCC(F)(F)c4ccccn4)[n+]3[O-])cc12

Procedure:
A mixture of 3-cyano-6-chloro-2-[3-(tert-butoxycarbonyl)amino-benzo[d]isoxazol-5-ylmethyl]aminocarbonylmethyl-pyridine 1-oxide (103 mg, 0.225 mmol) and 2,2-difluoro-2-pyridin-2-yl-ethylamine (89 mg, 0.534 mmol) (Organic Process Research & Development 8:192-200, 2004), in DMSO (3 mL) was stirred for 18 hrs at 80° C. LC/MS (ESI) (M+H+ 580.2) indicated the formation of desired product. After removing most DMSO by high-vacuum rotary evaporation, water was added, after which time precipitate formed. The liquid was loaded onto a 5 g FisherBrand PrepSep SPE C18 cartridge. The solid was washed with water a few times. The washes were also loaded onto the cartridge. The cartridge was then washed with water (40 mL), acetonitrile (20 mL), mixture of acetonitrile/DCM (1:1, 20 mL) and DMF (10 mL). All organic washes were combined and stripped off solvent by rotary evaporation. An orange solid was obtained and used without further purification. LC/MS (ESI): M+H+ 580.1.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH:3]([OH:8])[C:4]([F:7])([F:6])[F:5].[OH-].[Na+].[P:13](OC1C=CC=CC=1)([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[P:13]([O:8][CH:3]([C:4]([F:7])([F:6])[F:5])[C:2]([F:10])([F:9])[F:1])([O:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[O:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: OC(C(F)(F)F)C(F)(F)F
Reactant: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Product: FC(F)(F)C(OP(Oc1ccccc1)Oc1ccccc1)C(F)(F)F
Reaction time: 1 h
Yield: 18.5 %

Procedure:
An amount of 28.2 mmol of 1,1,1,3,3,3-hexafluoro-2-propanol together with 0.1 mmol of solid sodium hydroxide was added to 84.6 mmol of triphenyl phosphite at a temperature of 22° C. The mixture thus formed was stirred for one hour and then heated under reflux for another hour. Then the solvent was evaporated from the mixture, giving a residue which was distilled at sub-atmospheric pressure to isolate the title compound in a yield of 18.5%, calculated on starting 1,1,1,3,3,3-hexafluoro-2-propanol.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[N:28]1[C:37]2[C:32](=[CH:33][C:34]([C:38](O)=[O:39])=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:38]([C:34]5[CH:33]=[C:32]6[C:37](=[CH:36][CH:35]=5)[N:28]=[CH:29][CH:30]=[CH:31]6)=[O:39])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: O=C(O)c1ccc2ncccc2c1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1)c1ccc2ncccc2c1

Procedure:
The title compound, off-white solid (120 mg, 99%), MS (ISP) m/z=486.4 [(M+H)+], mp 227° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and quinoline-6-carboxylic acid.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.[I-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)C.[Br:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[O:38][C:39]([F:42])([F:41])[F:40])[CH:33]=O.O>CCCCCC.O1CCCC1>[Br:29][C:30]1[CH:31]=[C:32]([CH:33]=[C:2]([CH3:3])[CH3:1])[CH:35]=[CH:36][C:37]=1[O:38][C:39]([F:42])([F:41])[F:40]
Reactant: [Li]CCCC
Reactant: O=Cc1ccc(OC(F)(F)F)c(Br)c1
Agent: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)=Cc1ccc(OC(F)(F)F)c(Br)c1
Yield: 56.5 %

Procedure:
150 ml of 20% strength solution of n-butyl-lithium in n-hexane were added dropwise to a suspension of 129.6 g (0.3 mol) of dry isopropyl-triphenylphosphonium iodide in 500 ml of anhydrous tetrahydrofuran, under nitrogen at 0° C. and while stirring. The deep red solution thus obtained was stirred for a further 15 minutes at 0° C., and 80.7 g (0.3 mol) of 3-bromo-4-trifluoromethoxybenzaldehyde were then added dropwise at 0° to 10° C. The mixture was then stirred at room temperature until decolorization occurred (approximately 12 hours). 900 ml of water were then added to the reaction mixture, and the mixture was extracted with 5 times 200 ml of petroleum ether. The petroleum ether phases were dried over magnesium sulphate, and the solvent was then stripped off in a rotary evaporator, in the vacuum from a water jet. 150 ml of n-hexane were added to the residue, and the mixture was stirred thoroughly and then filtered. The solvent was then distilled off from the filtrate under normal pressure, and the oily residue was then distilled in vacuo. 50 g (56.5% of theory) of 1-(3-bromo-4-trifluoromethoxyphenyl)-2-methyl-prop-1-ene were obtained as a slightly yellowish liquid of boiling point 107° to 108° C./10 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[C:9]([OH:10])=[C:8]([O:11]C)[CH:7]=[C:6]([Cl:13])[C:3]=1[CH:4]=[O:5].B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[C:9]([OH:10])=[C:8]([OH:11])[CH:7]=[C:6]([Cl:13])[C:3]=1[CH:4]=[O:5]
Reactant: COc1cc(Cl)c(C=O)c(Cl)c1O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=Cc1c(Cl)cc(O)c(O)c1Cl
Temperature: -65 °C
Reaction time: 16 h
Yield: 96.2 %

Procedure:
Into an oven-dried, three-neck round bottom flask, fitted with a thermometer, 1.0 g (4.52 mmol; Aldrich, Milwaukee, Wis.) of 2,6-dichloro-3-hydroxy-4-methoxybenzaldehyde and 45 mL of dichloromethane were added under nitrogen atmosphere. The solution was cooled to −65° C. and 1.32 mL (14 mmol) of boron tribromide was added dropwise. The reaction mixture was left to warm up slowly to room temperature with stirring for 16 hours. The reaction mixture was carefully quenched with the addition of 5 mL of water, then transferred to a single-neck round bottom flask and volatiles were removed in vacuo. The residue was taken up with 50 mL of ethylacetate and washed three times with water and two times with brine. The organic layer was dried over MgSO4, then concentrated to yield 0.9 g (96%) of crude 2,6-dichloro-3,4-dihydroxybenzaldehyde, as an off-white solid, which was used without further purification. H-NMR δ (d6-acetone): 6.85 (1H, s), 9.1 (2H, br s), 10.2 (1H, s). Melting point=213-215° C.
Reaction SMILES: [Mg].[CH3:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.CON(C)[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=1)=[O:15]>C1(C)C=CC=CC=1.O1CCCC1.BrCCBr>[CH3:22][C:18]1[N:17]=[C:16]([C:14](=[O:15])[CH2:7][C:6]2[CH:9]=[CH:10][C:3]([CH3:2])=[CH:4][CH:5]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: CON(C)C(=O)c1cccc(C)n1
Reactant: Cc1ccc(CCl)cc1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: BrCCBr
Product: Cc1ccc(CC(=O)c2cccc(C)n2)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a slurry of magnesium turnings (406 mg, 16.7 mmol) in toluene (10 mL) is added 4-methylbenzylchloride (10 mg, 0.06 mmol) dropwise in tetrahydrofuran (0.2 mL). Two drops of 1,2-dibromoethane are added, the mixture heated to 50° C., and allowed to cool to room temperature. This process is repeated until reaction initiates. 4-Methylbenzylchloride (1.5 g, 10 mmol) in tetrahydrofuran (7 mL) is added slowly while keeping the internal temperature below 32° C. After the addition is complete the reaction is stirred at room temperature for 1 h. The reaction mixture is added dropwise over 5 minutes to a solution of 6-methyl-pyridine-2-carboxylic acid methoxy-methyl-amide (Prep 250, 1 g, 5.6 mmol) in toluene (5 mL). The reaction is stirred for an additional 45 minutes. The reaction is quenched with 1 N hydrochloric acid and stirred for 30 minutes. The aqueous layer is neutralized with saturated sodium bicarbonate and extracted twice with ethyl acetate. The combined organic extracts are washed with brine, dried (sodium sulfate), filtered and concentrated in vacuo. The crude residue is chromatographed on SiO2 (50% ethyl acetate/hexane to 75% ethyl acetate/hexane) to yield the title compound, 633 mg (25%), as a brown oil.
Reaction SMILES: [Br:1]C1C=C2C(=CC=1)NN=C2.ClC1C=C2C(=NC=1)NC=C2.FC1C=C2C(=NC=1)NC=C2.N1C2C(=CC=CN=2)C=C1.[F:40][C:41]1[C:46]([C:47]([C:49]2[C:57]3[C:52](=[N:53][CH:54]=[C:55](F)[CH:56]=3)[NH:51][CH:50]=2)=[O:48])=[CH:45][CH:44]=[CH:43][C:42]=1[NH:59][S:60]([CH2:63][CH2:64][CH3:65])(=[O:62])=[O:61].FC1C(C(C2C3C(=NC=CC=3)NC=2)=O)=CC=CC=1NS(CCC)(=O)=O>>[Br:1][C:55]1[CH:56]=[C:57]2[C:49]([C:47]([C:46]3[C:41]([F:40])=[C:42]([NH:59][S:60]([CH2:63][CH2:64][CH3:65])(=[O:62])=[O:61])[CH:43]=[CH:44][CH:45]=3)=[O:48])=[CH:50][NH:51][C:52]2=[N:53][CH:54]=1
Reactant: CCCS(=O)(=O)Nc1cccc(C(=O)c2c[nH]c3ncc(F)cc23)c1F
Reactant: Brc1ccc2[nH]ncc2c1
Agent: CCCS(=O)(=O)Nc1cccc(C(=O)c2c[nH]c3ncccc23)c1F
Agent: Clc1cnc2[nH]ccc2c1
Agent: Fc1cnc2[nH]ccc2c1
Product: CCCS(=O)(=O)Nc1cccc(C(=O)c2c[nH]c3ncc(Br)cc23)c1F

Procedure:
Using the protocol of Scheme 14, substituting 5-bromo-azaindole with either 5-chloro-7-azaindole (80, prepared as described in Example 9), 5-fluoro-7-azaindole (81, prepared as described in Example 9) or 7-azaindole in Step 6, propane-1-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide P-1013 (MS (ESI) [M−H+]−=394.1), propane-1-sulfonic acid [2-fluoro-3-(5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide P-1028 (MS (ESI) [M−H+]−=378.1), and propane-1-sulfonic acid [2-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide P-1056 (MS (ESI) [M+H+]+=362.2) were prepared, respectively;
Reaction SMILES: [CH3:1][C@@H:2]([O:6][C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([O:17]CC2C=CC=CC=2)[CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])[CH2:3][O:4][CH3:5]>C1COCC1.C(O)C.[Pd]>[OH:17][C:15]1[CH:14]=[C:9]([CH:8]=[C:7]([O:6][C@H:2]([CH3:1])[CH2:3][O:4][CH3:5])[CH:16]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC[C@@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)OC)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COC[C@@H](C)Oc1cc(O)cc(C(=O)OC)c1
Reaction time: 16 h

Procedure:
A solution of methyl 3-{[(1R)-1-methyl-2-(methyloxy)ethyl]oxy}-5-[(phenylmethyl)oxy]benzoate in THF (5 mL) and ethanol (5 mL), containing 10% palladium on carbon, was stirred under an atmosphere of hydrogen for 16 hours. The palladium on carbon was removed by filtration and the filtrate evaporated under reduced pressure to give the desired material as a clear gum (723 mg).
Reaction SMILES: [CH:1]1([O:6][CH2:7][C:8]([OH:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:11]1(C)C=CC(S(O)(=O)=O)=CC=1.CO>O>[CH:1]1([O:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)COC1CCCC1
Solvent: O
Solvent: CO
Product: COC(=O)COC1CCCC1
Temperature: 25 °C
Yield: 4424.1 %

Procedure:
In a three necks 500 ml flask were introduced, in the following order, 65 g (451 mmol) of (cyclopentyloxy)acetic acid (obtained according to U.S. Pat. No. 4,735,932), 1.4 g of para-toluenesulfonic acid and 280 ml of MeOH. After 6 hours at reflux, the reaction mixture was cooled at room temperature diluted into 300 ml of water and extracted with 300 ml of ether. The organic phase thus obtained was washed twice with water, dried over MgSO4 and concentrated. It was thus obtained 56.9 g of product (yield=80%) having a GC purity of 99%.
Reaction SMILES: Cl.[CH2:2]([O:9][NH2:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(OCC)C.[OH-].[Na+].[C:18]1([N:24]=[C:25]=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[CH2:2]([O:9][NH:10][C:25]([NH:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:26])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NOCc1ccccc1
Reactant: O=C=Nc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: O=C(NOCc1ccccc1)Nc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
Under a nitrogen atmosphere, a flask was charged sequentially with O-benzylhydroxylamine hydrochloride (37.5 g, 0.23 mole), water (40 mL) and diethyl ether (400 mL). The resulting mixture was cooled to 0° C. and a solution of sodium hydroxide (9.4 g, 0.23 mole) in water (40 mL) was added dropwise. After 0.5 hour, phenyl isocyanate (25.5 mL, 0.23 mole) was added. A white precipitate formed. The reaction was maintained at ambient temperature for 2 hours. The precipitate was isolated by filtration, washed with water and dried to provide 46.2 g of 1-benzyloxy-3-phenyl urea as a white crystalline solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C@@H:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:9][NH:10][C:11](=[O:15])[C@@H:12]([CH3:14])[NH2:13])([CH3:4])([CH3:3])[CH3:2].[C:24]([O:28][C:29]([NH:31][C@H:32]([C:43](O)=[O:44])[CH2:33][C:34]1[C:39]([CH3:40])=[CH:38][C:37]([OH:41])=[CH:36][C:35]=1[CH3:42])=[O:30])([CH3:27])([CH3:26])[CH3:25].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C.CCOC(C)=O>[C:24]([O:28][C:29]([NH:31][C@H:32]([C:43]([NH:13][C@@H:12]([C:11]([NH:10][CH2:9][C@@H:8]([NH:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:23])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:15])[CH3:14])=[O:44])[CH2:33][C:34]1[C:35]([CH3:42])=[CH:36][C:37]([OH:41])=[CH:38][C:39]=1[CH3:40])=[O:30])([CH3:26])([CH3:27])[CH3:25]
Reactant: C[C@@H](N)C(=O)NC[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: Cc1cc(O)cc(C)c1C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(O)cc(C)c1C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C)C(=O)NC[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 109.4 %

Procedure:
tert-Butyl-[(1S)-2-(D-alanylamino)-1-benzylethyl]carbamate (described in PC33903A Preparation 36; 3.43 g, 9.94 mmol) and N-(tert-butoxycarbonyl)-2,6-dimethyl-L-tyrosine (described in BioOrg. Med. Chem. Letts, 2003, p 599; 2.92 g, 9.25 mmol) were added sequentially to a stirred solution of 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride salt (2.29 g, 11.9 mmol), 1-hydroxybenzotriazole monohydrate (1.57 g, 10.2 mmol) and N-methylmorpholine (1.01 g, 9.94 mmol) in DMF (70 mL) at room temperature under a nitrogen atmosphere. The mixture was stirred at room temperature for 16 h and then diluted with 280 mL of EtOAc and washed with 280 mL of a 10% aqueous solution of citric acid, 280 mL of water, 280 mL of a 3% aqueous solution of sodium bicarbonate, and finally 200 mL of a saturated aqueous brine solution. The organic layer was dried over sodium sulfate and evaporated under reduced pressure to give 6.2 g (92%) of a white foam of the title compound, which was used with no further purification.
Reaction SMILES: [BH4-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[C:11](=O)[CH3:12].[C:14]([S-:16])#[N:15].[K+].Cl>C(O)C.CCCCCCC.C(OCC)(=O)C.O>[Cl:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]2[C:5]=1[CH:11]([CH3:12])[NH:15][C:14](=[S:16])[NH:3]2
Reactant: N#C[S-]
Reactant: CC(=O)c1c(N)cccc1Cl
Agent: Cl
Agent: [BH4-]
Agent: [K+]
Solvent: CCCCCCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC1NC(=S)Nc2cccc(Cl)c21
Temperature: 65 °C

Procedure:
At a temperature of 65° C., sodium borohydride was added to a solution of 1-(2-amino-6-chloro-phenyl)-ethanone in ethanol, and the mixture was heated overnight (65° C.). Water, KSCN and HCl were then added subsequently, and the mixture was again heated (3 h, 65° C.). The majority of the title compound precipitated upon cooling and could be isolated in sufficiently pure form by filtration. A small additional amount of the desired product was obtained by workup of the mother liquor (evaporation of solvent, column chromatography [silica gel, solvent gradient n-heptan/ethyl acetate=100/0−60/40]). The title compound was obtained in a combined yield of 1.46 g (43%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=[O:7])[C:5]2=[CH:11][C:12]=1[Cl:13].[NH3:14]>C1COCC1>[C:9]([C:4]1[CH:3]=[C:2]([Cl:1])[C:12]([Cl:13])=[CH:11][C:5]=1[C:6]([OH:8])=[O:7])(=[O:10])[NH2:14]
Reactant: O=C1OC(=O)c2cc(Cl)c(Cl)cc21
Reactant: N
Solvent: C1CCOC1
Product: NC(=O)c1cc(Cl)c(Cl)cc1C(=O)O
Yield: 80 %

Procedure:
4,5-Dichlorophthalic acid, anhydride (20.0 g, 92.2 mmol) was dissolved in dry THF (400 mL) and cooled in an ice bath. Ammonia gas was then passed through this solution for 10 minutes to afford a precipitate. The THF was removed and water (400 mL) was added. This aqueous solution was brought to acidic pH with 10% aqueous HCl whereupon a precipitate appeared. This solid was collected, washed with water and dried in vacuo to provide the product (17.3 g, 80%) as a tan solid, m.p. 197°-201° C.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([NH2:28])[C:5]2[N:6]=[C:7]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[CH2:29]=[CH:30][CH2:31][CH2:32][CH2:33][CH3:34]>>[CH:29](/[C:2]1[N:3]=[C:4]([NH2:28])[C:5]2[N:6]=[C:7]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11])=[CH:30]\[CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: C=CCCCC
Reactant: Nc1nc(I)nc2c1nc(NCc1ccccc1)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Product: CCCC/C=C/c1nc(N)c2nc(NCc3ccccc3)n([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Reaction time: 0.58 h

Procedure:
The reaction was performed with 2-iodo-8-benzylaminoadenosine (11, 410 mg, 0.82 mmol) and (E)-1-borocatechol)-1-hexene (2.47 mmol). The mixture was purified by column chromatography (10% MeOH in CH2Cl2). Yield 41 mg (0.10 mmol, 11%), mp 153–155÷C; 1H NMR (MeOD-d4) δ 7.64 (t, 1H, J=6.10 Hz, NH), 7.36–7.18 (m, 5H, phenyl), 6.59 (bs, 2H, NH2), 6.94–6.80 (m, 1H, ═CHCH2), 6.28 (d, 1H, J=15.42 Hz, ═CH), 5.92 (d, 1H, J=7.71 Hz, H-1′), 5.77 (t, 1H, J=4.85 Hz, OH-2′), 5.32 (d, 1H, J=6.74 Hz, OH-5′), 5.18 (d, 1H, J=4.18 Hz, OH-3′), 4.64 (q, 1H, J=4.64 Hz, H-2′), 4.58 (t, 2H, J=4.65 Hz, NHCH2), 4.09 (t, 1H, J=4.09 Hz, H-3′), 3.98 (d, 1H, J=1.60 Hz, H-4′), 3.62 (q, 2H, J=2.58 Hz, H-5′), 2.29–2.05 (m, 2H, ═CHCH2), 1.72–1.20 (m, 4H, CH2CH2), 1.00–0.83 (m, 3H, CH3) ppm; MS m/z 456 (M+H)+; HPLC, System A: 20–100% CH3CN in H2O in 35 min., retention time=9.61 min.; System B: 30–100% CH3OH in H2O in 40 min., retention time=26.10 min.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([OH:10])[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>C(Cl)(Cl)Cl>[C:11]([NH:1][CH2:2][C:3]1([OH:10])[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]1)(=[O:13])[CH3:12]
Reactant: CN1CCC(O)(CN)CC1
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)NCC1(O)CCN(C)CC1
Reaction time: 0.5 h

Procedure:
4-Aminomethyl-4-hydroxy-1-methylpiperidine (0.83 g., 5.7 mmole) was dissolved in 10 ml. chloroform, and acetic anhydride (0.58 g., 5.7 mmole) was added. The reaction mixture warmed spontaneously to 40°-50° C. After 30 minutes, the solvent was evaporated and the crude residue was chromatographed on a silica gel column (Merck 7734), using 33:67 2% aqueous ammonia-methanol as eluent.
Reaction SMILES: [CH:1]([NH:4][C:5]1[O:6][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]=[C:13]3[N+:19]([O-])=O)=[N:8][N:9]=1)([CH3:3])[CH3:2].NN>CO.[Ni]>[NH2:19][C:13]1[C:12]2[C:16](=[CH:17][CH:18]=[C:10]([C:7]3[O:6][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[N:9][N:8]=3)[CH:11]=2)[NH:15][CH:14]=1
Reactant: CC(C)Nc1nnc(-c2ccc3[nH]cc([N+](=O)[O-])c3c2)o1
Agent: [Ni]
Agent: NN
Solvent: CO
Product: CC(C)Nc1nnc(-c2ccc3[nH]cc(N)c3c2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.8 %

Procedure:
To a suspension of Raney-Ni (100 mg) in MeOH (2 mL) was added N-isopropyl-5-(3-nitro-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (200 mg, 0.698 mmol) followed by addition of NH2NH2 (0.2 mL). The reaction mixture was stirred at RT for 1 h. The mixture was then filtered through a plug of Celite and the filtrate was concentrated. The residue was treated with water and the resulting suspension was filtered, washed with water and dried. The crude product was purified by washing with petroleum ether (2×5 mL) to afford 5-(3-amino-1H-indol-5-yl)-N-isopropyl-1,3,4-oxadiazol-2-amine (50 mg, 27%) as a brown solid. MS (ESI, pos. ion) m/z: 258.2 (M+1); 1H-NMR (400 MHz, DMSO-d6): δ 10.43 (s, 1H), 8.02 (s, 1H), 7.46-7.49 (m, 2H), 7.30 (d, 1H, J=8.4 Hz), 6.67 (brs, 1H), 4.27 (s, 2H), 3.70-3.76 (m, 1H), 1.23 (d, 6H, J=6.4 Hz).
Reaction SMILES: Br[C:2]1[C:22]([O:23][CH3:24])=[CH:21][C:5]2[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[C:4]=2[CH:3]=1.C1(B(O)O)C=CC=CC=1.[F:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1>>[F:34][C:35]1[CH:40]=[CH:39][C:38]([C:2]2[C:22]([O:23][CH3:24])=[CH:21][C:5]3[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]4[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=4)[C:14]#[N:15])[C:4]=3[CH:3]=2)=[CH:37][CH:36]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: COc1cc2c(cc1Br)C(c1cccc(C#N)c1)=NCC(=O)N2C
Agent: OB(O)c1ccccc1
Product: COc1cc2c(cc1-c1ccc(F)cc1)C(c1cccc(C#N)c1)=NCC(=O)N2C
Yield: 43 %

Procedure:
Prepared from 3-(7-bromo-8-methoxy-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-benzonitrile Intermediate 9 using the same method described for Example 1 and instead of using benzene boronic acid, we used p-fluorophenyl boronic acid. The title compound (66 mg) was obtained as a white solid, (yield=43%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[C:4]([C:19]#[N:20])[N:3]=1.[SH2:21].CCN(CC)CC>C(O)(C)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[C:4]([C:19](=[S:21])[NH2:20])[N:3]=1
Reactant: N#Cc1nc(N)nc2c1ncn2Cc1ccccc1F
Reactant: S
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: NC(=S)c1nc(N)nc2c1ncn2Cc1ccccc1F
Temperature: 50 °C
Yield: 100 %

Procedure:
A suspension of 2-amino-9-(2-fluorobenzyl)-9H-purine-6-carbonitrile (680 mg, 1.85 mmol) in isopropanol (50 mL) was treated with H2S gas for 15 min, then treated with Et3N (0.51 mL, 3.7 mmol), heated at 50° C. for 1 h, concentrated in vacuo, diluted with Et2O and filtered to give the title compound (757 mg, 100%) as a yellow solid; NMR δH (400 MHz, DMSO) 5.36 (2H, s), 6.66 (2H, br s), 7.06-7.43 (4H, m), 8.15 (1H, s), 9.81 (1H, br s) and 10.22 (1H, br s).