Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[C:10]([O-:13])(=O)[CH3:11].[Na+].[C:15](OC(=O)C)(=[O:17])[CH3:16]>C(O)(=O)C>[C:15]([O:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:10](=[O:13])[CH3:11])=[C:3]([CH3:9])[CH:4]=1)(=[O:17])[CH3:16]
Reactant: Cc1cc(O)ccc1N
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(OC(C)=O)cc1C
Temperature: 125 °C
Reaction time: 1 h

Procedure:
4.66 g (37.5 mmol) 4-amino-3-methylphenol, 5.00 mL glacial acetic acid, 0.500 g (6.09 mmol) sodium acetate and 7.87 mL (83.3 mmol) acetic anhydride were combined and stirred for 1 h at 125° C. After cooling to RT, ice water was added to the reaction mixture. The precipitate formed was suction filtered, washed with water and dried under HV.
Reaction SMILES: [Cl:1][C:2]1[N:10](CC=C)[C:9]2[C:8](=[O:14])[N:7]([CH3:15])[C:6](=[O:16])[NH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:23](I)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].N1CCOCC1>CN(C=O)C.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:14])[N:7]([CH3:15])[C:6](=[O:16])[N:5]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:4]=2[N:3]=1
Reactant: C=CCn1c(Cl)nc2[nH]c(=O)n(C)c(=O)c21
Reactant: CCCCCCI
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCN1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCn1c(=O)n(C)c(=O)c2[nH]c(Cl)nc21
Temperature: 25 °C
Reaction time: 90 h
Yield: 54.4 %

Procedure:
To a solution of 8-chloro-1-methyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (100 mg, 0.42 mmol) in anhydrous DMF (3 ml) was added sodium carbonate (58 mg, 0.54 mmol), after 10 minutes stirring hexyl iodide (0.08 ml, 0.54 mmol) was added and the reaction mixture stirred at room temperature under nitrogen for 90 hours. Pd(PPh3)4 (73 mg, 0.063 mmol) was then added and the reaction vessel evacuated and flushed with nitrogen (x3), morpholine (0.37 ml, 4.3 mmol) was added and stirring at room temperature under nitrogen continued for 4 hours. The reaction mixture was diluted with EtOAc (25 ml) and washed with 2M HCl aq. (25 ml). The organic extract was dried (MgSO4) filtered and evaporated. Purification by aminopropyl SPE (5 g) loading the compound and washing with MeOH before eluting the product with 5% AcOH/MeOH afforded the title compound as a white solid (65 mg, 54%). NMR; δH (400 MHz, d6-DMSO) ) 0.85 (t, 3H, J=7 Hz), 1.23-1.33 (m, 6H), 1.58-1.68 (m, 2H), 3.22 (s, 3H), 3.91 (t, 2H, J=7.5 Hz), 14.46 (br. s, 1H); m/z 285.3 [MH+].
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[CH2:7][N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[NH:10][C:9]1=[O:19])(O)=[O:2].[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>O.CN(C=O)C>[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:30][CH2:31][N:32]([C:1]([C:4]2[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=2)[CH2:7][N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[NH:10][C:9]2=[O:19])=[O:2])[CH2:33][CH2:34]1
Reactant: O=C(O)c1cccc(Cn2c(=O)[nH]c(=O)c3ccccc32)c1
Reactant: c1ccc(N2CCNCC2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(c1cccc(Cn2c(=O)[nH]c(=O)c3ccccc32)c1)N1CCN(c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 8.7 %

Procedure:
1-(3-carboxybenzyl)quinazoline-2,4(1H,3H)-dione (0.2 mmol), 1-(pyridin-2-yl)piperazine (0.2 mmol), 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU, 0.26 mmol), N,N-diisopropylethylamine (DIPEA, 0.4 mmol) and DMF (5 mL) were added into a 50 mL two-mouth flask. The obtained mixture was stirred at room temperature for 3 hours. To the mixture was added 50 mL of water and it was extracted by dichloromethane (DCM, 50 mL×2). The organic layer was washed by 1N HCl (50 mL×2) and saturated NaCl aquenous solution (50 mL×2), dried with anhydrous sodium sulphate, and evaporated under reduced pressure to give the crude product. The crude product was purified by column chromatography (ethyl acetate) to give the title compound as white solid (7.7 mg, 8.6% yield). 1H NMR (DMSO-d6): 11.69 (s, 1H), 8.09 (dd, J=5.0 and 1.7 Hz, 1H), 7.99 (dd, J=8.0 and 1.7 Hz, 1H), 7.64 (t, J=7.1 Hz, 1H), 7.53 (t, J=7.8 Hz, 1H), 7.40-7.21 (m, 6H), 6.77 (d, J=8.7 Hz, 1H), 6.64 (dd, J=7.1 and 5.0 Hz, 1H), 5.34 (s, 2H), 3.40-3.20 (m, 8H). MS: m/z 442.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[CH:11][C:12](=O)[NH:13][CH:14]=2)=[CH:5][CH:4]=1.P(Br)(Br)([Br:18])=O>O>[Br:18][C:12]1[CH:11]=[N:10][C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:14][N:13]=1
Reactant: COc1ccc(-c2c[nH]c(=O)cn2)cc1
Reactant: O=P(Br)(Br)Br
Solvent: O
Product: COc1ccc(-c2cnc(Br)cn2)cc1
Reaction time: 18 h

Procedure:
26.1 g of 5-(4-methoxyphenyl)-2(1H)pyrazinone and 140 g of phosphorusoxybromide are heated to 100° C. for 45 minutes. After cooling, the hardened mass is added in batches to ice and water, with stirring. After 30 minutes stirring the mixture is left to stand for 18 hours and the precipitate is suction filtered. The filtrate is extracted with methylene chloride and the precipitate is dissolved in methylene chloride extract. The methylene chloride solution is washed with sodium bicarbonate solution, dried, filtered over activated charcoal and evaporated down.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:7]([OH:14])=[C:6]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:5]=1)([O-])=O.[H][H]>C(O)C.ClCCl.[Pd].CCCCCCC>[NH2:1][C:4]1[CH:5]=[C:6]([C:15]([CH3:16])([CH3:17])[CH3:18])[C:7]([OH:14])=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:9]=1
Reactant: [H][H]
Reactant: CC(C)(C)c1cc([N+](=O)[O-])cc(C(C)(C)C)c1O
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Solvent: CCCCCCC
Product: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O
Yield: 50 %

Procedure:
In a 250 ml Parr flask, 3.6 g (14 mmoles) of 4-nitro-2,6-bis-(1,1-dimethylethyl)-phenol (J. Org; Chem. (1968), 33 (1), 223-226) is dissolved in 60 ml of a (2/1) mixture of ethanol and dichloromethane in the presence of a catalytic quantity of 10% Pd/C. The mixture is agitated for 2 hours, at 20° C., under 20 PSI of hydrogen. After filtration on celite, the filtrate is concentrated to dryness under reduced pressure. The reddish-brown powder obtained is suspended in heptane (30 ml), filtered and rinsed with the same volume of heptane. The expected product is obtained in the form of an salmon pink powder with a yield of 50% (1.56 g). Melting point: 123-124° C.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([O:17][C:18]([N:20]1[C:24]([CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=O)=[CH:23][N:22]=[CH:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[CH2:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH:33]1[NH:41][C:42]1[N:43]=[CH:44][C:45]2[CH2:51][NH:50][CH2:49][CH2:48][C:46]=2[N:47]=1.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH2:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH:33]1[NH:41][C:42]1[N:43]=[CH:44][C:45]2[CH2:51][N:50]([C:29](=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][C:24]3[N:20]([C:18]([O:17][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:19])[CH:21]=[N:22][CH:23]=3)[CH2:49][CH2:48][C:46]=2[N:47]=1
Reactant: c1ccc2c(c1)CC(Nc1ncc3c(n1)CCNC3)C2
Reactant: CC(C)(C)OC(=O)n1cncc1CCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1cncc1CCCCC(=O)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Temperature: 40 °C
Yield: 32.3 %

Procedure:
Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.092 g; 1.5 equiv; 0.48 mmoles) to a solution of 5-(3-tert-butoxycarbonylimidazol-4-yl)pentanoic acid (0.084 g; 1.0 equiv; 0.31 mmoles), N-indan-2-yl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (0.064 g; 0.77 equiv; 0.24 mmoles), 1-hydroxybenzotriazole (0.065 g; 1.5 equiv; 0.48 mmoles), and triethylamine (0.20 mL; 4.5 equiv; 1.44 mmoles) in dichloromethane (15 mL). Heat the mixture to 40° C. for 16 hours. Concentrate the mixture, and then purify the crude product by column chromatography (0 to 10% methanol in dichloromethane) to afford tert-butyl 5-[5-[2-(indan-2-ylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-5-oxo-pentyl]imidazole-1-carboxylate (0.040 g; 25%) as a white solid: MS (m/z): 517 (M+1).
Reaction SMILES: [Cl-].[NH4+:2].[Al](C)(C)C.C[O:8][C:9]([C:11]1[CH:16]=[N:15][C:14]([Cl:17])=[CH:13][N:12]=1)=O>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:17][C:14]1[N:15]=[CH:16][C:11]([C:9]([NH2:2])=[O:8])=[N:12][CH:13]=1
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: [NH4+]
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: NC(=O)c1cnc(Cl)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 34 %

Procedure:
Suspend ammonium chloride (0.465 g, 8.69 mmol) in toluene (14 mL). Cool to 0° C. and slowly add 2.0 M Al(CH3)3 in toluene (4.3 mL, 8.69 mmol). After the gas stops evolving, add 5-chloropyrazine-2-carboxylic acid methyl ester (0.500 g, 2.89 mmol). Heat at 50° C. overnight. Cool the reaction mixture to room temperature, then slowly pour into a slurry of silica gel (10 g) in CHCl3 (50 mL). Stir for 10 minutes before filtering. Wash the silica plug with methanol (2×100 mL) before concentrating. Take the resulting solid up in dichloromethane and wash with water (30 mL) and brine (40 mL). Dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatographly, eluting with 50% ethyl acetate in hexanes to give the title compound (0.155 g, 34.0%): TOF MS EI+ 157.0 (M+), HRMS calcd for C5H4N3OCl 157.0043 (M+H)+, found 157.0047, time 4.19 min HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95% over 19 min], tR=7.1 min, 100% purity.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:16])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[CH:8]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)c1cccc(N)c1
Reaction time: 3 h
Yield: 100 %

Procedure:
A solution of 3-nitro-benzoic acid t-butyl ester (3.77 g, 16.9 mmol), prepared as in Intermediate 15, in absolute ethanol (50 mL) is combined with palladium on carbon (10 wt %, 0.30 g) and stirred under atmospheric hydrogen for approximately 3 hrs. The reaction mixture is filtered through a pad of diatomaceous earth and then concentrated in vacuo to an oil which crystallized when dried under high vacuum providing the title compound as a tan solid (3.28 g, 16.9 mmol). 1H NMR (300 MHz, CDCl3) δ=1.58 (s, 9H); 6.79-6.87 (m, 1H), 7.19 (t, J=8.5 Hz, 1H); 7.24-7.34 (m, 1H); 7.38 (d, J=8.0 Hz, 1H). MS (Cl): [M+H]+ =194.
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([C:16](O)=[O:17])[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[NH:23]1[CH2:33][CH2:32][CH:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:25][CH2:24]1>C1(C)C=CC=CC=1.CN(C)C=O>[CH:11]1[C:12]2[C:13]3([C:16]([N:23]4[CH2:24][CH2:25][CH:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:32][CH2:33]4)=[O:17])[CH2:15][CH:6]([C:5]4[C:14]3=[CH:1][CH:2]=[CH:3][CH:4]=4)[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=C(O)C12CC(c3ccccc31)c1ccccc12
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCN(C(=O)C23CC(c4ccccc42)c2ccccc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
A solution of 9,10-dihydro-9,10-methano-9-anthracenecarboxylic acid (21.8 g, 92.4 mmol) in toluene (160 mL) was treated with thionyl chloride (11.7 g, 99 mmol) and N,N-dimethylformamide (0.1 g). The resulting solution was heated to reflux temperature for 2 h, then was cooled to room temperature. The mixture was then treated dropwise with a solution of ethyl isonipecotate (31.1 g, 198 mmol) in toluene (20 mL), using an ice/water bath to keep the reaction temperature <35° C. Upon complete addition, the mixture was stirred for 1 h at room temperature, then was washed sequentially with 10% hydrochloric acid (40 mL), water (40 mL), 1N aqueous sodium hydroxide (40 mL), water (40 mL) and brine (40 mL). The aqueous washes were extracted with toluene (100 mL). The organic extracts were combined, dried (MgSO4), filtered and concentrated to afford the title compound (33.0 g, 85.2 mmol, 92%) as an off-white solid. 1H NMR (d6-DMSO): δ7.33-7.14 (m, 4H), 6.99 (m, 4H), 4.54 (br, 1H), 4.38 (s, 1H, H--C(10)), 4.09 (q, J=6.5 Hz, 2H, CH2CH3), 3.8 (br, 1H), 3.0-2.5 (br, 6H), 2.05-1.45 (br, 5H), 1.19 (t, J=6.5 Hz, 3H, CH2CH3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([C:23]([NH:25][C:26]([CH3:37])([CH3:36])[CH2:27][NH:28]C(=O)OC(C)(C)C)=[O:24])=[C:16]2[N:15]=1.[ClH:38].O1CCOCC1>C(Cl)Cl>[ClH:38].[NH2:28][CH2:27][C:26]([NH:25][C:23]([C:22]1[CH:21]=[N:20][N:17]2[CH:18]=[CH:19][C:14]([N:10]3[CH2:11][CH2:12][CH2:13][C@@H:9]3[C:3]3[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=3[F:1])=[N:15][C:16]=12)=[O:24])([CH3:37])[CH3:36]
Reactant: CC(C)(CNC(=O)OC(C)(C)C)NC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(CN)NC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(R)-tert-butyl 2-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamido)-2-methylpropylcarbamate (109 mg, 0.212 mmol) was dissolved in DCM (1.0 mL) and 4N HCl in dioxane (0.530 mL, 2.12 mmol) was added. The mixture was stirred at ambient temperature for 4 hours and was concentrated afford the title compound (105 mg). MS (apci) m/z=415.2 (M+H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=[O:10])[NH:2]1.[CH3:11][C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[CH2:14][N:15]=[C:16]=[O:17]>>[CH3:11][C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[CH2:14][NH:15][C:16]([N:2]1[C:3](=[O:10])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1]1)=[O:17]
Reactant: O=c1[nH]sc2ccccc12
Reactant: Cc1ccccc1CN=C=O
Product: Cc1ccccc1CNC(=O)n1sc2ccccc2c1=O

Procedure:
Following the synthetic procedure of 6a as described in Example 1, compound 6j (56% yield) was synthesized from benzo[d]isothiazol-3-one and 2-methylbenzyl isocyanate as a white solid. mp 184-186° C.; IR(CHCl3) 3281, 1705, 1652, 1528 cm−1; 1H-NMR (DMSO-d6) δ2.32 (s, 3H), 4.52 (d, J=5.9 Hz, 2H), 7.15-7.19 (m, 3H), 7.27-7.30 (m, 1H), 7.48 (t, J=7.6 Hz, 1H), 7.78 (t, J=8.2 Hz, 1H), 7.93 (d, J=8.2 Hz, 1H), 8.01 (d, J=8.2 Hz, 1H), 9.18 (t, J=5.9 Hz, 1H); ESIMS m/e 299 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:5]=[N:6][C:7]=1[N+:8]([O-])=O.O.Cl[Sn]Cl>CCO.C(Cl)Cl>[Br:1][C:2]1[C:7]([NH2:8])=[N:6][CH:5]=[C:4]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[CH:3]=1
Reactant: O=[N+]([O-])c1ncc(N2CCOCC2)cc1Br
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: Nc1ncc(N2CCOCC2)cc1Br
Temperature: 80 °C
Yield: 83.9 %

Procedure:
4-(5-Bromo-6-nitropyridin-3-yl)morpholine (95 mg, 0.33 mmol) was dissolved in EtOH (12 mL) and water (3.0 mL) was added, followed by SnCl2 (313 mg, 1.65 mmol). The reaction mixture was heated to 80° C. for 2 h, cooled to room temperature and diluted with DCM. The two phases were separated, the organic phase was washed with water. The water phase was back extracted with DCM. The pH was adjusted to 12 with 6N NaOH and the mixture was further extracted with DCM. The organic extracts were combined, dried (Na2SO4) and evaporated under reduced pressure obtaining the desired 3-bromo-5-morpholinopyridin-2-amine (71.5 mg, 84%). LCMS (m/z): 260.0 (MH+), 0.37 min.
Reaction SMILES: [C:1]1([O:7][C:8]([C:10]2[CH:18]=[CH:17][C:13]3[NH:14][N:15]=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:19](Cl)=[O:20].[CH2:22]([O:34][C:35]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][C:36]=1[NH:42][C:43]([C:45]1[CH:46]=[C:47]([O:56][C:57](=[O:66])[C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=2[NH:64][CH3:65])[C:48]2[C:53]([C:54]=1[OH:55])=[CH:52][CH:51]=[CH:50][CH:49]=2)=[O:44])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].CN(C)C1C=CC=CC=1>C1COCC1.C(#N)C>[CH2:22]([O:34][C:35]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][C:36]=1[NH:42][C:43]([C:45]1[CH:46]=[C:47]([O:56][C:57]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=2[N:64]([CH3:65])[C:19]([N:14]2[C:13]3[CH:17]=[CH:18][C:10]([C:8]([O:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[O:9])=[CH:11][C:12]=3[N:16]=[N:15]2)=[O:20])=[O:66])[C:48]2[C:53]([C:54]=1[OH:55])=[CH:52][CH:51]=[CH:50][CH:49]=2)=[O:44])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: O=CCl
Reactant: CCCCCCCCCCCCOc1ccc(C)cc1NC(=O)c1cc(OC(=O)c2ccccc2NC)c2ccccc2c1O
Reactant: O=C(Oc1ccccc1)c1ccc2[nH]nnc2c1
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CN(C)c1ccccc1
Product: CCCCCCCCCCCCOc1ccc(C)cc1NC(=O)c1cc(OC(=O)c2ccccc2N(C)C(=O)n2nnc3cc(C(=O)Oc4ccccc4)ccc32)c2ccccc2c1O
Reaction time: 8 h

Procedure:
1H-Benzotriazole-5-carboxylic acid phenyl ester, compound with formyl chloride(15.4 g, 0.051 mol) was dissolved in THF (200 ml) and added dropwise during 20 min to a solution of 2-methylamino-benzoic acid 3-(2-dodecyloxy-5-methyl-phenylcarbamoyl)-4-hydroxy-naphthalen-1-yl ester (31.1 g, 0.051 mol) and N,N-dimethylaniline (11.8 g, 0.097 mol) in THF (120 ml). The solution was stirred overnight. Liquid chromatography coupled to mass spectrometry indicated that the major product was the desired coupler, present as a mixture of two isomers. The solvent was removed by evaporation under reduced pressure and the crude oil re-dissolved in ethyl acetate (900 ml). The solution was washed with aqueous 2 M hydrochloric acid (500 ml) and then water (500 ml) in a separating funnel, separated, dried over anhydrous magnesium sulfate, filtered and re-evaporated to give a brownish gum. The residue was re-dissolved by warming in acetonitrile (500 ml), using a steam bath. This solution was then stirred for 60 hr at room temperature. A beige solid formed which was filtered and dried under vacuo. Analysis was consistent with the desired product as a mixture of 1H and 3H triazole isomers. The total yield of product was 39.6 g (88%).
Reaction SMILES: [CH:1]([N:4]([C:18]([C:20]1[CH:28]=[C:27]2[C:23]([C:24]([CH3:37])([CH3:36])[C:25](=[O:35])[N:26]2[CH2:29][CH2:30][CH2:31][CH2:32][O:33][CH3:34])=[CH:22][CH:21]=1)=[O:19])[C@@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1)([CH3:3])[CH3:2].C1C(=O)N([Cl:45])C(=O)C1.CN(C=O)C>O>[Cl:45][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][C:20]=1[C:18]([N:4]([CH:1]([CH3:3])[CH3:2])[C@@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1)=[O:19])[N:26]([CH2:29][CH2:30][CH2:31][CH2:32][O:33][CH3:34])[C:25](=[O:35])[C:24]2([CH3:36])[CH3:37]
Reactant: COCCCCN1C(=O)C(C)(C)c2ccc(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc21
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: COCCCCN1C(=O)C(C)(C)c2cc(Cl)c(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc21
Temperature: 65 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
To tert-butyl (3R)-3-(isopropyl{[1-(4-methoxybutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl]carbonyl}amino)piperidine-1-carboxylate (220 mg) were added NCS (86 mg) and DMF (5 ml), and the mixture was stirred at 65° C. for one hour. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with ethyl acetate solution. This ethyl acetate was washed with water and an aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to give the title compound (200 mg) as a colorless liquid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[C:23](=[O:24])[CH:22]=[C:21]3[C:16]([CH:17]=[C:18](Br)[N:19]=[CH:20]3)=[CH:15]2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:27]([N:30]1[CH:34]=[CH:33][N:32]=C1)[C:28]#[CH:29].C([N:37](CC)CC)C>CN(C)C=O.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:26])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[C:23](=[O:24])[CH:22]=[C:21]3[C:16]([CH:17]=[C:18]([C:29]#[C:28][CH2:27][N:30]4[CH:34]=[CH:33][N:32]=[N:37]4)[N:19]=[CH:20]3)=[CH:15]2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCn1ccnc1
Reactant: CC(C)(C)OC(=O)c1ccc(Cn2cc3cc(Br)ncc3cc2=O)cc1
Reactant: CCN(CC)CC
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(Cn2cc3cc(C#CCn4ccnn4)ncc3cc2=O)cc1

Procedure:
The coupling of 4-(7-bromo-3-oxo-2H-6-azaisoquinolin-2-ylmethyl)benzoic acid tert-butyl ester (0.70 g, 1.69 mmol) with 1-prop-2-ynyl-1H-imidazole (0.45 g, 4.22 mmol) using triethylamine (0.94 mL, 6.76 mmol), CuI (0.023 g, 0.12 mmol), and Pd(Ph3P)4 (0.08 g, 0.07 mmol) in dimethyl-formamide is carried out as described in Example 1, Step (2). The silica gel mesh is purified on a 3.5×18 cm silica gel column eluted with hexanes/ethyl acetate 1:1, methylene chloride/THF 7:1, then methylene chloride/THF 4:1. Evaporation and drying will afford the desired product.
Reaction SMILES: [CH3:1][CH:2]([NH:4][CH2:5][C@H:6]([OH:19])[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([NH2:18])=[O:17])=[CH:13][CH:14]=1)[CH3:3].C[C:21]1[CH:22]=[CH:23][C:24]([C:27]([OH:29])=[O:28])=[CH:25][CH:26]=1>CC(C)=O>[CH3:3][CH:2]([NH:4][CH2:5][C@H:6]([OH:19])[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([NH2:18])=[O:17])=[CH:13][CH:14]=1)[CH3:1].[C:25]1([CH3:1])[C:24]([C:27]([O-:29])=[O:28])=[CH:23][CH:22]=[CH:21][CH:26]=1
Reactant: Cc1ccc(C(=O)O)cc1
Agent: CC(C)NC[C@H](O)COc1ccc(CC(N)=O)cc1
Solvent: CC(C)=O
Product: Cc1ccccc1C(=O)[O-]
Reaction time: 8 h

Procedure:
S-atenolol (optical purity, 91% ee, 4.43 g) and p-toluic acid (2.28 g) are dissolved in acetone (300 ml) by heating, and the mixture is allowed to stand overnight at room temperature. The precipitated crystals are separated by filtration, and the filtrate is concentrated under reduced pressure to give S-atenolol toluate having an optical purity of 98.8% ee (5.01 g).
Reaction SMILES: O.Cl.C([NH:6][C:7](=[NH:9])[SH:8])C=C.[Cl:10][C:11]([SH:14])(Cl)Cl.[OH-].[Na+].[C:17](OC)(C)([CH3:19])[CH3:18]>>[CH2:19]([S:8][C:7]1[N:6]=[C:11]([Cl:10])[S:14][N:9]=1)[CH:17]=[CH2:18]
Reactant: SC(Cl)(Cl)Cl
Reactant: C=CCNC(=N)S
Reactant: COC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCSc1nsc(Cl)n1
Reaction time: 4 h

Procedure:
To 50 ml of water, 9.33 g of allylisothiourea hydrochloride and 8.82 g of perchloromethylmercaptan were added, followed the solution of 7.58 g of sodium hydroxide dissolved to 50 ml of water was added dropwise at about 0° C., followed by stirring for 4 hours. Then, t-butylmethylether was added to the reaction mixture, and extracted. The organic layer was dried by anhydrous sodium salfate, and concentrated. The residue obtaind was subjected to silica gel column chromatography to obtain 3.6 g of 3-allylthio-5-chloro-1,2,4-thiadiazole.