Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[C:6]1([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[B:17](OC)([O:20]C)[O:18]C.Cl>C1COCC1>[C:6]1([C:12]2[S:13][C:14]([B:17]([OH:20])[OH:18])=[CH:15][CH:16]=2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COB(OC)OC
Reactant: c1ccc(-c2cccs2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(-c2ccccc2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
n-Butyllithium (1.6M in hexanes) (24 ml, 38.1 mmol) was added drop wise to a solution of 2-phenylthiophene (6.1 g, 38.1 mmol) in anhydrous THF (150 ml), at 0° C., under nitrogen. The ice-bath was removed, and the mixture heated to reflux for 20 min. After cooling, the reaction mixture was added drop wise to a solution of trimethyl borate (8.7 ml, 76.25 mmol) in anhydrous THF (100 ml), at −78° C., under nitrogen. This was allowed to warm to room temperature overnight, then was acidified with concentrated HCl, stirred for 1 h, then extracted with Et2O (3×100 ml). The combined extracts were washed with water (2×100 ml), dried (Na2SO4), and the solvent removed. The resulting grey solid was recrystallised from ethanol/water (50:50), then dissolved in aqueous NaOH (2M, 500 ml), Et2O (250 ml) added, the aqueous layer precipitated with concentrated HCl, extracted with Et2O (300 ml), dried (Na2SO4) and the solvent removed under pressure to give the title compound (2.72 g, 35%) as an off white solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7](Cl)[S:8][C:4]=2[CH:3]=1.C(O)C.[CH3:15][NH2:16].Cl>>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH:16][CH3:15])[S:8][C:4]=2[CH:3]=1
Reactant: CN
Reactant: Clc1nc2ccc(Br)cc2s1
Agent: Cl
Solvent: CCO
Product: CNc1nc2ccc(Br)cc2s1
Reaction time: 0.25 h
Yield: 79 %

Procedure:
6-bromo-2-chlorobenzo[d]thiazole (1.100 g, 4.4 mmol) and ethanol (20 ml, 343 mmol) was added to a microwave vial equipped with a stirbar. Then methylamine solution, 40% (2.3 ml, 66 mmol) was added to the mixture with stirring. Then HCl (0.34 ml, 11 mmol) was added to the mixture. The vial was capped then placed into the CEM Voyager Microwave (large-scale unit) for 15 minutes at 100° C., while 60 watts of energy was supplied via Powermax® (Simultaneous heating while cooling technology). The progress of the reaction was monitored by LC/MS, which showed mostly desired material in the mixture. The mixture was transferred to a round-bottom flask, then made the mixture basic with sat. Na2HCO3. The precipitate was collected by filtration and washed with Hexanes. The solid was allowed dry in a reduced pressure oven overnight. This gave 6-bromo-N-methylbenzo[d]thiazol-2-amine (0.850 g, 79% yield) as a tan crystalline solid. MS (ESI pos. ion) m/z: 244 (MH+). Calc'd exact mass for C8H7BrN2S: 243. 1H NMR (400 MHz, DMSO-d6): 2.93 (d, J=4.52 Hz, 3H), 7.33 (q, J=8.53 Hz, 2H), 7.90 (s, 1H), 8.06 (d, J=4.52 Hz, 1H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:9](O)=O)[C:5](C)=[N:6][CH:7]=1.C1C(=O)[N:16](Br)[C:14](=O)[CH2:13]1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[O-]CC>C(O)C.N1C=CC=CC=1>[N:16]1[C:5]2[C:4](=[CH:3][CH:2]=[CH:7][N:6]=2)[CH:9]=[CH:13][CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ncc(I)cc1C(=O)O
Agent: CC[O-]
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: CCO
Product: c1cnc2ncccc2c1

Procedure:
5-Hydroxy-[1,7]naphthyridine-6-carboxamides. Preparation of specific examples of heterocycle W3.6 follows established precedent for 5-hydroxy--[1,7]naphthyridine ring synthesis (Just. Liebigs. 1979, 443-445.), Chart P. 5-Iodo-2-methylpyridine-3-carboxylic acid (P.1) (J. Am. Chem. Soc. 1953, 75, 737) is brominated under radical conditions (e.g. NBS, benzoylperoxide) to afford pyridine P.2. P.2 is treated with ethyl 2-N-toluenesulfonylaminoacetate to provide P.3. Upon treatment of P.3 with ethoxide in ethanol, ring cyclization and elimination occurs to afford naphthyridine P.4. The resulting ester is then treated with a benzylamine (e.g. 4-chlorobenzylamine, 4-bromobenzylamine, or 4-fluorobenzylamine) at high temperature to afford the corresponding amides of the general formula P.5 or, alternatively, ester P.4 is saponified to afford the corresponding acid which is then coupled with a benzylamine employing standard amide coupling protocols (e.g. HOBT/EDC or other suitable carboxylic acid activating agent) to likewise provide amides of the general formula P.5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9]([CH:11]2[CH2:13][CH2:12]2)O)=[C:4]([F:14])[CH:3]=1.FC(F)(F)C(O)=O.[CH3:22][S:23]([CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:35]=1[NH:34][CH:33]=[CH:32]2)(=[O:25])=[O:24]>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9]([CH:11]2[CH2:13][CH2:12]2)[C:32]2[C:31]3[C:35](=[C:27]([CH2:26][S:23]([CH3:22])(=[O:25])=[O:24])[CH:28]=[CH:29][CH:30]=3)[NH:34][CH:33]=2)=[C:4]([F:14])[CH:3]=1
Reactant: OC(c1c(F)cc(Cl)cc1F)C1CC1
Reactant: CS(=O)(=O)Cc1cccc2cc[nH]c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)Cc1cccc2c(C(c3c(F)cc(Cl)cc3F)C3CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
104 mg (0.48 mmol) of the compound from Example 156A and 0.04 ml (0.57 mmol) of trifluoroacetic acid were added to 100 mg (0.48 mmol) of the compound from Example 86A in 4 ml of dichloromethane. The reaction mixture was stirred at RT for 45 min, the solvent was removed in vacuo, and the crude product was then purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 100 mg (51% of theory) of the title compound were obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[N+:27]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)([O-:29])=[O:28]>>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:34]2[CH:33]=[CH:32][CH:31]=[C:30]([N+:27]([O-:29])=[O:28])[CH:35]=2)=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(C(=O)c1ccc(I)cc1)c1ccc(Cl)c(Cl)c1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(-c2cccc([N+](=O)[O-])c2)cc1)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[1-(3,4-dichloro-phenyl)-2-(4-iodo-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester and 3-nitrobenzene-boronic acid in analogy to Example 2b): MS (ISN): 499.1 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([C:11]([OH:13])=O)=[CH:6][CH:5]=2.[CH2:14]1[C@H:23]2[C@H:18]([CH2:19][CH2:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=32)[NH:17][CH2:16][CH2:15]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[CH2:14]1[C@H:23]2[C@H:18]([CH2:19][CH2:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=32)[N:17]([C:11]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[NH:3][C:2]([CH3:1])=[CH:10]3)=[O:13])[CH2:16][CH2:15]1
Reactant: Cc1cc2cc(C(=O)O)ccc2[nH]1
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1cc2cc(C(=O)N3CCC[C@@H]4c5ccccc5CC[C@@H]43)ccc2[nH]1
Yield: 46 %

Procedure:
The title compound is prepared from 2-methyl-1H-indole-5-carboxylic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 46% of theory; LC (method 4): tR=2.03 min; Mass spectrum (ESI+): m/z=345 [M+H]+.
Reaction SMILES: O=[C:2]([CH2:9][CH2:10][CH3:11])[CH2:3][C:4](OCC)=[O:5].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][NH2:21])=[CH:16][CH:15]=1.CCN(CC)CC>CC(O)=O>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:4](=[O:5])[CH2:3][C:2]([CH2:9][CH2:10][CH3:11])=[N:21]2)=[CH:16][CH:15]=1
Reactant: COc1ccc(NN)cc1
Reactant: CCCC(=O)CC(=O)OCC
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CCCC1=NN(c2ccc(OC)cc2)C(=O)C1
Temperature: 120 °C
Reaction time: 30 h
Yield: 58.9 %

Procedure:
To a suspension of ethyl 3-oxohexanoate (0.58 mL, 3.62 mmol) and (4-methoxyphenyl)hydrazine (0.50 g, 3.62 mmol) in AcOH (3.5 mL) was added Et3N (0.58 mL, 4.16 mmol). The mixture was stirred at 120° C. for 30 h. The solvent was removed by evaporation, and the residue was dissolved in DCM/EtOAc which was washed with saturated aqueous NaHCO3, followed by water and dried using phase separator. Concentration in vacuo, and purification using silica chromatography (CH2Cl2:Et2O 3:1) gave 1-(4-methoxyphenyl)-3-propyl-1H-pyrazol-5(4H)-one (495 mg, 59%).
Reaction SMILES: O[CH:2]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:11]=2)[CH:6]=[CH:5][C:4]2[CH:19]=[CH:20][C:21]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][C:3]1=2.O=S(Cl)Cl.[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>C(Cl)Cl>[C:13]1([C:10]2[CH:11]=[C:12]3[CH:2]([N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)[C:3]4[CH:22]=[C:21]([NH:23][S:24]([CH3:27])(=[O:25])=[O:26])[CH:20]=[CH:19][C:4]=4[CH:5]=[CH:6][C:7]3=[N:8][CH:9]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C1CCNC1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)C(O)c1cc(-c3ccccc3)cnc1C=C2
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CS(=O)(=O)Nc1ccc2c(c1)C(N1CCCC1)c1cc(-c3ccccc3)cnc1C=C2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of N-(5-hydroxy-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide (40 mg, 0.11 mmol) in CH2Cl2 (2 mL) was added SOCl2 (30 uL, 0.41 mmol) at 0° C. The mixture was left to stir at 0° C. for 1 h and concentrated in vacuo. To the residue were added CH2Cl2 (2 mL) and pyrroldine (0.10 mL, 1.2 mmol) at 0° C. The mixture was allowed to warm to room temperature as the bath did, and left to stir overnight. The mixture was concentrated and purified by flash chromatography to afford the title compound. 1H NMR (600 MHz, CD3OD) δ 8.83 (s, 1EI); 7.91 (s, 1H); 7.15-7.64 (m, 10H); 4.31 (br s, 1H); 3.02 (s, 3H); 2.09 (br s, 4H); 1.61 (br s, 4H). LRMS (APCI) calc'd for (C25H26N3O2S) [M+H]+, 432.2; found 432.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([OH:34])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:36][C:37]1[CH:46]=[CH:45][C:44]2[C:39](=[CH:40][C:41]([O:47][CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])=[CH:42][CH:43]=2)[CH:38]=1.[H-].[Na+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:36][C:37]2[CH:46]=[CH:45][C:44]3[C:39](=[CH:40][C:41]([O:47][CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:53])([CH3:55])[CH3:54])=[CH:42][CH:43]=3)[CH:38]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2O)cc1
Reactant: C[Si](C)(C)CCOCOc1ccc2ccc(CCl)cc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3ccc(OCOCC[Si](C)(C)C)cc3c2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.2 %

Procedure:
25.4 g (53.86 mmol) of (3R,4R)-3-hydroxy-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butylester and 17.78 g (55.06 mmol) of 2-chloromethyl-7-(2-trimethylsilanyl-ethoxymethoxy)-naphthalene (WO 97/09311) were dissolved in 180 ml of dimethylformamide under argon and then 2.49 g (57.09 mmol) of sodium hydride dispersion (55% in mineral oil) was added. Subsequently, the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured onto ice-water, the product was extracted 3 times with methylene chloride, the organic phases were washed twice with distilled water, then dried over magnesium sulphate, filtered and concentrated in a water-jet vacuum. The resulting crude product was chromatographed on silica gel with methylene chloride and methanol to give 36.43 g (89.2% of theory) of (3R,4R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-[7-(2-trimethylsilanyl-ethoxymethoxy)-naphthalen-2-ylmethoxy]-piperidine-1-carboxylic acid tert-butylester as a yellowish oil; MS: 759 (M+H)+.
Reaction SMILES: C(O)C.Cl.[OH:5][C:6]1[C:7]([CH2:21][OH:22])=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[CH:11]([NH:17][CH:18]([CH3:20])[CH3:19])[CH2:10][CH2:9]2.[H][H]>[Pd].C(N(CC)CC)C>[OH:16][CH:12]1[C:13]2[C:8](=[C:7]([CH2:21][OH:22])[C:6]([OH:5])=[CH:15][CH:14]=2)[CH2:9][CH2:10][CH:11]1[NH:17][CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)NC1CCc2c(ccc(O)c2CO)C1=O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)NC1CCc2c(ccc(O)c2CO)C1O

Procedure:
In a mixture of 20 ml. ethanol and 2 ml. of triethylamine is dissolved 200 mg. of 6-hydroxy-5-hydroxymethyl-2-isopropylamino-3,4-dihydro-1(2H)-naphthalenone hydrochloride and, with the addition of 50 mg. of 5 % palladium-on-carbon, the solution is agitated in a current of hydrogen for 15 hours. The catalyst is filtered off and the filtrate is concentrated under reduced pressure. The resiude is dissolved in tetrahydrofuran. The insolubles are filtered off and the filtrate is concentrated under reduced pressure. The residue is recrystallized from ethanol-ethyl acetate. The procedure yields colorless crystals of 1,6-dihydroxy-5-hydroxymethyl-2-isopropylamino-1,2,3,4-tetrahydronaphthalene which is identical with the product according to the procedure of Example 71. Yield 108 mg.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[NH:6][C:5]2[N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]=[CH:11][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:26][C:27]1[N:28]([CH3:32])[N:29]=[CH:30][N:31]=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[CH:11]=[N:10][N:9]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:5]2=[N:6][C:7]=1[O:8][CH2:26][C:27]1[N:28]([CH3:32])[N:29]=[CH:30][N:31]=1
Reactant: Cn1ncnc1CCl
Reactant: O=c1[nH]c2c(cnn2-c2ccccc2)cc1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cn1ncnc1COc1nc2c(cnn2-c2ccccc2)cc1Br
Temperature: 60 °C
Yield: 103.8 %

Procedure:
To a solution of 5-bromo-1,7-dihydro-1-phenylpyrazolo[3,4-b]pyridin-6-one (0.29 g, 1.0 mmol) in DMF (4 ml) under nitrogen was added cesium carbonate (0.98 g, 3.0 mmol) followed by 3-chloromethyl-2-methyl-2H-[1,2,4]triazole hydrochloride (0.25 g, 1.5 mmol). The resulting suspension was heated at 60° C. for 17 h. The mixture was partitioned between ammonium chloride solution (saturated aqueous) and ethyl acetate. The layers were separated and the aqueous phase extracted a second time with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo to give 5-bromo-6-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-1-phenyl-1H-pyrazolo[3,4-b]pyridine (0.40 g) of adequate purity. δH (400 MHz; CDCl3) 4.04 (3H, s), 5.70 (2H, s), 7.33-7.37 (1H, m), 7.52-7.56 (2H, m), 7.90 (1H, s), 8.06 (1H, s), 8.16-8.19 (2H, m), 8.27 (1H, s); m/z (ES+) 387 (M+H+), 385 (M+H+).
Reaction SMILES: Cl.Cl[C:3]1[N:12]=[CH:11][C:10]2[N:9]3[CH:13]=[N:14][N:15]=[C:8]3[C@@H:7]([CH2:16][CH3:17])[N:6]([C@@H:18]3[CH2:22][CH2:21][C:20]([F:24])([F:23])[CH2:19]3)[C:5]=2[N:4]=1.[NH2:25][C:26]1[CH:36]=[CH:35][C:29]([C:30]([NH:32][CH2:33][CH3:34])=[O:31])=[CH:28][C:27]=1[O:37][CH3:38]>C(O)C.O>[F:23][C:20]1([F:24])[CH2:21][CH2:22][C@@H:18]([N:6]2[C:5]3[N:4]=[C:3]([NH:25][C:26]4[CH:36]=[CH:35][C:29]([C:30]([NH:32][CH2:33][CH3:34])=[O:31])=[CH:28][C:27]=4[O:37][CH3:38])[N:12]=[CH:11][C:10]=3[N:9]3[CH:13]=[N:14][N:15]=[C:8]3[C@H:7]2[CH2:16][CH3:17])[CH2:19]1
Reactant: CCNC(=O)c1ccc(N)c(OC)c1
Reactant: CC[C@@H]1c2nncn2-c2cnc(Cl)nc2N1[C@@H]1CCC(F)(F)C1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCNC(=O)c1ccc(Nc2ncc3c(n2)N([C@@H]2CCC(F)(F)C2)[C@H](CC)c2nncn2-3)c(OC)c1
Temperature: 95 °C
Reaction time: 18 h
Yield: 78.3 %

Procedure:
Concentrated hydrochloric acid (36 □l) was added to a mixture of (R)-7-chloro-5-((R)-3,3-difluorocyclopentyl)-4-ethyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridine (70 mg, 0.21 mmol) and 4-amino-N-ethyl-3-methoxybenzamide (59.84 mg, 0.31 mmol) in ethanol (0.9 mL) and water (3.6 mL). The reaction mixture was heated to 95° C. and stirred for 18 hours. The reaction mixture was concentrated in vacuo. The residue was taken up with ethyl acetate, washed with an aqueous saturated solution of sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography to afford the desired compound as a white solid (82 mg, 80% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[C:11]([NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccccc1[N+](=O)[O-]
Product: CC(=O)Nc1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 3 h

Procedure:
o-Nitroaniline (300 g, 2.17 mols) was dissolved in acetic anhydride (620 ml) and stirred at 40°-50° C. for 3 hours. The reaction mixture was poured in ice water. Crystals which formed were collected by filtration and dried. o-Acetylaminonitrobenzene thus-obtained was suspended in methanol (2.4 l). After adding 20 g of 10% palladium-carbon, the suspension was subjected to catalytic reduction at room temperature and atmospheric pressure. After completion of reaction, the catalyst was removed by filtration and the solvent was distilled off under reduced pressure to precipitate crystals which then were washed with ethanol and dried over phosphorus pentoxide under reduced pressure to give 248 g of o-aminoacetanilide.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]2[CH2:14]O)=[CH:4][CH:3]=1.C(N(CC)CC)C.CS([Cl:29])(=O)=O.C(=O)([O-])O.[Na+]>ClCCl>[Cl:29][C@@H:12]1[CH2:11][CH2:10][CH2:14][CH2:9][N:8]([CH2:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:17][CH:16]=2)[CH2:13]1
Reactant: OC[C@H]1CCCCN1CCc1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Clc1ccc(CCN2CCCC[C@@H](Cl)C2)cc1
Reaction time: 14 h

Procedure:
(R)-1-(4-chlorophenethyl)-2-hydroxymethylpiperidine (354 mg) was dissolved in 10 ml of dichloromethane. Triethylamine (184 mg, 1.82 mmol) and methanesulfonyl chloride (208 mg, 1.82 mmol) were added to the obtained solution under stirring under cooling on ice. They were stirred under cooling on ice for 1 hour and then at room temperature for 14 hours. The reaction liquid was distributed in dichloromethane and saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain (R)-3-chloro-1-(4-chlorophenethyl) homopiperidine in the form of a light yellow oil (380 mg, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC1N=C(OC)N=C(OC)N=1.Cl.[NH2:33][C@@:34]1([C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:41][C:38]2([CH2:40][CH2:39]2)[C@@H:37]2[C@H:35]1[C@H:36]2[C:42]([O:44][CH2:45][CH3:46])=[O:43]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:13])[C:10]([NH:33][C@@:34]1([C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:41][C:38]2([CH2:40][CH2:39]2)[C@@H:37]2[C@H:35]1[C@H:36]2[C:42]([O:44][CH2:45][CH3:46])=[O:43])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@H]1[C@H]2[C@@H]1[C@](N)(C(=O)OCC)CC21CC1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCOC(=O)[C@H]1[C@H]2[C@@H]1[C@](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)(C(=O)OCC)CC21CC1
Temperature: 22.5 °C
Yield: 100 %

Procedure:
Charge tetrahydrofuran (45 mL, 10 volumes) and (2S)-2-(tert-butoxycarbonylamino)propanoic acid (3.4 g, 1.2 equivalents) to a reactor followed by N-methylmorpholine (1.96 mL, 1.2 equivalents) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (3.12 g, 1.2 equivalents). Stir the resulting thin slurry between 20-25° C. for at least 3 hours until the reaction is complete by HPLC. Charge diethyl (1S,2S,5R,6S)-2-aminospiro[bicyclo[3.1.0]hexane-4,1′-cyclopropane]-2,6-dicarboxylate hydrochloride (4.55 g, 14.81 mmol) in one portion between 20-25° C. followed by N-methylmorpholine (1.63 mL, 1.0 equivalents) over at least 10 minutes keeping the temperature between 20-25° C. Stir the resulting slurry between 20-25° C. for at least 2 hours until the reaction is complete by HPLC. Filter the resulting solids and wash the wet cake with tetrahydrofuran (2×10 mL, 2.2 volumes) to provide the title compound assuming 100% yield. Use the pale amber tetrahydrofuran solution of the title compound without further purification assuming a 100% yield. 1H NMR (DMSO-d6, 400 MHz): δ 8.46 (s, 1H), 6.72 (d, J=7.9, 1H), 4.08-3.92 (m, 5H), 2.42-2.37 (m, 1H), 1.81-1.64 (m, 3H), 1.47 (dd, J=6.6, 3.1, 1H), 1.34 (s, 9H), 1.18-1.08 (m, 9H), 0.66-0.59 (m, 1H), 0.57-0.52 (m, 1H), 0.46-0.36 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[Br:12]N1C(=O)CCC1=O.C1(=O)NC(=O)CC1>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2ccccc2c1
Agent: O=C1CCC(=O)N1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2ccccc2c1
Yield: 101.8 %

Procedure:
A mixture of 250 g (1.75 m) of 2-methylnaphthalene and 312.5 g (1.75 m) of N-bromosuccinimide in 1125 ml of carbon tetrachloride in a 3 liter round bottom flask fitted with a stirrer and reflux condenser with a drying tube was refluxed for twenty hours. The insoluble succinimide (171 g, 1.73 moles) was filtered and washed with 250 ml of carbon tetrachloride. Concentrated in vacuo gave 395 g of an oil to which was added 800 ml of petroleum ether. Solid crystallized immediately and was filtered and washed with 500 ml of petroleum ether. The first crop was air-dried to give 298 g, m.p. 48°-65° C. (Lit. m.p. 56° ). Concentration of the filtrate led to the isolation of another 33 g, m.p. 45°-50° C. of product to give a total of 331 g (86%) of good quality crude product.
Reaction SMILES: [CH2:1]([N:5]1[C:10]([NH2:11])=[C:9]([NH2:12])[C:8](=[O:13])[NH:7][C:6]1=[O:14])[CH2:2][CH2:3][CH3:4].[C:15](O)(=O)[CH3:16]>>[CH2:1]([N:5]1[C:10]2[N:11]=[C:15]([CH3:16])[NH:12][C:9]=2[C:8](=[O:13])[NH:7][C:6]1=[O:14])[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)O
Reactant: CCCCn1c(N)c(N)c(=O)[nH]c1=O
Product: CCCCn1c(=O)[nH]c(=O)c2[nH]c(C)nc21

Procedure:
A solution of 7.6 g of 1-butyl-5,6-diamino-2,4-(1H,3H)-pyrimidinedione in 20 ml of acetic acid was refluxed for 2 hours. The solution was evaporated. The residue was refluxed in 40 ml of 2N NaOH for 2 hours and then neutralized with 5N HCl. The crystals were filtered off and recrystallized from 350 ml ethanol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.Cl[CH2:10][CH:11]=O>C(O)C.O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:10]=[CH:11][N:1]=2)[CH:4]=1
Reactant: O=CCCl
Reactant: Nc1ccc(Br)cn1
Solvent: O
Solvent: CCO
Product: Brc1ccc2nccn2c1
Yield: 100 %

Procedure:
2.00 g of 2-amino-5-bromopyridine (3) is dissolved in ethanol (35 mL), and chloroacetaldehyde in water (2.52 mL, 6.1 mol/L) was added and the reaction mixture was heated at reflux for 3 hours. The reaction mixture was concentrated, and saturated aqueous NaHCO3 was added to the residue, and it is extracted with ethyl acetate. After conventional workup afford 2.30 g of the titled compound as a brown powder (yield: 100%).