Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=1>CN(C=O)C>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=2)[N:3]=1
Reactant: Cc1cccc(CCl)n1
Reactant: O=[N+]([O-])c1cccc2[nH]nc(Br)c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(Cn2nc(Br)c3c([N+](=O)[O-])cccc32)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.3 %

Procedure:
To a stirred solution of 3-bromo-4-nitro-1H-indazole (Preparation B; 40 g, 165 mmol) in anhydrous DMF (320 mL) was added at ambient temperature potassium carbonate (45.7 g, 331 mmol). 2-(Chloromethyl)-6-methylpyridine hydrochloride (31 g, 174 mmol) was added in portions, and the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between water (800 mL) and methylene chloride (1000 mL). The phases were separated and the aqueous phase was extracted further with methylene chloride (200 mL). The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure to give a brown solid. The crude product was triturated with ether (400 mL) and the solids were collected by filtration, washed with ether, and dried under vacuum to afford the desired product as brown solid (46 g).
Reaction SMILES: C(#N)C.[C:4]([O:8][C:9]([NH:11][C@@H:12]1[C:21]2[C:16](=[CH:17][C:18]([C:22]([OH:24])=O)=[CH:19][CH:20]=2)[S:15][CH2:14][CH2:13]1)=[O:10])([CH3:7])([CH3:6])[CH3:5].[NH2:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1.[I-].ClC1C=CC=C[N+]=1C>O.C(N(CC)CC)C>[C:4]([O:8][C:9]([NH:11][C@@H:12]1[C:21]2[C:16](=[CH:17][C:18]([C:22]([NH:25][C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)=[O:24])=[CH:19][CH:20]=2)[S:15][CH2:14][CH2:13]1)=[O:10])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCSc2cc(C(=O)O)ccc21
Reactant: Nc1ccncc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@H]1CCSc2cc(C(=O)Nc3ccncc3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.8 %

Procedure:
To an acetonitrile (75 ml) solution of (S)-4-(tert-butoxycarbonylamino)thiochromane-7-carboxylic acid (1.00 g) and 4-aminopyridine (335 mg) were added triethylamine (1.35 ml) and 2-chloro-1-methylpyridinium iodide (991 mg), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture and extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent of this solution was evaporated and purified by silica gel column chromatography (chloroform-methanol) to give the objective (S)-4-(tert-butoxycarbonylamino)-N-(4-pyridyl)thiochromane-7-carboxamide (845 mg) as pale yellow crystals.
Reaction SMILES: [H][H].[CH3:3][O:4][C:5]1[C:6]([O:18][CH2:19][CH2:20][CH2:21][Cl:22])=[CH:7][C:8]([N+:15]([O-])=O)=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11]>[Pt]=S.[C].CO>[CH3:3][O:4][C:5]1[CH:14]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[C:8]([NH2:15])=[CH:7][C:6]=1[O:18][CH2:19][CH2:20][CH2:21][Cl:22]
Reactant: COC(=O)c1cc(OC)c(OCCCCl)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: S=[Pt]
Solvent: CO
Product: COC(=O)c1cc(OC)c(OCCCCl)cc1N
Reaction time: 8 h
Yield: 97.7 %

Procedure:
In a 50 mL volume glass flask equipped with a stirrer, a thermometer, a reflux condenser and a balloon containing hydrogen gas were placed 1.01 g (3.29 mmol) of methyl 5-methoxy-4-(3-chloropropoxy)-2-nitrobenzoate (purity: 99%) obtained in Reference Example III-4, 0.2 g of 3 wt. % platinum sulfide/carbon (containing 65.7% water), and 40 mL of methanol. The reaction was carried out at 40° C. for 8 hours. After the reaction was complete, the reaction mixture was filtered. The filtrate was analyzed by high performance liquid chromatography (absolute quantitative analysis). There was produced 0.88 g (reaction yield: 98.0%) of methyl 5-methoxy-4-(3-chloropropoxy)anthranilate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][OH:16])[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].[C:24](OC(OC(OC(C)(C)C)=O)=O)(C)(C)C.O>O1CCCC1.C(OCC)(=O)C.CO.C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:17])[N:7]([CH2:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([CH2:15][OH:16])[CH2:13][CH2:14]1)[CH3:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](CO)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1CCOC1
Product: CN(C[C@H]1CC[C@H](CO)CC1)C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 4 h

Procedure:
2.90 g (11.0 mmol) trans-(4-hydroxymethyl-cyclohexylmethyl)-carbamic acid tert-butyl ester [U.S. (2000) U.S. Pat. No. 6,022,969 A] dissolved in 15 ml of tetrahydrofuran were added slowly to a suspension of 0.92 g of lithium aluminium hydride in 10 ml of tetrahydrofuran. The reaction mixture was then stirred at 50° C. for 4 hours, cooled to 0° C., treated with 2 g of ice, stirred at room temperature for 30 min., diluted with ethyl acetate, dried over sodium sulfate, filtered and evaporated. Thus, crude trans-(4-methylaminomethyl-cyclohexyl)-methanol was obtained [MS: 158 (MH+)], which was dissolved in 20 ml of methanol, cooled to −10° C. and treated at once with 2.77 g di-tert-butyl-dicarbonate. Then, the reaction mixture was stirred at −10° C. for 30 min. and at room temperature for 1 hour. Subsequently, 5 ml of water and 5 ml of triethylamine were added and the reaction mixture evaporated under reduced pressure. It was then poured into 100 ml of an ice/water mixture and extracted 3 times with 100 ml of dichloromethane. The combined dichloromethane phases were dried over magnesium sulfate and evaporated under reduced pressure. The residue formed was chromatographed on silica gel with a 1:1 v/v mixture of dichloromethane and ethylacetate as the eluent giving 2.5 g (82%) trans-(4-hydroxymethyl-cyclohexylmethyl)-methyl-carbamic acid tert-butyl ester as colorless viscous oil, MS: 257 (M+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][NH:8][C:9](=O)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:2]1.P(Cl)(Cl)(Cl)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[C:10]1([C:9]2[C:2]3[S:1][CH:5]=[CH:4][C:3]=3[CH2:6][CH2:7][N:8]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(NCCc1ccsc1)c1ccccc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=P(Cl)(Cl)Cl
Product: c1ccc(C2=NCCc3ccsc32)cc1
Yield: 92.6 %

Procedure:
N-(2-(Thiophen-3-yl)ethyl)benzamide (1.5 g, 6.48 mmol) suspended in xylenes (20 mL) was treated with phosphorous oxychloride (3.62 mL, 38 mmol) and phosphorous pentoxide (5.39 g, 19 mmol). The mixture was heated to reflux for 3 h and the volatiles were removed in vacuo. The residue was diluted with cold water and ethyl acetate. 5 N sodium hydroxide was added and the mixture and the layers were separated. The aqueous layer was extracted twice more with ethyl acetate. All the organic layers were combined and washed with aqueous solution of sodium bicarbonate, water, then brine. The organic layer was dried with sodium sulfate and purified by flash chromatography using a gradient of 20 to 60% of ethyl acetate in hexanes to afford a light yellow clear oil (1.28 g). MS (M+H)+ 214.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH:7]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[CH2:6]1.[Li+].[OH-]>C1COCC1.O.Cl>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([N:8]2[CH2:9][CH2:10][CH:5]([CH2:4][C:3]([OH:28])=[O:2])[CH2:6][CH:7]2[C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:22][CH:23]=2)=[CH:12][CH:13]=1
Reactant: COC(=O)CC1CCN(c2ccc(Cl)cc2)C(c2ccc(C(F)(F)F)cc2)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CC1CCN(c2ccc(Cl)cc2)C(c2ccc(C(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 47.1 %

Procedure:
A solution of methyl{1-(4-chlorophenyl)-2-[4(trifluoromethyl)phenyl]piperidine-4-yl}acetate (34 mg, 0.08 mmol) in THF (2 ml) and H2O (2 ml) was treated with LiOH (19 mg, 0.8 mmol) and the mixture was stirred at room temperature for 20 hours. The reaction was diluted with hydrochloric acid (1N, 20 ml) and extracted with EtOAc (2×20 ml). The combined extracts were washed with brine (×1), then dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica, eluting with 7.5% MeOH/DCM give the acid as a clear gum (15 mg, 45%). 1H NMR (400 MHz, CD3OD) δ: 1.34-1.40 (1H, m), 1.54-1.67 (1H, m), 1.84-2.12 (3H, m), 2.24-2.30 (2H, m), 2.86 (1H, dt, J 12.1, 2.4), 3.47-3.54 (1H, m), 4.15 (1H, dd, J 11.5, 2.7), 6.95 (2H, d, J 8.8), 7.06 (2H, d, J 8.8), 7.44 (4H, s).
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][NH:5][C:6]([C:8]1[S:9][C:10]([C:14]([CH2:32][CH3:33])([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([CH2:29][CH3:30])([OH:28])[CH2:26][CH3:27])=[C:19]([CH3:31])[CH:18]=2)[CH2:15][CH3:16])=[CH:11][C:12]=1[CH3:13])=[O:7].[OH-].[Na+].Cl>CO.O>[CH2:15]([C:14]([C:10]1[S:9][C:8]([C:6]([NH:5][CH2:4][C:3]([OH:34])=[O:2])=[O:7])=[C:12]([CH3:13])[CH:11]=1)([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([CH2:26][CH3:27])([OH:28])[CH2:29][CH3:30])=[C:19]([CH3:31])[CH:18]=1)[CH2:32][CH3:33])[CH3:16]
Reactant: CCC(O)(CC)COc1ccc(C(CC)(CC)c2cc(C)c(C(=O)NCC(=O)OC)s2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC(O)(CC)COc1ccc(C(CC)(CC)c2cc(C)c(C(=O)NCC(=O)O)s2)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.9 %

Procedure:
2-[(5-{1-Ethyl-1-[4-(2-ethyl-2-hydroxy-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carbonyl)-amino]-acetic acid methyl ester (Example 52) (0.34 g, 0.69 mmol) is dissolved in MeOH (2 mL), treated with H2O (0.5 mL) and NaOH (0.14 g, 3.47 mmol) and the resulting mixture is heated at a reflux for two hours cooled to at ambient temperature and stirred overnight. The solution is diluted with H2O (10 mL), the pH value is adjusted to about 3-4 using 1 M HCl, it is extracted with EtOAc (40 mL). The EtOAc layer is washed with brine (20 mL), dried with MgSO4, filtered and concentrated to yield the titled compound (0.244 g, 0.51 mmol, 74%). 1H NMR (CD3OD), δ 0.72 (t, J=7.4 Hz, 6H), 0.94 (t, J=7.4 Hz, 6H), 1.64-1.74 (m, 4H), 2.03-2.20 (m, 4H), 2.18 (s, 3H), 2.44 (s, 3H), 3.79 (s, 2H), 3.97-3.99 (m, 2H), 6.71 (s, 1H), 6.79 (d, J=8.2 Hz, 1H), 6.99-7.02 (m, 1H), 7.06-7.10 (m, 1H), 7.88-7.94 (t, J=5.7 Hz, 1H). LC/MS (m/z): calcd. for C26H36NO5S (M−H)−: 475.6; found: 474.3
Reaction SMILES: Br[C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=3[Cl:23])=[O:12])[CH2:10][C:5]2=[N:4][N:3]=1.[CH3:24]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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:23][C:14]1[C:15]([C:19]([F:22])([F:21])[F:20])=[CH:16][CH:17]=[CH:18][C:13]=1[C:11]([N:9]1[CH2:8][CH2:7][N:6]2[C:2]([CH3:24])=[N:3][N:4]=[C:5]2[CH2:10]1)=[O:12]
Reactant: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCn2c(Br)nnc2C1
Reactant: CB1OB(C)OB(C)O1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nnc2n1CCN(C(=O)c1cccc(C(F)(F)F)c1Cl)C2
Temperature: 110 °C

Procedure:
3-Bromo-7-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine (150 mg, 0.366 mmol, e.g. see Example 1 for methods of preparation) was dissolved in 1,4-dioxane (3 mL) and treated with trimethylboroxine (55.2 mg, 0.439 mmol, commercially available e.g. from Sigma-Aldrich or Thermo Fischer Scientific), potassium carbonate (76 mg, 0.549 mmol) and tetrakis(triphenylphosphine)palladium(0) (42.3 mg, 0.037 mmol). The reaction mixture, under argon, was heated at 110° C. for 20 hours. The mixture was then cooled, diluted with water and extracted with ethyl acetate (three times). The organic phase was dried and evaporated. The residue was purified on the mass-directed automated (preparative) HPLC (MDAP) and the residue was triturated with isohexane to give 7-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-methyl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine (0.028 g) as a white solid.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:15]2[NH:19][CH:18]=[N:17][N:16]=2)=[C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:6]=1.O1CCCC1.[O:25]1[CH:30]=[CH:29][CH2:28][CH2:27][CH2:26]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C([O-])(O)=O.[Na+]>[Br:1][C:2]1[S:3][C:4]([C:15]2[N:19]=[CH:18][N:17]([CH:26]3[CH2:27][CH2:28][CH2:29][CH2:30][O:25]3)[N:16]=2)=[C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:6]=1
Reactant: Clc1ccc(Cc2nc(Br)sc2-c2nnc[nH]2)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Clc1ccc(Cc2nc(Br)sc2-c2ncn(C3CCCCO3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
In a 250 mL round bottomed flask were placed 3-[2-bromo-4-(4-chlorobenzyl)-1,3-thiazol-5-yl]-4H-1,2,4-triazole (0.7 g, 2 mmol) and tetrahydrofuran (50 mL, 600 mmol). To the mixture were added dihydropyran (2 mL, 20 mmol) and p-toluenesulfonic acid monohydrate (911.3 mg, 4.791 mmol). The mixture was refluxed for 2 h then was allowed to cool to rt and then a saturated aqueous solution of NaHCO3 (50 mL) was added. The resulting biphasic mixture was vigorously stirred for 30 min at rt. The aqueous phase was separated then was extracted with EtOAc (50 mL×2). The combined organic phases were dried over anhydrous MgSO4. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica, elution with a 10%-80% mixture of EtOAc in hexane (linear gradient, 30 min) to afford 3-[2-bromo-4-(4-chlorobenzyl)-1,3-thiazol-5-yl]-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazole (778 mg; 67% six steps) as a yellow syrup which spontaneously solidified on standing at rt for 2 days. LC/MS (FA) ES+ 441. 1H NMR (d6-DMSO, 400 MHz): δ: 8.89 (1H, s), 7.28-7.34 (4H, m), 5.62 (1H, dd, J=2.8 and 9.6 Hz), 4.52 (2H, s), 3.92-3.96 (1H, m), 3.63-3.70 (1H, m), 1.91-2.14 (3H, m), 1.52-1.72 (3H, m)
Reaction SMILES: [I:1]I.N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:28][C@@H:29]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30]1>C(OCC)C.O1CCOCC1>[I:1][CH2:28][C@@H:29]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CO)C1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CC[C@@H](CI)C1
Yield: 93.1 %

Procedure:
Iodine (1.91 g) was added in portions to a vigorously stirred, ice cooled suspension of imidazole (0.681 g) and triphenylphosphine (1.97 g) in diethyl ether (12 mL). The mixture was then stirred for 10 minutes before a solution of tert butyl (R)-3-hydroxymethylpyrrolidine-1-carboxylate (1 g) in dioxane (6 mL) was added dropwise. The resulting mixture was stirred at room temperature overnight, then diluted with diethyl ether and filtered. The solid was washed with diethyl ether and the combined filtrate was evaporated to dryness. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and pentane with a gradient of 0-20% to give tert-butyl (R)-3-iodomethylpyrrolidine-1-carboxylate (1.44 g) as an oil.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]2[CH2:19][CH2:18][C@H:17]([NH:20][C@@H:21]([C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)[CH3:22])[CH2:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:23]1([C@H:21]([NH:20][C@H:17]2[CH2:18][CH2:19][C@@H:15]([C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=3)[CH2:16]2)[CH3:22])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: [H][H]
Reactant: C[C@@H](N[C@H]1CC[C@@H](c2ccc(OCc3ccccc3)cc2)C1)c1cccc2ccccc12
Agent: [Pd]
Solvent: CO
Product: C[C@@H](N[C@H]1CC[C@@H](c2ccc(O)cc2)C1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.6 %

Procedure:
Under a nitrogen stream, (1S,3R)-3-[4-(benzyloxy)phenyl]-N-[(1R)-1-(naphthalen-1-yl)ethyl]cyclopentanamine (740 mg, 1.8 mmol) was dissolved in methanol (10 mL). After adding 10% palladium/carbon (70 mg) to the mixture, the atmosphere was replaced with hydrogen, and then the mixture was stirred for 16 hours at room temperature. The catalyst was filtered off, and the solvent of the filtrate was distilled off under reduced pressure. The residue obtained was purified by column chromatography (methanol/methylene chloride: 0/100-10/90) to give the title compound (427 mg, 73%).
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[CH:10][S:9][C:8]=2[NH2:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.[C:20]12[C:28](=[O:29])[O:27][C:25](=[O:26])[C:21]=1[CH2:22][CH2:23][CH2:24]2>C1COCC1>[C:1]1([C:7]2[CH:11]=[CH:10][S:9][C:8]=2[NH:12][C:28]([C:20]2[CH2:24][CH2:23][CH2:22][C:21]=2[C:25]([OH:27])=[O:26])=[O:29])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1sccc1-c1ccccc1
Reactant: O=C1OC(=O)C2=C1CCC2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(O)C1=C(C(=O)Nc2sccc2-c2ccccc2)CCC1
Temperature: 25 °C
Yield: 36 %

Procedure:
3-Phenyl-thiophen-2-ylamine (73 mg, 417 μmol, Int1.1), NEt3 (84.3 mg, 116 μL, 833 μmol) and 1-cyclopentene-1,2-dicarboxylic anhydride (144 mg, 1.04 mmol) were dissolved in dry THF (3 mL). The green-yellow suspension was stirred at RT over the week-end and filtered. The filtrate was concentrated in vacuo and the residue was purified by preparative HPLC (MeOH/H2O with 0.1% formic acid) to give the title compound as a yellow oil (47 mg, 32%, purity estimated at 90%). MS (ESI): m/z=312.2 [M−H]−.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:11]1[NH:12][C:13]2[C:18]([CH:19]=1)=[CH:17][C:16]([N+:20]([O-:22])=[O:21])=[CH:15][CH:14]=2)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:23](I)[CH3:24]>CN(C=O)C.O>[CH2:3]([C:11]1[N:12]([CH2:23][CH3:24])[C:13]2[C:18]([CH:19]=1)=[CH:17][C:16]([N+:20]([O-:22])=[O:21])=[CH:15][CH:14]=2)[CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])c1ccc2[nH]c(CCc3ccccc3)cc2c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(CCc2ccccc2)cc2cc([N+](=O)[O-])ccc21
Reaction time: 0.5 h

Procedure:
A 60% dispersion of NaH (0.5 g, 2.02 mmol) was added to a solution of 2-phenethyl-5-nitro-1H-indole (0.16 g, 0.6 mmol) in DMF (30 ml). The reaction mixture was kept under stirring for 30 minutes. Then, ethyl iodide (0.15 ml, 1.9 mmol) was added, and the mixture was left under stirring overnight at room temperature. The next morning, the mixture was poured in H2O left under stirring overnight, obtaining a precipitate which was filtered to give 2-phenethyl-1-ethyl-5-nitro-1H-indole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.C1C=CC=CC=1.[CH3:24][CH:25]([N:27]1[C:31]([NH2:32])=[CH:30][CH:29]=[N:28]1)[CH3:26]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:30]3[CH:29]=[N:28][N:27]([CH:25]([CH3:26])[CH3:24])[C:31]=3[N:32]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc(Cl)cc1
Reactant: CC(C)n1nccc1N
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(-c2ccc(Cl)cc2)nc2c1cnn2C(C)C

Procedure:
The title compound was prepared in the same manner as described for intermediate 61 using ethyl 4-(4-chlorophenyl)-2,4-dioxobutanoate (610 mg, 2.397 mmol), benzene (5 mL), 1-(1-methylethyl)-1H-pyrazol-5-amine (300 mg, 2.397 mmol), and acetic acid (4 mL). The crude product was purified by column chromatography (Silica gel, eluent: 0 to 100% EtOAc/hexanes) to give 621 mg (75%) of product. LCMS E-S (M+H)=344.1. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.48-1.57 (m, 3 H), 1.64-1.74 (m, 6 H), 4.56 (q, J=7.1 Hz, 2 H), 5.46 (m, 1 H), 7.49-7.55 (m, 2 H), 8.15-8.18 (m, 2 H), 8.21 (s, 1 H), 8.42 (s, 1 H).
Reaction SMILES: C([O:3][CH:4]1[CH:8]([NH:9][C:10]([CH2:12][N:13]2[CH2:19][CH:18]=[CH:17][CH2:16][CH:15]([NH:20][C:21]([C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][N:24]=3)=[O:22])[C:14]2=[O:33])=[O:11])[CH2:7][C:6](=[O:34])[O:5]1)C.FC(F)(F)C(O)=O>CC#N.O>[OH:3][CH:4]1[CH:8]([NH:9][C:10]([CH2:12][N:13]2[CH2:19][CH:18]=[CH:17][CH2:16][CH:15]([NH:20][C:21]([C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][N:24]=3)=[O:22])[C:14]2=[O:33])=[O:11])[CH2:7][C:6](=[O:34])[O:5]1
Reactant: CCOC1OC(=O)CC1NC(=O)CN1CC=CCC(NC(=O)c2nccc3ccccc23)C1=O
Solvent: CC#N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(CN1CC=CCC(NC(=O)c2nccc3ccccc23)C1=O)NC1CC(=O)OC1O
Reaction time: 0.5 h

Procedure:
To a solution of isoquinoline-1-carboxylic acid {1-[(2-ethoxy-5-oxo-tetra-hydrofuran-3-ylcarbamoyl)methyl]-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-yl} amide, 6, from above in CH3CN/H2O is added trifluoroacetic acid. After stirring for 30 minutes the solution is concentrated in vacuo and the crude product purified by preparative reverse phase HPLC to afford the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[CH:46][C:6]([CH2:7][N:8]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([CH2:23][N:24]4[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]4)[CH:19]=[N:20][C:21]=3F)[N:10]=2)=[CH:5][CH:4]=1.[F:48][C:49]1[CH:50]=[C:51]([NH2:57])[CH:52]=[N:53][C:54]=1[O:55][CH3:56].O1CCCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>>[CH3:1][O:2][C:3]1[CH:47]=[CH:46][C:6]([CH2:7][N:8]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([CH2:23][N:24]4[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:35])([CH3:36])[CH3:34])=[O:31])[CH2:26][CH2:25]4)[CH:19]=[N:20][C:21]=3[NH:57][C:51]3[CH:52]=[N:53][C:54]([O:55][CH3:56])=[C:49]([F:48])[CH:50]=3)[N:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ncc(N)cc1F
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(C(=O)OC(C)(C)C)CC4)cnc3F)n2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(C(=O)OC(C)(C)C)CC4)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Yield: 90.2 %

Procedure:
A solution of tert-butyl 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-fluoropyridin-3-yl)methyl)piperazine-1-carboxylate (25 g, 38.8 mmol) and 5-fluoro-6-methoxypyridin-3-amine (Anichem LLC, Monmouth N.J.) (8.28 g, 58.3 mmol) in tetrahydrofuran (400 mL, 38.8 mmol) contained in an oven dried 1 L 3-neck round-bottomed flask equipped with N2 inlet was stirred at a temperature between −5° C. and −10° C. and treated dropwise with a 1.0 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (117 mL, 117 mmol). The dark pink solution was stirred between −5° C. and −10° C. for 1 h. The reaction was quenched with water (100 mL) and NH4Cl (100 mL) and diluted with EtOAc (350 mL). The separated aqueous layer was extracted with EtOAc (2×300 mL) and the combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to give the crude product which was adsorbed onto silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (Teledyne ISCO, Lincoln, Nebr.) (330 g) eluting with a gradient of 10% to 50% EtOAc in hexane to give tert-butyl 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)methyl)piperazine-1-carboxylate (26.8 g, 35.0 mmol, 90% yield). m/z (ESI, positive ion) m/z 766 (M+H)+.