Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([S:4]([C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10])(=[O:6])=[O:5])=[C:2]=[O:3].[NH2:17][C:18]1[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([O:25][CH:26]([CH3:32])[C:27]([O:29]CC)=[O:28])[N:19]=1.S(N=C=O)(N=C=O)(=O)=O.[OH-].[Na+].Cl>C(Cl)Cl.O>[C:27]([CH:26]([O:25][C:20]1[N:21]=[C:22]([CH3:24])[N:23]=[C:18]([NH:17][C:2]([NH:1][S:4]([C:7]2[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=2[C:9]([O:11][CH3:12])=[O:10])(=[O:6])=[O:5])=[O:3])[N:19]=1)[CH3:32])([OH:29])=[O:28]
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: CCOC(=O)C(C)Oc1nc(C)nc(N)n1
Agent: Cl
Agent: O=C=NS(=O)(=O)N=C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)nc(OC(C)C(=O)O)n1
Yield: 23.8 %

Procedure:
Methyl 2-(isocyanatosulfonyl)benzoate (10.1 g) and 8.0 g of ethyl 2-[(4-amino-6-methyl-1,3,5-triazin-2-yl)-oxy]propanoate were stirred in 80 ml of methylene chloride at ambient temperature for 18 hours. An additional 2 g of the sulfonylisocyanate was added and the reaction mixture was stirred for four more hours and then 2 g more of the sulfonylisocyanate was added. After stirring for four more hours at ambient temperature, 400 ml of water was added and the pH of this mixture was adjusted to pH 8 by the addition of 10% aqueous sodium hydroxide. The aqueous phase was separated and acidified to pH 1 with hydrochloric acid to precipitate a thick white gum. Sufficient 50% aqueous sodium hydroxide was added to achieve pH 12 and the mixture was heated on a steam bath until a clear solution resulted. The solution was again acidified with hydrochloric acid to pH 3 and the resultant cloudy solution was extracted with dichloromethane. The organic phase was dried and the solvent was removed to afford 3.7 g of the title compound as a glass.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[N:13]=[C:12]([C@H:14]([N:19]([CH2:27][C@H:28]2[C@@H:32]([F:33])[CH2:31][N:30](C(OCC3C=CC=CC=3)=O)[CH2:29]2)[C:20]([C@@H:22]2[CH2:26][CH2:25][CH2:24][O:23]2)=[O:21])[C:15]([CH3:18])([CH3:17])[CH3:16])[N:11]([CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[CH:46]=2)[N:10]=1>CCOC(C)=O.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[N:13]=[C:12]([C@H:14]([N:19]([CH2:27][C@H:28]2[C@@H:32]([F:33])[CH2:31][NH:30][CH2:29]2)[C:20]([C@@H:22]2[CH2:26][CH2:25][CH2:24][O:23]2)=[O:21])[C:15]([CH3:16])([CH3:18])[CH3:17])[N:11]([CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[CH:46]=2)[N:10]=1
Reactant: CC(C)(C)[C@H](c1nc(-c2cc(F)ccc2F)nn1Cc1cccc(F)c1)N(C[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1F)C(=O)[C@@H]1CCCO1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)[C@H](c1nc(-c2cc(F)ccc2F)nn1Cc1cccc(F)c1)N(C[C@@H]1CNC[C@@H]1F)C(=O)[C@@H]1CCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.4 %

Procedure:
To a solution of (3R,4R)-benzyl 3-(((S)—N—((R)-1-(3-(2,5-difluorophenyl)-1-(3-fluorobenzyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropyl)tetrahydrofuran-2-carboxamido)methyl)-4-fluoropyrrolidine-1-carboxylate (580 mg, 0.82 mmol) in degassed EtOAc (80 mL, 0.1 M solution) was added Pd/C (873 mg, 10 wt %) under anhydrous N2 atmosphere. After flushed with hydrogen gas, the reaction mixture equipped with a hydrogen gas balloon was stirred at room temperature for overnight. The reaction mixture was filtered through Celite® pad that was washed with EtOAc. The volatile organic filtrate was removed in vacuo to give the crude product, which was purified by preparative reverse phase HPLC. The combined fractions of the product were neutralized with saturated NaHCO3 solution, which was then extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The dried product was then dissolved in acetonitrile and water (1:1 ratio) and lyophilized for 48 h. The white powdery (S)—N—((R)-1-(3-(2,5-difluorophenyl)-1-(3-fluorobenzyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropyl)-N-(((3S,4R)-4-fluoropyrrolidin-3-yl)methyl)tetrahydrofuran-2-carboxamide was obtained in 10.4% yield (48.9 mg) as a free amine. 1H NMR (CD3Cl, 400 MHz): 7.82 (1H, m), 7.34-7.25 (3H, m), 7.22 (1H, m), 7.15 (1H, m), 7.07 (1H, m), 6.98 (1H, m), 6.10 (1H, s), 5.44 (2H, m), 4.86 (2H, m), 4.19 (1H, m), 3.96 (1H, m), 3.86 (2H, m), 3.05 (1H, m), 3.05 (1H, m), 2.37-1.70 (2H, m), 1.35-1.02 (5H, m), 0.99 (9H, s). LC/MS (uplc): MH+ 574.4, 0.98 min.
Reaction SMILES: C([O:3][C:4]([C:6]12[CH2:23][CH:22]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]([CH3:24])[C:14](=[O:25])[CH:13]1[CH:9]([CH2:10][CH:11]([O:26][C:27]3[CH:32]=[C:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:30]=[C:29]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[N:28]=3)[CH2:12]1)[C:8](=[O:45])[NH:7]2)=[O:5])C.[Li+].[OH-]>C1COCC1.CO>[C:39]1([C:29]2[N:28]=[C:27]([O:26][CH:11]3[CH2:10][CH:9]4[CH:13]([C:14](=[O:25])[N:15]([CH3:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH:21][CH:22]5[C:6]([C:4]([OH:5])=[O:3])([NH:7][C:8]4=[O:45])[CH2:23]5)[CH2:12]3)[CH:32]=[C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:30]=2)[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CCOC(=O)C12CC1C=CCCCCN(C)C(=O)C1CC(Oc3cc(-c4ccccc4)nc(-c4ccccc4)n3)CC1C(=O)N2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN1CCCCC=CC2CC2(C(=O)O)NC(=O)C2CC(Oc3cc(-c4ccccc4)nc(-c4ccccc4)n3)CC2C1=O
Yield: 76.7 %

Procedure:
A solution of the ethyl ester 17e (0.67 g, 1.1 mmol) in THF/MeOH 1:1 (30 ml) was treated with a 1M solution of LiOH (15 ml) as described in Example 13 step d which gave the title compound, (0.49 g, 76%), (M+H)+581.
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4([NH:27]C(=O)OC(C)(C)C)[CH2:26][CH2:25][CH2:24]4)=[CH:19][CH:18]=3)=[N:15][C:8]3[O:9][CH2:10][C:11](=[O:14])[N:12]([CH3:13])[C:7]=3[CH:6]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>ClCCl>[NH2:27][C:23]1([C:20]2[CH:21]=[CH:22][C:17]([C:16]3[C:5]([CH2:4][CH:1]4[CH2:2][CH2:3]4)=[CH:6][C:7]4[N:12]([CH3:13])[C:11](=[O:14])[CH2:10][O:9][C:8]=4[N:15]=3)=[CH:18][CH:19]=2)[CH2:24][CH2:25][CH2:26]1
Reactant: CN1C(=O)COc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(CC3CC3)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C(=O)COc2nc(-c3ccc(C4(N)CCC4)cc3)c(CC3CC3)cc21
Reaction time: 0.01 h
Yield: 46.1 %

Procedure:
Tert-butyl (1-(4-(7-(cyclopropylmethyl)-1-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (0.5 mg, 1.79 μmol) was dissolved in dichloromethane (1 ml). TFA (0.5 ml) was added at room temperature and the reaction mixture was stirred for 30 seconds. The solution was immediately concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether (˜1 ml) and concentrated to dryness under reduced pressure. This was repeated three times. The residue was then slurred in diethyl ether (1 ml) and after settling the supernatant solvent was removed by pipette. This was repeated twice. The residue was then slurred in n-hexane (1 ml) and after settling the supernatant solvent was removed by pipette. This was repeated twice. The residue remaining solvent was dried to give the desired product as an off-white solid as the title compound (0.3 mg, 77% yield). LCMS (Method D) RT=0.77 min, M+1=364. 1H-NMR (500 MHz, CD3OD) δ 7.66-7.50 (4H, m), 7.47 (1H, s), 4.48 (2H, s), 4.15-4.09 (2H,m), 3.06 (3H, s), 2.75-2.65 (2H, m), 2.51-2.42 (2H, m), 2.28-2.20 (1H, m), 1.97-1.90 (1H, m), 1.76-1.71 (1H, m), 1.66-1.55 (2H, m), 1.38-1.31 (2H, m).
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([CH:12]1[CH2:21][C:20]2[C:15]3=[C:16]([CH2:22][C:23](=[O:24])[N:14]3[CH2:13]1)[CH:17]=[CH:18][CH:19]=2)=[O:11])(=O)C.O.CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[OH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([CH:12]1[CH2:21][C:20]2[C:15]3=[C:16]([CH2:22][C:23](=[O:24])[N:14]3[CH2:13]1)[CH:17]=[CH:18][CH:19]=2)=[O:11]
Reactant: CC(=O)OCCCCCC(=O)C1Cc2cccc3c2N(C1)C(=O)C3
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: O=C(CCCCCO)C1Cc2cccc3c2N(C1)C(=O)C3
Reaction time: 5 h
Yield: 93.5 %

Procedure:
5-(6-Acetyloxy-1-oxohexyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-one (10.0 g, 30.6 mmol) is suspended in anhydrous ethanol (150 ml), mixed with catalyst amounts of 4-methylbenzenesulfonic acid monohydrate and stirred for five hours at boiling temperature. The solvent volume is concentrated by evaporation to one third, and the product is obtained in the form of light yellow needles (8.22 g, 93.5%) by crystallization at −20° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+]([O-])(O)=O.[Br:16]Br>C(O)(=O)C.O.[N+]([O-])([O-])=O.[Ag+]>[Br:16][C:8]1[CH:9]=[C:10]([CH3:11])[C:2]([CH3:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: BrBr
Reactant: Cc1cccc(C(=O)O)c1C
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CC(=O)O
Solvent: O
Solvent: O=[N+]([O-])O
Product: Cc1cc(Br)cc(C(=O)O)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
To a solution of 2,3-dimethylbenzoic acid (5 g, 33.3 mmol, 1.0 eq) in acetic acid (167 mL) at room temperature was added a solution of conc. nitric acid (25.2 g, 399 mmol, 12 eq), water (15 g, 0.83 mmol, 25 eq) and bromine (5.85 g, 36.6 mmol, 1.1 eq). A solution of silver nitrate (7.35 g, 43 mmol, 1.3 eq) in water (43 mL) was then added dropwise over 30 min. Once addition was completed, the reaction was stirred at room temperature for 1 h, then quenched by addition of water and EtOAc. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo to give the title compound as a yellow solid (6.4 g, 83%).
Reaction SMILES: CCCCCC.[S:7]1[CH:11]=[CH:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]1=2.[Br:16][C:17]1[CH:18]=[CH:19][C:20]([Cl:25])=[C:21]([CH:24]=1)[CH:22]=[O:23].[Cl-].[NH4+]>O1CCCC1>[S:7]1[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[CH:10]=[C:11]1[CH:22]([C:21]1[CH:24]=[C:17]([Br:16])[CH:18]=[CH:19][C:20]=1[Cl:25])[OH:23]
Reactant: O=Cc1cc(Br)ccc1Cl
Reactant: c1ccc2sccc2c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC(c1cc2ccccc2s1)c1cc(Br)ccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
1.6 M n-butylithium hexane solution (26.9 mL) was added to a mixture of benzo[b]thiophene (5.8 g, 0.043 mol) and tetrahydrofuran (58 mL) at −78° C. over 20 minutes. After stirred for 0.5 hours, the mixture was added with a tetrahydrofuran (50 mL) solution of 5-bromo-2-chlorobenzaldehyde (9.0 g, 0.041 mol) and stirred for further five minutes. The reaction mixture was warmed to room temperature. After the reaction mixture was added with a saturated ammonium chloride aqueous solution and extracted with ethyl acetate, the organic phase was washed with brine and then dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain pale yellow oily (1-benzothien-2-yl)(5-bromo-2-chlorophenyl)methanol (10.3 g, 71%).
Reaction SMILES: [H-].[Na+].[C:3](=[O:10])([O:7][CH2:8][CH3:9])OCC.[H-].[Na+].C1COCC1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[C:26](=[O:30])[CH2:25][CH2:24][CH2:23]2>C1COCC1.CCOCC.CC(O)=O>[CH2:8]([O:7][C:3]([CH:25]1[CH2:24][CH2:23][C:22]2[C:27](=[CH:28][CH:29]=[C:20]([O:19][CH3:18])[CH:21]=2)[C:26]1=[O:30])=[O:10])[CH3:9]
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOC(=O)C1CCc2cc(OC)ccc2C1=O
Temperature: 25 °C
Yield: 106.5 %

Procedure:
NaH (3.4 g, 60% in mineral oil, 83.3 mmol) was washed with hexanes (3×70 mL) and THF (1×30 mL) in an oven dried 3 neck round-bottomed flask. Diethyl carbonate (5.5 mL, 45.4 mmol) was added to the NaH/THF suspension in anhydrous THF (20 mL) and the slurry was heated at reflux under N2. 6-Methoxy-1-tetralone (4 g, 22.7 mmol) in THF (40 mL) was added dropwise via an addition funnel to the suspension at reflux. The reaction mixture was then heated at reflux for 2 days. The solution was cooled to room temperature and glacial AcOH (3.6 mL) was added in a dropwise manner. Et2O (150 mL) was then added and the organic layer was washed with saturated NaCl solution (5×25 mL), dried (MgSO4), and concentrated under reduced pressure to provide a crude brown oil (6.0 g). The oil was subjected to medium pressure chromatography on silica (CHCl3) to provide a dark oil which solidified upon standing (5.17 g, 91.8% yield). The solid was recrystallized from EtOAc/hexane to provide a white solid. mp 58-60° C. 1H-NMR (300 MHz, CDCl3) δ 1.27-1.36 (t, 3H), 2.20-3.56 (m, 5H), 3.85 (s, 3H), 4.23-4.28 (m, 2H), 6.70 (s, 1H), 6.77-6.85 (d, 1H), 7.72-8.03 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6](=[O:17])[C:7]3[CH:14]=[CH:13][C:12]([O:15]C)=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1.Br>C(O)(=O)C>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6](=[O:17])[C:7]3[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: COc1ccc2c(c1)CCc1cc(Cl)ccc1C2=O
Agent: Br
Solvent: CC(=O)O
Product: O=C1c2ccc(O)cc2CCc2cc(Cl)ccc21

Procedure:
For the synthesis of the title compound, 1.0 g (4.87 mmol) of 2-chloro-8-methoxy-10,11-dihydrodibenzo[a,d]cyclohepten-5-one, 10 ml of HBr (48%, aqueous) and 10 ml of glacial acetic acid are employed in method L. C15H11ClO2(Mr=258.71)
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]CCCCCCC)=[N+:2]=[N-:3].[I:22]C1C=CC=CC=1C(Cl)=O.N(CCN)=[N+]=[N-].C(N(CC)CC)C>ClCCl>[N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=1[I:22])=[N+:2]=[N-:3]
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Reactant: O=C(Cl)c1ccccc1I
Agent: [N-]=[N+]=NCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NCCNC(=O)c1ccccc1I
Yield: 74 %

Procedure:
As in the synthesis of N-(2-azidoethyl)tetradecanamide, 2-iodobenzoyl chloride (0.312 g, 1.17 mmol) was reacted with 2-azidoethanamine (0.101 g, 1.17 mmol) and triethylamine (0.237 g, 2.34 mmol) in dichloromethane (5 mL) to give N-(2-azidoethyl)-2-iodobenzamide (0.272 g, 74% yield). 1H NMR (300 MHz, CDCl3) δ 7.84 (d, J=7.2 Hz, 1H), δ 7.33 (m, 2H), S 7.08 (t, J=3.3 Hz, 1H), δ 6.51 (s, 1H), δ 3.54 (s, 2H), δ 3.53 (s, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 169.9, 141.9, 140.0, 131.5, 128.4, 128.4, 92.7, 50.8, 39.6 ppm; HRMS (ESI) calcd for C9H91N4O (M+) 315.9821. found 315.9820.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][C:11](OC)=[O:12].[C:15]([OH:19])([CH3:18])([CH3:17])[CH3:16].C(OC(C)C)(C)C>[Zn]>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][C:11]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:12]
Reactant: COC(=O)CCCOC1CCCCO1
Reactant: CC(C)(C)O
Agent: [Zn]
Solvent: CC(C)OC(C)C
Product: CC(C)(C)OC(=O)CCCOC1CCCCO1
Yield: 92.9 %

Procedure:
Under a nitrogen atmosphere, a mixture of methyl 4-(tetrahydro-2H-pyran-2-yloxy)butyrate (3.0 mmol), t-butanol (3. 6 mmol), a zinc cluster Zn4O (OCOCF3)6 (0.0375 mmol) and diisopropyl ether (5.0 ml) was refluxed for 18 hours. As a result, t-butyl 4-(tetrahydro-2H-pyran-2-yloxy)butyrate was obtained in a yield of 92.9%.
Reaction SMILES: CCO.O.[CH:5]1([C:10]2[CH:14]=[C:13]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=3[Cl:26])=[O:17])[N:12]([C:27]3[CH:35]=[C:34]4[C:30]([CH2:31][CH2:32][CH:33]4[C:36]([O:38]CC)=[O:37])=[CH:29][CH:28]=3)[N:11]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1.[OH-].[Li+]>C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(OCC)(=O)C.O1CCOCC1>[CH:5]1([C:10]2[CH:14]=[C:13]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=3[Cl:26])=[O:17])[N:12]([C:27]3[CH:35]=[C:34]4[C:30]([CH2:31][CH2:32][CH:33]4[C:36]([OH:38])=[O:37])=[CH:29][CH:28]=3)[N:11]=2)[CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: CCOC(=O)C1CCc2ccc(-n3nc(C4CCCC4)cc3NC(=O)Nc3cccc(Cl)c3Cl)cc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(Nc1cccc(Cl)c1Cl)Nc1cc(C2CCCC2)nn1-c1ccc2c(c1)C(C(=O)O)CC2
Temperature: 25 °C

Procedure:
In a 1:1:1 mix of EtOH:H2O:dioxane (6 mL) was placed ethyl 6-(3-cyclopentyl-5-(3-(2,3-dichlorophenyl)ureido)-1H-pyrazol-1-yl)-2,3-dihydro-1H-indene-1-carboxylate (520 mg, 0.986 mmol) and lithium hydroxide (71 mg, 2.96 mmol). The solution warmed to 40 C and stirred, ON. LC shows complete reaction. The solution cooled to RT and diluted with 5% citric acid (20 mL) and Ethyl acetate (20 mL). The organic phase separated, washed with brine and dried over sodium sulfate. The solvents were evaporated at reduced pressure to give 6-(3-cyclopentyl-5-(3-(2,3-dichlorophenyl)ureido)-1H-pyrazol-1-yl)-2,3-dihydro-1H-indene-1-carboxylic acid as a foam, 474 mg (96%), used as is. In DMF (5 mL) was placed 6-(3-cyclopentyl-5-(3-(2,3-dichlorophenyl)ureido)-1H-pyrazol-1-yl)-2,3-dihydro-1H-indene-1-carboxylic acid (474 mg, 0.949 mmol), HOBt (196 mg, 1.09 mmol) and EDAC (218 mg, 1.42 mmol). The mixture was stirred at RT for 1 hr and then treated with a solution of 0.5N ammonia in dioxane (7.59 mL, 3.80 mmol). The mixture was stirred at RT, ON. LC shows complete reaction. The mixture was diluted with 5% citric acid (20 mL) and Ethyl acetate (20 mL). The organic phase separated, washed with saturated sodium bicarbonate (20 mL), brine (20 mL) and dried over sodium sulfate. The solvents evaporated at reduced pressure to give a foam, dried on high vacuum line at RT for 2 hrs. The foam was then purified by Biotage chromatography (S1-25 column, 65-95% Ethyl acetate/Hex). Fractions 10-19 were combined and evaporated at reduced pressure to give 1-(1-(3-carbamoyl-2,3-dihydro-1H-inden-5-yl)-3-cyclopentyl-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea as a white solid. The solid was dried on the high vacuum line at 65 C in the abderhalden for 3 hrs, 210 mg (44%). 1H NMR (DMSO-d6) 1.59-1.73 (m, 6H), 1.95-1.99 (m, 2H), 2.23-2.33 (m, 2H), 2.88-3.06 (m, 3H), 3.90-4.04 (m, 1H), 6.31 (s, 1H), 6.98 (s, 1H), 7.26-7.42 (m, 5H), 7.63 (br s, 1H), 8.07-8.09 (m, 1H), 8.77 (s, 1H), 9.21 (s, 1H). LC-MS (EI) m/z: 500.0 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:17]#[N:18])([CH3:16])[CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=[O:20].[K+].[K+].OO.O>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]([C:17](=[O:20])[NH2:18])([CH3:16])[CH3:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCN(C(C)(C)C#N)CC1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(C)(C)C(N)=O)CC1
Temperature: 40 °C
Yield: 309.7 %

Procedure:
To a cooled (ice/water bath) solution of 4-(cyano-dimethyl-methyl)-piperazine-1-carboxylic acid tert-butyl ester (102.9 mg) in dry DMSO was added K2CO3 (9.8 mg) followed by 28% hydrogen peroxide solution (200 μL) dropwise. The resultant was heated at 40° C. overnight. Water was added and the white solid collected, washed with water and air dried to give 4-(1-carbamoyl-1-methyl-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (59.6 mg). (See Tetrahedron 2002, 58, 3217). Treatment of this compound with HCl in DCM/MeOH yielded the desired amine, which was isolated as the hydrochloride salt.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1>[Ru].C(O)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH:8]2[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2ccccc2)CC1
Agent: [Ru]
Solvent: CCO
Product: CN1CCN(C2CCCCC2)CC1
Temperature: 120 °C
Reaction time: 8 h
Yield: 94.1 %

Procedure:
A 500 mL steel bomb hydrogenator was charged with 38 g of 1-methyl-4-phenylpiperazine, 200 mL of degassed ethanol, and 4 g of a ruthenium 5% on carbon catalyst. The flask was evacuated and purged with hydrogen gas twice, the second time leaving the flask at 800 psig (5620 kPa). The reaction mixture was then heated to 120° C. and left overnight. The next morning the pressure in the flask had decreased significantly; the reaction was cooled, re-pressurized and again brought up to temperature. This was repeated until a minimal pressure decrease was noticed. The reaction mixture was then passed through a thin pad of celite producing a liquid that was subsequently distilled to give 37 g of 1-methyl-4-cyclohexylpiperazine.
Reaction SMILES: [N+](CCCC)(CCCC)(CCCC)CCCC.[F-].O.O.O.C([Si](C)(C)[O:27][C@H:28]1[CH2:37][CH2:36][CH2:35][C@@:34]2([CH3:38])[C@H:29]1[CH2:30][CH2:31][CH:32]=[C:33]2[C@H:39]([CH3:47])[CH2:40][C:41]#[C:42][C:43]([CH3:46])([OH:45])[CH3:44])(C)(C)C>C1COCC1>[OH:45][C:43]([CH3:44])([CH3:46])[C:42]#[C:41][CH2:40][C@H:39]([C:33]1[C@:34]2([CH3:38])[C@@H:29]([CH2:30][CH2:31][CH:32]=1)[C@@H:28]([OH:27])[CH2:37][CH2:36][CH2:35]2)[CH3:47]
Reactant: C[C@H](CC#CC(C)(C)O)C1=CCC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](CC#CC(C)(C)O)C1=CCC[C@H]2[C@@H](O)CCC[C@]12C
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
5.43 g (17.2 mmol) of nBu4NF.3H2O in 10 ml of THF was carefully dried by stirring during 2 h at RT over 7.5 g of 3 Å molecular sieve. This solution was then added to 866 mg (2.14 mmol) of (R)-6-[(4aR,5S,8aS)-5-(tert-butyl-dimethyl-silanyloxy)-8a-methyl-3,4,4a,5,6,7,8,8a-octahydro-naphthalen-1-yl]-2-methyl-hept-3-yn-2-ol and the mixture kept for 24 h at 55°. The reaction mixture was then poured onto crushed ice, extracted twice with ether, washed with water and brine, dried over sodium sulfate, and evaporated to dryness. Flash chromatography (SiO2, hexane/AcOEt=7/3) afforded 590 mg of the title compound as colorless oil.
Reaction SMILES: [C:1]1([C:15]([OH:17])=[O:16])[C:14]2[C:5](=[CH:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[Cl:18]N1C(=O)CCC1=O>CN1CCCC1=O.O>[Cl:18][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[C:14]2[C:5]=1[CH:4]=[CH:3][CH:2]=[C:1]2[C:15]([OH:17])=[O:16]
Reactant: O=C(O)c1cccc2cc3ccccc3cc12
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(O)c1cccc2c(Cl)c3ccccc3cc12
Yield: 59.2 %

Procedure:
Anthracene-1-carboxylic acid (15B, 24g, 0.108 mol) was treated with N-chlorosuccinimide (Aldrich, 24 g, 0.18 mol) in N-methylpyrrolidinone (Eastman, 600 mL) and heated under N2 at 90° for 1.5 h. The reaction mixture was diluted with H2O (3.5 L), filtered, dried, and the precipitate recrystallized from EtOAc to afford 16.41 g (59%) of 10-chloroanthracene-1-carboxylic acid mp 275°-277°, (C, H, Cl).
Reaction SMILES: C(=O)([O-])O.[Na+].[N+:6]([C:9]1[CH:10]=[C:11]([OH:16])[C:12](=[CH:14][CH:15]=1)[OH:13])([O-:8])=[O:7].[CH2:17]([CH:19]1[O:21][CH2:20]1)Cl>CN(C=O)C.O>[N+:6]([C:9]1[CH:15]=[CH:14][C:12]2[O:13][CH2:17][CH:19]([CH2:20][OH:21])[O:16][C:11]=2[CH:10]=1)([O-:8])=[O:7]
Reactant: ClCC1CO1
Reactant: O=[N+]([O-])c1ccc(O)c(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)OC(CO)CO2
Yield: 39.9 %

Procedure:
3.0 g of sodium hydrogen carbonate was suspended in 90 mL DMF. At 0° C. a solution of 5.15 g of 4-nitrocatechol was added dropwise over 15 min. Subsequently, 3.9 g of epichlorohydrin in 10 mL DMF were added over 15 min. Stirring was continued at room temperature, then at 80° C. overnight. The mixture was diluted with water and extracted three times with ethyl acetate, dried (anhyd. Na2SO4), filtered and concentrated under vacuum to give a yellow oil. The oil was purified by column chromatography on silica gel using EtOAc-hexanes (0-100% gradient) to give the product (2.8 g) as a yellow solid.