Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C@@H:16]([CH2:33][CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[C:17]([NH:19][C:20]3[CH:25]=[N:24][C:23]([CH:26]4[CH2:30][O:29]C(C)(C)[O:27]4)=[CH:22][N:21]=3)=[O:18])[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH2:3][CH2:2]1.Cl>C1COCC1>[CH:1]1([C:4]2[CH:5]=[C:6]([C@@H:16]([CH2:33][CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[C:17]([NH:19][C:20]3[CH:25]=[N:24][C:23]([CH:26]([OH:27])[CH2:30][OH:29])=[CH:22][N:21]=3)=[O:18])[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:14][CH2:15]2)(=[O:12])=[O:11])[CH2:3][CH2:2]1
Reactant: CC1(C)OCC(c2cnc(NC(=O)[C@H](CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)c(C4CC4)c3)cn2)O1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(Nc1cnc(C(O)CO)cn1)[C@H](CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)c(C2CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.6 %

Procedure:
To a solution of (2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-N-[5-(2,2-dimethyl-1,3-dioxolan-4-yl)pyrazin-2-yl]-3-(tetrahydro-2H-pyran-4-yl)propanamide (150 mg) in THF (10 mL) was added 1 M hydrochloric acid at room temperature, followed by stirring at room temperature for 3 hours. After extraction with ethyl acetate, the organic layer was sequentially washed with saturated aqueous sodium bicarbonate and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated to obtain (2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-N-[5-(1,2-dihydroxyethyl)pyrazin-2-yl]-3-(tetrahydro-2H-pyran-4-yl)propanamide (133 mg) as a white amorphous substance.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.[NH:19]1[CH2:24][CH2:23][C:22]2([C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26](=[O:33])[O:25]2)[CH2:21][CH2:20]1>CC(N(C)C)=O>[CH3:18][O:17][C:13]1[CH:12]=[C:11]([C:9]2[CH:8]=[CH:7][C:5]3[NH:6][C:2]([N:19]4[CH2:24][CH2:23][C:22]5([C:32]6[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=6)[C:26](=[O:33])[O:25]5)[CH2:21][CH2:20]4)=[N:3][C:4]=3[CH:10]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: O=C1OC2(CCNCC2)c2ccccc21
Reactant: COc1cccc(-c2ccc3nc(Cl)[nH]c3c2)c1
Solvent: CC(=O)N(C)C
Product: COc1cccc(-c2ccc3[nH]c(N4CCC5(CC4)OC(=O)c4ccccc45)nc3c2)c1

Procedure:
Stir 2-chloro-5-(3-methoxyphenyl)benzimidazole (185 mg) and spiro[isobenzofuran-1,4′-piperidin]-3-one (263 mg) in dimethylacetamide (6 mL) at 195° C. for 1 hour. Cool the mixture and partition between EtOAc and half-saturated NaHCO3, wash several times with water, dry and concentrate in vacuo. Purify the residue by chromatography (1:1 hexanes/EtOAc) to obtain 1′-(5-(3-methoxyphenyl)-1H-benzimidazol-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one.
Reaction SMILES: [Si]([O:8][CH:9]1[C:19]2[C:14](=[N:15][C:16]([CH3:26])=[C:17]([C:20]([NH:22][C:23]([NH2:25])=[NH:24])=[O:21])[CH:18]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1)(C(C)(C)C)(C)C>CO.Cl>[OH:8][CH:9]1[C:19]2[C:14](=[N:15][C:16]([CH3:26])=[C:17]([C:20]([NH:22][C:23]([NH2:25])=[NH:24])=[O:21])[CH:18]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Cc1nc2c(cc1C(=O)NC(=N)N)C(O[Si](C)(C)C(C)(C)C)CCCC2
Agent: Cl
Solvent: CO
Product: Cc1nc2c(cc1C(=O)NC(=N)N)C(O)CCCC2
Temperature: 25 °C
Reaction time: 14 h
Yield: 135 %

Procedure:
5-tert-Butyldirnethylsilyloxy-2-methyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carbonylguanidine (252.5 mg, 0.37 mmol) was dissolved in 5% hydrochloric acid methanol solution (10.1 ml) at 0° C. and stirred at room temperature for 14 hours. The solvent was evaporated under reduced pressure, and the thus obtained residue was mixed with chloroform:methanol (4:1), adjusted to pH 9 to 10 with 5% sodium hydroxide aqueous solution and then extracted with chloroform:methanol (4:1). The thus obtained organic layer was washed with water and saturated brine in that order and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was crystallized from chloroform-ether to obtain the title compound (131.0 mg, 74.9%) as white powder.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.Cl.[CH3:14][O:15][NH2:16].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH3:14][O:15][NH:16][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: ClCc1cccc2ccccc12
Reactant: CON
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CONCc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 50.6 %

Procedure:
1-Chloromethylnaphthalene (1.85 g, 10 mmol) in 4 ml dimethylformamide (hereinafter DMF) was added dropwise to a mixture of methoxyamine hydrochloride (9.19 g, 110 mmol) and sodium carbonate (11.66 g, 110 mmol) in 100 ml of DMF at 0°-5° C. After stirring 20 minutes, the reaction was warmed to room temperature. After about 18 hours, the reaction was concentrated in vacuo and partitioned between ethyl ether and water. The aqueous layer was extracted twice with ethyl ether. Combined ethereal layers were washed once with water, twice with brine, dried over sodium sulfate and concentrated to 1.19 g of crude product which was further purified by bulb-to-bulb distillation (148°-168° C. at 0.7 mm of Hg), affording 0.947 g of N-methoxy-1-naphthalenemethanamine.
Reaction SMILES: [O:1]=[S:2]1(=[O:49])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH:10][C@:11]23[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:12]2[C@@H:13]2[C@@:26]([CH3:29])([CH2:27][CH2:28]3)[C@@:25]3([CH3:30])[C@@H:16]([C@:17]4([CH3:42])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:32])([CH3:31])[C:20]([CH2:33][CH2:34][C:35]([CH3:41])([CH3:40])[CH2:36][C:37](O)=[O:38])=[CH:19][CH2:18]4)[CH2:15][CH2:14]2)[CH2:4][CH2:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:83][OH:84]>C(Cl)Cl>[O:49]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH:10][C@:11]23[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:12]2[C@@H:13]2[C@@:26]([CH3:29])([CH2:27][CH2:28]3)[C@@:25]3([CH3:30])[C@@H:16]([C@:17]4([CH3:42])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:31])([CH3:32])[C:20]([CH2:33][CH2:34][C:35]([CH3:40])([CH3:41])[CH2:36][C:37]([NH:83][OH:84])=[O:38])=[CH:19][CH2:18]4)[CH2:15][CH2:14]2)[CH2:4][CH2:3]1
Reactant: NO
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(CCC(C)(C)CC(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(CCC(C)(C)CC(=O)NO)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 16 h
Yield: 5.3 %

Procedure:
A solution of 5-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-3,3-dimethylpentanoic acid (35 mg, 0.050 mmol) in DCM (2 mL) was treated with HATU (28.6 mg, 0.075 mmol), N,N-diisopropylethylamine (0.026 mL, 0.150 mmol), and hydroxylamine (1.8 mg, 0.055 mmol). The reaction mixture was stirred at rt for 16 h. The mixture was concentrated and the crude product was purified by prep HPLC (Method 10) to afford 5-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-N-hydroxy-3,3-dimethylpentanamide (1.9 mg, 5% yield). LC/MS m/e 714.5 (M+H)+, 2.23 min (ionization peak, no UV) (method 3). 1H NMR (500 MHz, DMSO-d6) δ 10.29 (2, 1H), 5.20 (d, J=5.5 Hz, 1H), 4.69 (s, 1H), 4.55 (s, 1H), 3.14-3.01 (m, 4H), 2.98-2.84 (m, 4H), 2.65-2.55 (m, 3H), 2.50-2.44 (m, J=5.9 Hz, 1H), 2.40-2.31 (m, J=5.1 Hz, 1H), 1.97-0.76 (m, 28H), 1.65 (s, 3H), 1.03 (s, 3H), 0.95 (s, 3H), 0.94 (s, 9H), 0.87 (s, 3H), 0.79 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:14]([C:15]3[N:20]=[C:19]([CH3:21])[N:18]=[C:17]([N:22](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)[N:16]=3)=[CH:13][CH:12]=[C:11]([CH3:41])[N:10]=2)[CH:5]=[N:6][CH:7]=1>C(O)(C(F)(F)F)=O.OS(C(F)(F)F)(=O)=O>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:14]([C:15]3[N:20]=[C:19]([CH3:21])[N:18]=[C:17]([NH2:22])[N:16]=3)=[CH:13][CH:12]=[C:11]([CH3:41])[N:10]=2)[CH:5]=[N:6][CH:7]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3ccc(C)nc3Nc3cncc(F)c3)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-c2nc(C)nc(N)n2)c(Nc2cncc(F)c2)n1
Temperature: 80 °C
Yield: 90.2 %

Procedure:
A solution of 4-(2-(5-fluoropyridin-3-ylamino)-6-methylpyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (118 mg, 0.214 mmol) in 2 mL of TFA was treated with 2 drops of triflic acid. The brown solution was heated in an oil bath at 80° C. for 8 h. The solution was concentrated and the residue was stirred in 5 mL of EtOAc and 2 mL of 0.5N NaOH. The precipitated solid was collected by filtration, rinsed with 2×2 mL of water, followed by 2 mL of EtOAc and 2×2 mL of DCM. The yellow crystalline solid was collected and dried in a vacuum oven at 40° C. for 18 h to give 4-(2-(5-fluoropyridin-3-ylamino)-6-methylpyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (60 mg, 0.193 mmol, 90% yield). 1H NMR (400 MHz, d6-DMSO) δ 12.33 (1H, s); 8.66 (1H, s); 8.73 (1H, d, J=8.2 Hz); 8.60 (1H, d, J=12.9 Hz); 8.16 (1H, s); 7.90 (1H, br.); 7.75 (1H, br.); 6.91 (1H, d, J=8.0 Hz); 2.48 (3H, s); 2.44 (3H, s). m/z (ESI, +ve ion) 312 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][O:7][C:8]2[C:9]([NH:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)=S)=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[NH3:27]>>[CH3:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][O:7][C:8]2[C:9]([NH:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)=[NH:27])=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(COc2cccnc2NC(=S)Nc2ccc(Cl)cc2)cc1
Reactant: N
Product: Cc1ccc(COc2cccnc2NC(=N)Nc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of yellow mercuric oxide (0.68 g, 0.0031 mol), N-[3-(4-methylbenzyloxy)pyrid-2-yl]-N'-(4-chlorophenyl)thiourea (1.01 g, 0.0026 mol) and methanolic ammonia solution (40 ml) was stirred for 2 days at room temperature. The solvent was removed in vacuo and the black residue was boiled with chloroform and filtered hot. Evaporation of the solvent and recrystallisation from acetonitrile gave the desired product. Yield 0.5 g (52%), m.p. 174°-175 ° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:39]#[N:40])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][CH:34]3[CH2:37][CH2:36][CH2:35]3)[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26]C(C)(C)C)=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:38])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:39]#[N:40])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][CH:34]3[CH2:35][CH2:36][CH2:37]3)[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:38])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC2CCC2)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(C(CC2CCC2)C(=O)Nc2ccc(C(=O)O)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
64 mg (purity 86%, 0.10 mmol) of tert-butyl 4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-cyclobutylpropanoyl}amino)benzoate (racemate) were hydrolysed with TFA according to General Method 2. Yield: 33 mg (67% of theory)
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[OH:14])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=O.Br[CH2:16][C:17](=[O:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[C:17]([C:18]1[O:14][C:13]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=2[CH:1]=1)(=[O:19])[CH3:16]
Reactant: CC(=O)CBr
Reactant: CCOC(=O)c1ccc(O)c(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1ccc2oc(C(C)=O)cc2c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 246.8 %

Procedure:
To a solution of ethyl 3-formyl-4-hydroxybenzoate (4.00 g, 11.5 mmol) in acetonitrile (85 mL) were added bromoacetone (9.68 g, 64.1 mmol) and potassium carbonate (14.7 g, 106 mmol), and the mixture was stirred at 70° C. overnight. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solution was passed through silica gel. The solvent was evaporated under reduced pressure, and the obtained solid was washed with diisopropyl ether to give the title compound (6.59 g, yield 67%).
Reaction SMILES: [Li]CCCC.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.C([O:16][C:17](=O)[CH:18]([F:20])[F:19])C.Cl>C1COCC1>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([C:17](=[O:16])[CH:18]([F:20])[F:19])[CH:8]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CCOC(=O)C(F)F
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(c1cc(Br)ccc1F)C(F)F
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of diisoprpopylamine (343 g, 3.39 mol) in THF (4 L) was added slowly n-BuLi (1.4 L, 3.5 mol, 2.5 M in hexane) at −78° C. while keeping reaction temperature under −55° C. After addition, the mixture was stirred at −78° C. for 15 min. At this point, a solution of 4-bromo-1-fluorobenzene (540 g, 3.08 mol) in THF (1 L) was cooled to −60° C. before adding to the reaction mixture gradually while keeping reaction temperature under −55° C. and the resulting yellow solution was stirred at −78° C. for 150 min. Ethyldifluoroacetate (421 g, 3.39 mol) was added to the reaction mixture over 15 min and then the mixture was stirred at −78° C. for 15 min. 1 M HCl (6.0 L) was added to the reaction mixture with stirring. Aqueous layer was extracted with TBME (3×4 L). The combined organic phases were washed with water, dried (MgSO4) and evaporated in vacuo. The resulting residue was distilled under vacuum (90˜95° C./0.19 mbar) and fraction at 54˜62° C. was collected to obtain the title compound as a colorless liquid. ESIMS: 253 [(M+H)+]; 1H NMR (400 MHz, CDCl3): δ 8.06 (dd, 1H), 7.75 (ddd, 1H), 7.13 (dd, 1H), 6.41 (dt, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH2:19][CH:20]2[O:22][CH2:21]2)[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:23]1([NH2:26])[CH2:25][CH2:24]1>>[C:1]([C:5]1[CH:9]=[C:8]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH2:19][CH:20]([OH:22])[CH2:21][NH:26][CH:23]2[CH2:25][CH2:24]2)[O:7][N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(C=Cc2ccccc2OCC2CO2)on1
Reactant: NC1CC1
Product: CC(C)(C)c1cc(C=Cc2ccccc2OCC(O)CNC2CC2)on1
Yield: 70.7 %

Procedure:
7 g (0.023 mole) of 3-tert.-butyl-5-[2-(2,3-epoxypropoxy)-styryl]-isoxazole and 2.7 g (0.047 mole) of cyclopropylamine are reacted by the method described in Example 1. 5.8 g of an oil are obtained; this is dissolved in diethyl ether and precipitated with 2 g of oxalic acid dissolved in a small amount of ethanol. 2.7 g (26% of theory) of colorless crystals are obtained. Melting point 170°-174° C.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.[NH:23]1[C:31]2[C:26](=[C:27]([CH2:32][OH:33])[CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24]1.[OH-].[Na+].CCOCC>C(Cl)Cl>[NH:23]1[C:31]2[CH:30]=[CH:29][CH:28]=[C:27]([CH:32]=[O:33])[C:26]=2[CH:25]=[CH:24]1
Reactant: OCc1cccc2[nH]ccc12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOCC
Product: O=Cc1cccc2[nH]ccc12
Reaction time: 1 h
Yield: 52.7 %

Procedure:
Dess-Martin periodane (1.04 g, 2.46 mmol) was dissolved into anhydrous CH2Cl2 (10 ml). (1H-Indol-4-yl)-methanol (449 mg, 3.07 mmol) in anhydrous CH2Cl2 (10 ml) was added and the mixture was stirred for 1 h. Sodium hydroxide (50 ml of 1N solution) and ether (50 ml) were added and the reaction was stirred for 30 min. The organic layer was separated and washed with water (10 ml), brine (10 ml), dried over MgSO4, filtered and concentrated to a thick brown oil. Purification by column chromatography (silica gel, gradient elution of 2% MeOH/CH2Cl2 to 5% MeOH/CH2Cl2) gave 1H-indole-4-carbaldehyde (235 mg, 53%) as a yellow solid: 1H NMR (300 MHz, DMSO-d6) δ 11.59 (bs, 1H), 10.18 (s, 1H), 7.78-7.75 (m, 1H), 7.66-7.60 (m, 2H), 7.33-7.28 (m, 1H), 7.08 (d, J=3.0 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[C:15]2[C:7](=[CH:8][C:9]3[C:14]2=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6](=[O:17])[C:5]=1[OH:18])([O-])=O.Cl[Sn]Cl.Cl.[OH-].[NH4+]>C(O)(=O)C>[NH2:1][C:4]1[CH:16]=[C:15]2[C:7](=[CH:8][C:9]3[C:14]2=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6](=[O:17])[C:5]=1[OH:18]
Reactant: O=C1C2=Cc3ccccc3C2=CC([N+](=O)[O-])=C1O
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [NH4+]
Solvent: CC(=O)O
Product: NC1=C(O)C(=O)C2=Cc3ccccc3C2=C1
Yield: 65 %

Procedure:
A mixture of 3-nitro-2-hydroxyfluorenone (1.6 g, 6.6 mmol) and SnCl2 (3 g, 6.6 mmol) was refluxed in 100 ml acetic acid:conc. HCl (1:1) for 1 hour. The mixture was allowed to cool to room temperature and neutralized with ammonium hydroxide. After extracting with EtOAc (3×100 ml), combined organic fractions were dried over magnesium sulfate and evaporated to leave the product as a brown solid (65%) (M+1, 212).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.[CH3:13][S-:14].[Na+]>C(#N)C.CN(C=O)C>[CH3:9][O:8][C:6]1[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=[C:2]([S:14][CH3:13])[N:7]=1
Reactant: COc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: C[S-]
Agent: [Na+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1nc(SC)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 91 %

Procedure:
To a solution of 6-chloro-2-methoxy-3-nitropyridine (300 mg, 1.591 mmol) in acetonitrile/DMF (2:1, 3 mL) was added sodium thiomethoxide (133 mg, 1.91 mmol). The reaction mixture was stirred at room temperature for 18 hours and then concentrated in vacuo. The residue was partitioned between water (30 mL) and EtOAc (30 mL). The organic layer was dried (MgSO4) and concentrated in vacuo to give the title compound (290 mg, 91%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[N:12][N:13]2[C:18]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)([CH2:23][CH3:24])[C:19]([O:21]C)=[O:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>O1CCOCC1.O>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[N:12][N:13]2[C:18]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)([CH2:23][CH3:24])[C:19]([OH:21])=[O:20])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ncc2c(NC(=O)OC(C)(C)C)cccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCC(C(=O)O)(c1ccc(Cl)cc1)n1ncc2c(NC(=O)OC(C)(C)C)cccc21
Temperature: 70 °C
Reaction time: 5 h

Procedure:
Methyl 2-(4-((tert-butoxycarbonyl)amino)-1H-indazol-1-yl)-2-(4-chlorophenyl)butanoate (0.5 g, 1.13 mmol) (enantiomer A intermediate), as described in example 18 step D, as described in Example 18 step D, was dissolved in a mixture of 1,4-dioxane (1.0 mL) and water (0.25 mL) followed by addition of LiOH (0.27 g, 11.26 mmol). The mixture was stirred at 70° C. for 5 hours, then concentrated to remove solvent. The residue was dissolved in water (20 mL) and acidified with 1 N aq. HCl solution (11.3 mL) to give white precipitate. The solid was filtered, washed with water, and dried under vacuum to give title compound. LC/MS m/z=430.1[M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:31]=[CH:32][C:33]=1[N+:34]([O-])=O)[O:7][C:8]1[C:17]2[C:12](=[C:13]([O:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[C:21]([N+:28]([O-])=O)[CH:20]=3)[CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)([O-])=O.O.NN>[Pd].C(O)C>[NH2:28][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[NH2:25])[O:18][C:13]1[C:12]2[C:17](=[C:8]([O:7][C:6]3[CH:31]=[CH:32][C:33]([NH2:34])=[C:4]([NH2:1])[CH:5]=3)[CH:9]=[CH:10][CH:11]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(Oc2cccc3c(Oc4ccc([N+](=O)[O-])c([N+](=O)[O-])c4)cccc23)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1ccc(Oc2cccc3c(Oc4ccc(N)c(N)c4)cccc23)cc1N
Yield: 99 %

Procedure:
A stirred mixture of 1,5-bis(3,4-dinitrophenoxy)naphthalene (6 g, 0.0122 mole) and 10 percent palladium on charcoal (0.6 g) in absolute ethanol (300 ml) was heated to reflux under nitrogen. A solution of hydrazine hydrate (8 ml) in ethanol (30 ml) was added dropwise over a period of 40 minutes. The reaction mixture was heated at reflux for 6 hours, chilled in an ice bath, and suction filtered through Celite filter aid into one liter of stirred, cold, concentrated hydrochloric acid. The resulting precipitate of hydrazine hydrochloride and the desired tetraamino hydrochloride was collected, partially dried, and dissolved in water (300 ml). Concentrated ammonium hydroxide solution (60 ml) was added and the resulting precipitate collected and vacuum dried to produce 4.5 g (90 percent) of the desired 1,5-bis(3,4-diaminophenoxy)naphthalene. Recrystallization from benzene gave a white product (melting point 230°-231°C).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[C@H:19]([CH2:24][C:25]4[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=4)[C:28]([OH:30])=[O:29])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[Pd]>[C:1]1([C:7]2[N:8]=[C:9]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]3[CH2:24][C:25]3[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=3)[C:28]([OH:30])=[O:29])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cccc(C[C@@H]2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: [Pd]
Solvent: CO
Product: O=C(O)c1cccc(C[C@@H]2CCCCC2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reaction time: 8 h
Yield: 99.5 %

Procedure:
A mixture of (S)-3-{[2-(4,5-diphenyloxazol-2-yl)-2- cyclohexen-1-yl]methyl}benzoic acid (0.1 g) and 10% Pd/C (0.1 g) in methanol (20 ml) was stirred under H2 for 8 hours. The catalyst was filtered off and filtrate was evaporated in vacuo to give 3-{[(lS)-2-(4,5-diphenyloxazol-2-yl)-1- cyclohexyl]methyl}benzoic acid (0.1 g).