Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:17][O:16][C@H:15]([CH2:18][F:19])[C@H:14]1[CH2:13][S:12][C:11]([NH2:20])=[N:10]2.S(=O)(=O)(O)O.[N+:26]([O-])([OH:28])=[O:27].[OH-].[Na+]>FC(F)(F)C(O)=O>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N+:26]([O-:28])=[O:27])=[CH:4][C:3]=1[C@:9]12[CH2:17][O:16][C@H:15]([CH2:18][F:19])[C@H:14]1[CH2:13][S:12][C:11]([NH2:20])=[N:10]2
Reactant: NC1=N[C@@]2(c3cccc(F)c3F)CO[C@H](CF)[C@H]2CS1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: NC1=N[C@@]2(c3cc([N+](=O)[O-])cc(F)c3F)CO[C@H](CF)[C@H]2CS1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
(4aS,5S,7aS)-7a-(2,3-difluorophenyl)-5-(fluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine (9.10 g, 0.03 mol, 1.0 equiv.) was dissolved in trifluoroacetic acid (36.4 mL), and the solution was cooled to 0° C. Sulfuric acid (conc., 12.0 mL) was added, followed by fuming nitric acid (6.9 mL) dropwise while maintaining the temperature below 5° C. After stirring at 0-5° C. for 4 h, the reaction mixture was slowly charged into a vigorously stirred solution of aq.NaOH (43.3 g in 273 mL water) while maintaining a temperature below 20° C. The mixture was extracted with CH2Cl2 (1×94 ml, and 2×64 mL), and the combined organic phases were washed with sat. aq. NaCl (46 mL). Celite (15.0 g) was added to the organics, and the mixture was filtered rinsing with CH2Cl2 (40 mL). The solvents were evaporated to afford the title compound (8.3 g) which was used in the subsequent step without purification. 1H NMR (500 MHz, DMSO) δ ppm 8.41-8.30 (m, 1H), 8.22-8.13 (m, 1H), 6.36 (s, 2H), 4.70-4.46 (m, 2H), 4.43-4.31 (m, 1H), 4.35 (d, J=8.7 Hz, 1H), 3.69 (dd, J=8.5, 1.6 Hz, 1H), 3.04-2.91 (m, 2H), 2.86-2.76 (m, 1H); 13C NMR (125 MHz, DMSO) δ ppm 152.36 (dd, JCF=246.8, 12.3 Hz), 151.13, 150.32 (dd, JCF=238.2, 12.2 Hz), 143.25 (dd, JCF=7.9, 2.5 Hz), 134.70 (d, JCF=9.5 Hz), 121.28, 113.02 (d, JCF=22.3 Hz), 83.74 (d, JCF=170.1 Hz), 79.44 (d, JCF=18.3 Hz), 78.02 (d, J=3.9 Hz), 36.96, 23.28.
Reaction SMILES: [OH:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1.[CH:40]1([CH2:46][N:47]=[C:48]=[O:49])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>>[CH:40]1([CH2:46][NH:47][C:48]([O:1][CH:2]2[CH2:20][CH:19]3[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH:12]=[CH:13][CH:14]4[C:16]([C:22]([NH:24][S:25]([CH:28]5[CH2:29][CH2:30]5)(=[O:26])=[O:27])=[O:23])([NH:17][C:18]3=[O:21])[CH2:15]4)[CH2:3]2)=[O:49])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: CC(C)(C)OC(=O)NC1CCCOCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CN2C1=O
Reactant: O=C=NCC1CCCCC1
Product: CC(C)(C)OC(=O)NC1CCCOCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(OC(=O)NCC3CCCCC3)CN2C1=O
Yield: 29 %

Procedure:
Prepared by way of method III using 18-hydroxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-10-oxatricyclo[14.3.0.04,6]-nonadec-7-ene (100 mg, 0.175 mmol) and cyclohexylmethyl isocyanate (53 μL, 0.35 mmol). The final trituration (diethyl ether/hexane) and filtration gave 36 mg (29%) of 18-cyclohexylmethylaminocarbonyloxyl-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-10-oxatricyclo-[14.3.0.04,6]-nonadec-7-ene as a white powder: 99.0% pure (HPLC), MS m/z 708 (M−H)−, HRMS calcd. 708.3278 and found 708.3269, mp 142-144° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH:24]([O:27][C:28]1[C:29]([CH2:43][O:44][CH3:45])=[N:30][CH:31]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:33]=1)([CH3:26])[CH3:25]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:32]5[CH:31]=[N:30][C:29]([CH2:43][O:44][CH3:45])=[C:28]([O:27][CH:24]([CH3:26])[CH3:25])[CH:33]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: COCc1ncc(B2OC(C)(C)C(C)(C)O2)cc1OC(C)C
Product: COCc1ncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cc1OC(C)C

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 3-isopropoxy-2-methoxymethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 191.1.1) to give the title compound as a white foam. (HPLC: tR 2.41 min (Method A); M+H=473 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.99 (s, 1H), 8.27-8.25 (m, 1H), 8.15-8.10 (m, 2H), 8.03-7.98 (m, 1H), 7.62-7.60 (m, 1H), 7.42-7.40 (m, 1H), 4.77 (hp, 1H), 4.47 (s, 2H), 3.88 (s, 3H), 3.58 (s, 3H), 3.31 (s, 3H), 1.97 (s, 3H), 1.37-1.32 (m, 6H))
Reaction SMILES: O=[C:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].[CH2:8]([C:10]1([CH2:16][CH3:17])[CH2:12][CH:11]1[C:13]([NH2:15])=[O:14])[CH3:9]>C1(C)C=CC=CC=1>[CH2:8]([C:10]1([CH2:16][CH3:17])[CH2:12][CH:11]1[C:13]([NH:15]/[C:2](=[CH:6]\[CH3:7])/[C:3]([OH:5])=[O:4])=[O:14])[CH3:9]
Reactant: CCC(=O)C(=O)O
Reactant: CCC1(CC)CC1C(N)=O
Solvent: Cc1ccccc1
Product: C/C=C(\NC(=O)C1CC1(CC)CC)C(=O)O
Yield: 9.7 %

Procedure:
A mixture of 2.3 g of 2-ketobutyric acid, 2.0 g of 2,2-diethylcyclopropanecaboxamide, and 25 ml of toluene was heated under reflux for 16 hrs with removal of H20 by a modified Dean-Stark trap containing molecular sieves (4A). No product precipitated upon cooling. Ether (25 ml) was added and the mixture was extracted with saturated NaHCO3 (3 times). The combined extracts were acidified with concentrated HCl. The gummy precipitate crystallized when triturated with water. Recrystallization from ethyl acetate gave 0.31 g of product, m.p. 129°-30°. The NMR spectrum was consistent with the desired structure.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[Br:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([C:35]([OH:37])=O)[CH:33]=2)[N:28]([C:38]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:27]=1.[NH2:57][C@@H:58]1[CH2:63][CH2:62][CH2:61][N:60]([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[CH2:59]1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Br:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([C:35]([NH:57][C@@H:58]3[CH2:63][CH2:62][CH2:61][N:60]([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[CH2:59]3)=[O:37])[CH:33]=2)[N:28]([C:38]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[N:27]=1
Reactant: O=C(O)c1ccc2c(c1)c(Br)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](NC(=O)c2ccc3c(c2)c(Br)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (3.1 mmol) was added to a suspension of 3-bromo-1-trityl-1H-indazole-5-carboxylic acid (1 g) in DMF (5 mL) and was stirred at room temperature for 15 minutes. A solution of (R)-tert-butyl 3-aminopiperidine-1-carboxylate (415 mg) in DMF (5 mL) was added to the reaction and followed by diisopropyl ethyl amine (DIEA) (0.72 mL). The mixture was stirred at room temperature for an additional 30 minutes. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (3×100 mL). The extracts were combined, dried using anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was progressed to the next step without purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]([CH3:7])[C:3]1=[N:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH2:20][CH2:19][S:18][CH2:17][CH2:16]1.I([O-])(=O)(=O)=[O:22].[Na+]>CO.O>[OH2:22].[CH3:1][N:2]1[CH2:6][CH2:5][N:4]([CH3:7])[C:3]1=[N:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH2:16][CH2:17][S:18](=[O:22])[CH2:19][CH2:20]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CN1CCN(C)C1=Nc1ccccc1N1CCSCC1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN1CCN(C)C1=Nc1ccccc1N1CCS(=O)CC1

Procedure:
Reaction of 4-[2-(1,3-dimethyl-2-imidazolidinylideneamino)phenyl]thiamorpholine (1.5 g prepared as described in Example 144) in methanol (20 ml) and sodium metaperiodate (1.4 g) in water (4 ml) for 4 hours at 10° C. yielded 4-[2-(1,3-dimethyl-2-imidazolidinylideneamino)phenyl]thiamorpholine-1-oxide monohydrate (m.p. 103°-105° C.) which was recrystallised from a 1:1 mixture of 1,2-dimethoxyethane and hexane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[N:12]([CH3:19])[CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[C:20]([BH3-])#N.[Na+].C(O)=O.C=O>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[N:12]([CH3:19])[CH:13]1[CH2:18][CH2:17][N:16]([CH3:20])[CH2:15][CH2:14]1
Reactant: [BH3-]C#N
Reactant: COc1ccc([N+](=O)[O-])cc1N(C)C1CCNCC1
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: O=CO
Product: COc1ccc([N+](=O)[O-])cc1N(C)C1CCN(C)CC1
Temperature: 27.5 °C
Reaction time: 0.08 h

Procedure:
To a 250 mL three neck round bottom flask added 2-Methoxy-5-nitro-N-methyl-N-(piperidin-4-yl) phenylamine (1.93 grams, 7.33 mmol) obtained at step (III), followed by the addition of methanol (20 mL) and stirred at 25-30° C. for 5 minutes. Added sodium cyanoborohydride (0.548 grams, 8.80 mmol) and formic acid (1.08 mL, 22.01 mmol) and stirred the reaction mass for 10 minutes. The reaction mass was cooled to 0-5° C. in an ice bath and added formaldehyde (1.46 mL, 14.6 mmol, 30-50%) through syringe. Clear solution was obtained. The reaction mass was further stirred for 6 hours at 20-25° C. After completion of reaction (thin layer chromatography), solvent was distilled off under reduced pressure. To the residual oily mass, added water (100 mL) and basified to pH: 8 using saturated solution of sodium bicarbonate. The product was extracted with ethyl acetate (3×100 mL). The combined organic layer was washed with brine solution (100 mL) and dried over anhydrous sodium sulfate. Solvent was removed under reduced pressure to obtain 1.96 grams of dark yellow colored oily mass.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([CH2:12][CH2:13][NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:21][CH3:22])[CH:8]=2)[N:3]=1.[C:23]1(OB(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C1C=CC=CC=1.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>[CH3:22][O:21][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:11]=[C:10]2[CH2:12][CH2:13][NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17]
Reactant: OB(O)Oc1ccccc1
Reactant: COc1ccc2nc(Cl)cc(CCNC(=O)C(F)(F)F)c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc2nc(-c3ccccc3)cc(CCNC(=O)C(F)(F)F)c2c1
Yield: 91713 %

Procedure:
A solution of N-[2-(2-chloro-6-methoxyquinolin-4-yl)ethyl]-2,2,2-trifluoroacetamide (0.5 g, 1.5 mmol), tetrakis(triphenylphosphine)palladium (58 mg, 0.05 mmol) and phenylboric acid (0.2 g, 1.65 mmol) in benzene (4.2 ml) was mixed with an aqueous solution (1.9 ml) of sodium carbonate (2 mol). This reaction mixture was heated under reflux in an atmosphere of argon for 64 hours. The reaction mixture was poured into water, and the organic layer was extracted with ethyl acetate. The extract was washed with saturated brine and water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (ethyl acetate:hexane=4:6) to obtain the title compound (515 g, 91%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:13][CH2:12][CH2:11][C@@H:10]2[CH3:14])[N:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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:8][C:6]1[CH:7]=[C:2]([C:19]2[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=2)[N:3]=[C:4]([N:9]2[CH2:13][CH2:12][CH2:11][C@@H:10]2[CH3:14])[N:5]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: C[C@H]1CCCN1c1nc(Cl)cc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: C[C@H]1CCCN1c1nc(Cl)cc(-c2ccc(F)cc2)n1

Procedure:
Heat a mixture of 4,6-dichloro-2-(2-(S)-methylpyrrolidin-1-yl)pyrimidine (2.25 g, 9.74 mmol), 4-fluorophenylboronic acid (10.23 mmol), Pd(PPh3)4 (562 mg, 0.487 mmol), and a 2M potassium phosphate solution (9.74 mL) in dioxane (35 mL) under nitrogen at 80° C. for 16 h. Evaporate the mixture and add water (50 mL). Extract with EtOAc (3×50 mL), dry (Na2SO4), and evaporate. Purify by SiO2 flash chromatography, eluting with 9:1 hexanes:EtOAc to provide the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:8]2[CH:9]=[C:10]3[C:15](=[O:16])[O:14][C:12](=O)[C:11]3=[CH:17][CH:18]=2)=[O:7])=[CH:4][CH:3]=1.C(O)(=O)C.[NH2:25][CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:9]=[C:10]3[C:11](=[CH:17][CH:18]=2)[C:12](=[O:14])[N:25]([CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[C:15]3=[O:16])=[O:7])=[CH:19][CH:20]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc2c(c1)C(=O)OC2=O
Reactant: NCc1cccnc1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: O=C(c1ccc(Cl)cc1)c1ccc2c(c1)C(=O)N(Cc1cccnc1)C2=O
Yield: 97.1 %

Procedure:
To a mixture of 870 mg of 4-(4-chlorobenzoyl) phthalic acid anhydride, 10 ml of acetic acid and 10 ml of toluene was added 394 mg of 3-aminomethylpyridine, and the resultant mixture was refluxed under heating for 2 hours. The reaction mixture was concentrated in vacuo, and the resultant residue was chromatographed on a column of silica gel, eluting with ethyl acetate to give 1.11 g of the titled compound.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:16][C:17](=[O:31])[C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[C:19]=2[O:26][CH:27]2[CH2:30][CH2:29][CH2:28]2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:15])[CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[Cl:25][C:20]1[C:19]([O:26][CH:27]2[CH2:30][CH2:29][CH2:28]2)=[C:18]([CH:23]=[C:22]([Cl:24])[CH:21]=1)[C:17]([NH:16][C:6]1([C:4]([OH:5])=[O:3])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:15])[CH:12]=2)[CH2:7]1)=[O:31]
Reactant: CCOC(=O)C1(NC(=O)c2cc(Cl)cc(Cl)c2OC2CCC2)Cc2ccc(F)cc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(NC1(C(=O)O)Cc2ccc(F)cc2C1)c1cc(Cl)cc(Cl)c1OC1CCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 71.3 %

Procedure:
The mixture of 2-(3,5-dichloro-2-cyclobutoxy-benzoylamino)-5-fluoro-indan-2-carboxylic acid ethyl ester (20) (300 mg, 0.64 mmol) and KOH (500 mg, 8.9 mmol) is dissolved in EtOH (5 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 6 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until pH˜3. The precipitate is filtered to give a pure product (21) as white solid (200 mg, 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[S:11][CH2:12][C:13](Cl)=C.[CH3:16]COC(C)=O.O>CC(O)=O.[Fe]>[NH2:8][C:5]1[C:4]2[CH:16]=[C:12]([CH3:13])[S:11][C:3]=2[C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: C=C(Cl)CSc1cc([N+](=O)[O-])ccc1Cl
Reactant: CCOC(C)=O
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc2c(N)ccc(Cl)c2s1
Temperature: 80 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
A solution of 1.09 g (4.67 mmol) of compound 260A in 20 mL AcOH with 10 mL EtOAc and 2 mL H2O was heated to 80° C. and treated with iron powder (1,3 g, 23.4 mmol). The mixture was heated at 80° C. for 40 min and then allowed to cool to rt. The mixture was filtered through Celite eluting with EtOAc. The filtrate was washed with sat. aq. NaHCO3, dried over MgSO4, and concentrated in vacuo. N,N-diethylaniline (10 mL) was added, and the reaction was heated at 215° C. for 6 h. After cooling to rt, 1 N aqueous HCl (20 mL) was added, and the reaction was stirred at room temperature for 2 h. The mixture was extracted with EtOAc (3×30 mL). The organic phase was washed with saturated aqueous NaHCO3, dried over MgSO4, and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel eluting with 25% EtOAc in hexanes to give compound 260B (320 mg, 35%) as a beige solid.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH:12]1([C:17]2([CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[O:22][C:21](=[O:23])[CH2:20][C:19](=[O:24])[CH2:18]2)[CH2:16][CH2:15][CH2:14][CH2:13]1.[CH2:35](Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[I-].[Na+]>C1C=CC=CC=1>[CH2:35]([CH:20]1[C:19](=[O:24])[CH2:18][C:17]([CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[O:22][C:21]1=[O:23])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1
Reactant: BrCc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccccc1
Product: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cc3ccccc3)C(=O)O2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 12.7 %

Procedure:
DBU (28.6 ul, 0.191 mmol) was added to a solution of 6-cyclopentyl-6-[2-(4-methoxyphenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dione (55 mg, 0.174 mmol, described below) in benzene (1.9 ml), under an atmosphere of argon. Benzyl bromide (21 ul, 0.174 mmol) was then added. The reaction mixture was stirred at room temperature for 20 minutes, followed by the addition of 5 crystals of sodium iodide. The reaction mixture was stirred for a further 24 hrs, after which time the mixture was filtered through a plug of Celite. The filtrate was concentrated in vacuo and the residue purified by prep HPLC to afford the title compound as a white solid (9.0 mg).
Reaction SMILES: [SH:1][C:2]1[C:11]([CH3:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][Cl:21].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O>[ClH:21].[CH3:12][C:11]1[C:2]([S:1][CH2:20][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=2)=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Cc1nc2ccccc2nc1S
Reactant: ClCc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1nc2ccccc2nc1SCc1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.7 %

Procedure:
In a mixture of 70 ml of acetone and 7 ml of water were suspended 1.9 g of 2-mercapto-3-methylquinoxaline and 1.95 g of 2-picolyl chloride hydrochloride. To the suspension was added 4.0 g of potassium carbonate. The resulting mixture was stirred at room temperature for 1 hr., and the solvent was removed under reduced pressure. The residue was extracted with chloroform after addition of chloroform and water. The organic layer was separated and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was placed under reduced pressure to remove the solvent. The residue was dissolved in 20 ml of ethanol. To the solution under chilling with ice were successively added 3.2 ml of 5.2N ethanolic hydrochloric acid and ether to precipitate crystals. The crystals were collected by filtration to give 2.25 g of 3-methyl-2-(2-pyridylmethylthio)quinoxaline hydrochloride as a violet crystalline powder.
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[C:12]([C:13](O)=[O:14])=[C:11]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])[N:10]=[C:9]([CH3:25])[CH:8]=1)[CH2:4][CH3:5])[CH3:2].CSC>C1COCC1>[Cl:24][C:18]1[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=1[NH:16][C:11]1[C:12]([CH2:13][OH:14])=[C:7]([O:6][CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH:8]=[C:9]([CH3:25])[N:10]=1
Reactant: CCC(CC)Oc1cc(C)nc(Nc2ccc(Cl)cc2Cl)c1C(=O)O
Solvent: C1CCOC1
Solvent: CSC
Product: CCC(CC)Oc1cc(C)nc(Nc2ccc(Cl)cc2Cl)c1CO
Reaction time: 0.5 h

Procedure:
To a solution of 4-(1-ethyl-propoxy)-6-methyl-2-(2,4-dichloro-phenylamino)-nicotinic acid in dry THF was added BH3.DMS. The resulting mixture was heated at reflux overnight. The mixture was quenched with dilute HCl and stirred for 30 min, adjusted pH to 7.5-8.5, then extracted with ethyl acetate. The organic layer was separated, dried and concentrated to give a golden oil. After silica gel column chromatography, the title compound was obtained as a golden oil. 1H NMR(CDCl3) d 8.44(d,1H), 8.18(s,1H), 7.32(d,1H), 7.179d,1H), 6.28(s,1H), 4.82(s,2H), 4.21(m,1H), 2.42(s,3H), 1.6-1.8(m,4H), 0.94(t,6H) ppm.
Reaction SMILES: [NH:1]1CCCCC1.[CH3:7][N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][N:14]([CH2:23][C:24]1[N:25]([CH3:29])[CH:26]=[CH:27][N:28]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21]>CN(C=O)C>[NH2:1][C@@H:19]([CH2:18][CH2:17][CH2:16][CH2:15][N:14]([CH2:13][C:9]1[N:8]([CH3:7])[CH:12]=[CH:11][N:10]=1)[CH2:23][C:24]1[N:25]([CH3:29])[CH:26]=[CH:27][N:28]=1)[C:20]([OH:22])=[O:21]
Reactant: Cn1ccnc1CN(CCCCCC(=O)O)Cc1nccn1C
Reactant: C1CCNCC1
Solvent: CN(C)C=O
Product: Cn1ccnc1CN(CCCC[C@H](N)C(=O)O)Cc1nccn1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
Piperidine (0.80 mL) was added to a solution of (S)-2-4(9H-fluoren-9-yl)methoxy)carbonylamino)-6-(bis((1-methyl-1H-imidazol-2-yl)methyl)amino)hexanoic acid (556 mg, 1.00 mmol) in DMF (4.0 mL). The mixture was stirred at room temperature for 2 hrs. Solvent was evaporated under reduce pressure to afford a residue, which was purified by Amberchrom to afford (S)-2-amino-6-(bis((1-methyl-1H-imidazol-2-yl)methyl)amino) hexanoic acid (330 mg, 99%). 1H NMR (400 MHz, DMSO-d6) 7.94 (s, 1H), 7.04 (d, J=3=1.2 Hz, 2H), 6.74 (d, J=1.2 Hz, 2H), 3.54 (s, 4H), 3.98 (brs, 1H), 2.88 (s, 3H), 2.72 (s, 3H), 2.35 (t, J=6.8 Hz, 2H), 1.60-1.54 (m, 1H), 1.43-1.29 (m, 3H), 1.16-1.11 (m, 2H); MS (ESI), 335 (M+H)+.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[CH3:9][S:10]SC>C1(C)C=CC=CC=1>[CH3:8][C:3]1[CH:4]=[CH:5][C:6]([OH:7])=[C:1]([S:10][CH3:9])[CH:2]=1
Reactant: CSSC
Reactant: Cc1ccc(O)cc1
Solvent: Cc1ccccc1
Product: CSc1cc(C)ccc1O
Temperature: 160 °C
Yield: 49.1 %

Procedure:
A mixture of para-cresol (65 grams, 0.60 moles) and toluene (20 ml) was distilled until the mixture was free of toluene. Aluminum turnings (1.1 grams, 0.04 gram atoms) were then added to the dried para-cresol and this mixture was heated at 150°-160° C. until cessation of hydrogen evolution. Methyldisulfide (36 ml, 0.4 moles) was added and the mixture heated at reflux (about 160° C.) overnight. The mixture was refluxed for another additional 4 hours and was then flashed under a vacuum. The flashed mixture was then distilled through a 0.7×30 cm packed column to yield 30.3 grams of 4-methyl-2-(methylthio)-phenol, a 55 percent yield. Subsequently, MMR analysis verified the identity of the compound.