Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17](OS(C(F)(F)F)(=O)=O)[CH:18]=2)[C:13]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[N:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:41]3[CH:42]=[CH:43][N:38]=[CH:39][CH:40]=3)[CH:18]=2)[C:13]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: OB(O)c1ccncc1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2cc(OS(=O)(=O)C(F)(F)F)ccc2c1-c1ccc(Cl)cc1
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: COCCOC
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2cc(-c3ccncc3)ccc2c1-c1ccc(Cl)cc1
Temperature: 110 °C

Procedure:
A solution of (S)-ethyl 2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-6-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate (0.060 g, 0.11 mmol), pyridin-4-ylboronic acid (0.020 g, 0.16 mmol), and Pd(PPh3)4 (0.012 g, 0.011 mmol) in DME (1 mL) was treated with 2 M K2CO3 (0.16 mL, 0.32 mmol) and sparged with Ar for 10 min. Following microwave heating at 110° C. for 20 min, the reaction mixture was absorbed onto silica gel in vacuo and purified by Yamazen column chromatography (15-100% EtOAc/Hex) to afford 0.043 g (82%) as a colorless glass. LCMS-ESI+ (m/z): [M+H]+ calcd for C30H31ClNO3: 488.20; found: 488.70.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:24])[C@H:12]2[C@H:15]([S:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:16])[C:9]=1[C:25]([O:27]CC1C=CC([N+]([O-])=O)=CC=1)=[O:26])(=[O:3])[CH3:2].C(=O)([O-])O.[Na+:42]>O1CCOCC1.O.[Pd]>[C:1]([NH:4][CH2:5][CH2:6][S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:24])[C@H:12]2[C@H:15]([S:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:16])[C:9]=1[C:25]([O-:27])=[O:26])(=[O:3])[CH3:2].[Na+:42]
Reactant: CC(=O)NCCSC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H]([C@@H](C)Sc3ccccc3)[C@H]2C1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)NCCSC1=C(C(=O)[O-])N2C(=O)[C@@H]([C@@H](C)Sc3ccccc3)[C@H]2C1

Procedure:
p-Nitrobenzyl (5R,6S)-3-(2-acetamidoethylthio)-6-[(R)-1-phenylthioethyl]-7-oxo-1-azabicyclo[3.2.0]-hept-2-ene-2-carboxylate (e 103) (10 mg) in a mixture of dioxan and water (7:3, 5 ml) was added to 5% palladium on carbon catalyst which had been prehydrogenated for 30 min. in a mixture of dioxan and water (7:3, 5 ml). The mixture was hydrogenated at slightly super-atmospheric pressure for 4 hr., when sodium hydrogen carbonate (1.9 mg) was added to the mixture. The catalyst was filtered off and washed with water (5 ml). The filtrate was evaporated in vacuo to remove most of the dioxan and the resultant mixture was diluted with water to 25 ml and extracted with ethyl acetate. The aqueous extract was washed with ethyl acetate. The u.v. spectrum of the aqueous layer showed a maximum of about 300 nm, indicating the presence of the sodium salt. The volume of the aqueous solution was reduced to about 1 ml, loaded onto a Biogel P-2 column and eluted with water to give sodium (5R,6S)-3-(2-acetamidoethylthio)-6-[(R)-1-phenylthioethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (e 104).
Reaction SMILES: C[C@]1(O)[C@@H]2C(=C(O)[C@]3(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]3C2)C(=O)C2C(O)=CC=CC1=2.[CH3:33][N:34]([CH3:73])[C@H:35]1[C@H:52]2[C@:39]([OH:67])([C:40]([OH:66])=[C:41]3[C@H:50]([CH2:51]2)[CH2:49][C:48]2[C:43](=[C:44]([OH:64])[C:45]([NH:54][C:55](=[O:63])[CH2:56][N:57]4[CH2:62][CH2:61][CH2:60][CH2:59][O:58]4)=[CH:46][C:47]=2I)[C:42]3=[O:65])[C:38](=[O:68])[C:37]([C:69]([NH2:71])=[O:70])=[C:36]1[OH:72].C1C=CC([As](C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([Sn](CCCC)(CCCC)[C:98]1[S:99][CH:100]=[CH:101][CH:102]=1)CCC>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:33][N:34]([CH3:73])[C@H:35]1[C@H:52]2[C@:39]([OH:67])([C:40]([OH:66])=[C:41]3[C@H:50]([CH2:51]2)[CH2:49][C:48]2[C:43](=[C:44]([OH:64])[C:45]([NH:54][C:55](=[O:63])[CH2:56][N:57]4[CH2:62][CH2:61][CH2:60][CH2:59][O:58]4)=[CH:46][C:47]=2[C:98]2[S:99][CH:100]=[CH:101][CH:102]=2)[C:42]3=[O:65])[C:38](=[O:68])[C:37]([C:69]([NH2:71])=[O:70])=[C:36]1[OH:72]
Reactant: CN(C)[C@@H]1C(O)=C(C(N)=O)C(=O)[C@@]2(O)C(O)=C3C(=O)c4c(O)c(NC(=O)CN5CCCCO5)cc(I)c4C[C@H]3C[C@@H]12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CN(C)[C@@H]1C(O)=C(C(N)=O)C(=O)[C@@]2(O)C(O)=C3C(=O)c4c(O)cccc4[C@@](C)(O)[C@H]3C[C@@H]12
Solvent: Cc1ccccc1
Product: CN(C)[C@@H]1C(O)=C(C(N)=O)C(=O)[C@@]2(O)C(O)=C3C(=O)c4c(O)c(NC(=O)CN5CCCCO5)cc(-c5cccs5)c4C[C@H]3C[C@@H]12

Procedure:
A mixture of 40 mg of Example 9 (4S,4aS,5aR,12aS)-4-(dimethylamino)-3,10,12,12a-tetrahydroxy-7-iodo-9-[(1,2-oxazinan-2-ylacetyl)amino]-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, 6 mg Pd(PPh3)2Cl2 (dichlorobis(triphenyl-phosphine)palladium(II), 2 mg AsPh3, 2 mg Cul (copper(1) iodide) and 2-(tributylstannyl)-thiophene in 10 mL toluene is heated to reflux under nitrogen for ca. 6 h. The reaction mixture is cooled, filtered and solvent removed. The crude residue is dissolved in water at pH 2 (by adding 10% HCl), and 10% ammonium hydroxide is added to adjust the pH to about 4 followed by extraction with methylene chloride. Organic layer dried over sodium sulfate, solvent removed and residue triturated with ether and 1M HCl in ether to give 8 mg of the product of the example.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([S:13]([NH2:16])(=[O:15])=[O:14])[C:7]=2[CH:6]=[CH:5][C:4]=1[NH2:17].O.O.[C:20](O)(=[O:24])[C:21](O)=[O:22]>Cl>[OH:22][C:21]1[C:20]([OH:24])=[N:17][C:4]2[CH:5]=[CH:6][C:7]3[C:8]([S:13](=[O:14])(=[O:15])[NH2:16])=[CH:9][CH:10]=[CH:11][C:12]=3[C:3]=2[N:2]=1
Reactant: O=C(O)C(=O)O
Reactant: Nc1ccc2c(S(N)(=O)=O)cccc2c1N
Agent: Cl
Solvent: O
Product: NS(=O)(=O)c1cccc2c1ccc1nc(O)c(O)nc12
Temperature: 25 °C
Yield: 122.6 %

Procedure:
A mixture of 5,0 g (21,0 mmol) 1,2-diamino-naphthalene-5-sulphonamide hydrochloride salt and 6,0 g oxalic acid dihydrate in 200 ml 2N hydrochloric acid was refluxed for 2,5 h. After cooling to 25° C., the precipitate was filtered off and washed with water. The crude product was recrystallized (dimethylformamide-water) to give 7,5 g (69%) 2,3-dihydroxy-7-sulphamoyl-benzo[f]quinoxaline.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:8]12[CH2:14][CH:11]([CH2:12][CH2:13]1)[CH2:10][C:9]2=O.N1C2C=CC=CC=2N=N1.[BH4-].[Na+]>CO.O.C1(C)C(C)=CC=CC=1>[C:8]12([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[NH2:1])[CH2:14][CH:11]([CH2:12][CH2:13]1)[CH2:10][CH2:9]2
Reactant: Nc1ccccc1
Reactant: O=C1CC2CCC1C2
Agent: [BH4-]
Agent: [Na+]
Agent: c1ccc2[nH]nnc2c1
Solvent: CO
Solvent: Cc1ccccc1C
Solvent: O
Product: Nc1ccccc1C12CCC(CC1)C2
Reaction time: 16 h
Yield: 106.9 %

Procedure:
In a 250 mL flask equipped with a Dean-Start separator, the following mixture is brought to reflux: 9.3 g of aniline, 12.1 g 2-norbornanone, 13.2 g benzotriazole and 120 mL xylene. After 16 h, the mixture is reduced to dryness, then it is solubilized in 300 mL methanol, and the product is reduced with 6 g NaBH4 at 50° C. for 1 h. The mixture is then poured into 200 mL water and the organic product is extracted with 3×100 mL toluene. The organic phase is recovered, dried over magnesium sulfate, and then reduced to dryness. In this manner, 20 g of the desired amine are produced.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].FC(F)(F)[C:16](O)=[O:17]>C1N2CN3CN(C2)CN1C3>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([CH:16]=[O:17])=[CH:12][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: O=C(O)C(F)(F)F
Reactant: CCCCCCCc1ccccc1
Agent: C1N2CN3CN1CN(C2)C3
Product: CCCCCCCc1ccc(C=O)cc1

Procedure:
88 g of n-heptylbenzene are taken up in 50 ml of trifluoroacetic acid and 70 g of hexamethylenetetramine. The whole is refluxed for 12 hours after which the excess of trifluoroacetic acid is distilled off by means of a water jet airpump. The mixture is then poured in ice water and neutralized with soda. After extraction with ether the resulting ether solution is evaporated and the resulting 4-heptylbenzaldehyde is used for the following process step.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([F:9])[C:5]([F:8])=[N:6][CH:7]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:18][N:19]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[N:20]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCOC(C)=O.O.O1CCOCC1>[F:8][C:5]1[C:4]([F:9])=[CH:3][C:2]([C:22]2[CH:21]=[N:20][N:19]([CH3:18])[CH:23]=2)=[CH:7][N:6]=1
Reactant: Fc1cc(Cl)cnc1F
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1cc(-c2cnc(F)c(F)c2)cn1
Temperature: 100 °C
Yield: 88.5 %

Procedure:
A sealable flask was charged with 5-chloro-2,3-difluoropyridine (1.541 g, 10.3 mmol), palladium(ii) acetate (0.116 g, 0.515 mmol), potassium phosphate tribasic (6.56 g, 30.9 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.57 g, 12.4 mmol), and X-Phos (0.491 g, 1.03 mmol). The flask was sealed with a septum cap, then dioxane (20 mL) and H2O (2 mL) were added. The resulting mixture was sparged with N2 for 10 min, and then heated at 100° C. for 2 h. The solution was cooled to rt and then concentrated and purified by flash chromatography using eluent 99:1 Hexanes:EtOAc to 60:40 Hexanes:EtOAc gradient to afford 2,3-difluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridine (1.78 g, 88.5% yield) as a colorless film. LRMS (ESI) m/z calcd for C9H7F2N3 (M+H) 197.1. found 197.4.
Reaction SMILES: C([O:3][C:4](=[O:12])[C:5]([CH2:9][CH2:10][CH3:11])=[CH:6][CH2:7][CH3:8])C.[OH-].[Na+].C(C(=CCC)C(O)=O)CC.C(C(C=CC)C(O)=O)CC>CO>[CH2:9](/[C:5](=[CH:6]\[CH2:7][CH3:8])/[C:4]([OH:12])=[O:3])[CH2:10][CH3:11]
Reactant: CCC=C(CCC)C(=O)OCC
Agent: CC=CC(CCC)C(=O)O
Agent: CCC=C(CCC)C(=O)O
Agent: [Na+]
Solvent: CO
Product: CC/C=C(\CCC)C(=O)O
Reaction time: 120 h

Procedure:
10 g of 2-propyl-2-pentenoic acid ethyl ester according to Example 1 are added to a solution of 20 g of sodium hydroxide in 150 ml of methanol and left stand at room temperature. After 5 days and accompanied by the recovery of the methanol, the mixture is worked up in conventional manner following acidification. A mixture of 2-propyl-2-pentenoic acid (E-isomer) and 2-propyl-3-pentenoic acid (E-isomer) in a ratio of approximately 80:20 is obtained in an almost quantitative yield, which is separated by precision distillation on an effective column and gives E-2-propyl-2-pentenoic acid with b.p.15 135° to 136° C.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([CH3:8])([CH3:7])[C:4]([NH2:6])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:20])=CC=1>C1COCC1>[F:1][C:2]([F:10])([F:9])[C:3]([CH3:8])([CH3:7])[C:4]([NH2:6])=[S:20]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C(N)=O)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(C(N)=S)C(F)(F)F
Temperature: 25 °C
Yield: 129.3 %

Procedure:
A mixture of 1.05 g (6.77 mmol) 3,3,3-trifluoro-2,2-dimethyl-propionamide and 1.48 g (3.66 mmol) Lawesson's reagent in 32 ml dry THF was stirred at reflux temperature for 20 h. After that the reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by chromatography on silicagel (heptane, EtOAc) to afford 0.81 g of the title compound as pure white crystals. MS: M+H=172.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:4]=1[C:5](OC)=[O:6].[NH4+:16]>>[N+:13]([C:11]1[CH:12]=[C:3]2[C:4](=[CH:9][CH:10]=1)[C:5](=[O:6])[NH:16][CH2:2]2)([O-:15])=[O:14]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1CBr
Reactant: [NH4+]
Product: O=C1NCc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of methyl 2-(bromomethyl)-4-nitrobenzoate in ammonium solution (7 N in methanol, 5 mL) was stirred at room temperature for 2 hours and concentrated in vacuum to obtain a yellow solid. This crude solid was triturated with ethyl acetate (15 mL) and was then cooled at −20° C. The mixture was filtered to obtain the product 5-nitroisoindolin-1-one as yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.04 (br s, 1H), 8.48 (d, 1H, J=2.0 Hz), 8.25 (dd, 1H, J=2.0 Hz, 8.4 Hz), 7.91 (d, 1H, J=8.4 Hz), 4.51 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:10]1[C:15]([O:16][CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])=[CH:14][CH:13]=[CH:12][N:11]=1)[OH:9]>C1(C)C=CC=CC=1.[O-2].[Mn+2]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[C:15]([O:16][CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:9]
Reactant: C[Si](C)(C)CCOCOc1cccnc1C(O)c1ccccc1Cl
Agent: [Mn+2]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCOCOc1cccnc1C(=O)c1ccccc1Cl
Yield: 50.1 %

Procedure:
Add manganese oxide (II) (463 mg, 5.33 mmol) to a solution of (2-chloro-phenyl)-[3-(2-trimethylsilanyl-ethoxymethoxy)-pyridin-2-yl]-methanol (390 mg, 1.07 mmol) in toluene (20 mL), heat to reflux overnight. Filter mixture through Celite® and concentrate. Purify the residue by flash chromatography on silica gel eluting with 0-20% EtOAc/hexanes to afford the title compound (195 mg, 49%) as pink oil. MS(IS) 364 (M+1). TLC: Rf=0.45 (35% EtOAc/hexanes).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]([O:14][CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH:11]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:28][CH:27]=2)[CH:10]([CH2:44][OH:45])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:46](Br)[CH:47]=[CH2:48]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]([O:14][CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH:11]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:33][CH2:34][CH2:35][O:36][CH2:37][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[CH:30][CH:31]=2)[CH:10]([CH2:44][O:45][CH2:48][CH:47]=[CH2:46])[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(CO)C(c2ccc(OCCCOCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: C=CCBr
Product: C=CCOCC1CN(C(=O)OC(C)(C)C)CC(OCc2ccc3ccccc3c2)C1c1ccc(OCCCOCc2ccccc2)cc1

Procedure:
In an analogous manner to that described in Example 13 (g), by alkylating (3SR,4RS,5RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-hydroxymethyl-5-(naphthalen-2ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester [WO 9709311, Example 148 (h)] with allylbromide there was obtained (3SR,4RS,5RS)-3-allyloxymethyl-4-[4-(3-benzyloxy-propoxy)-phenyl]-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester as a colorless solid; MS: 652 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:18]([N:20]3[CH2:25][CH2:24][C:23]4([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=5[CH2:27][O:26]4)[CH2:22][CH2:21]3)=[O:19])=[CH:7][N:8]2[CH2:11][C@H:12]2[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]2)=[CH:4][CH:3]=1.[CH3:34]C(O)=O.[BH3-]C#N.[Na+]>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:18]([N:20]3[CH2:21][CH2:22][C:23]4([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=5[CH2:27][O:26]4)[CH2:24][CH2:25]3)=[O:19])=[CH:7][N:8]2[CH2:11][C@H:12]2[CH2:17][CH2:16][CH2:15][N:14]([CH3:34])[CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=C(c1cn(C[C@H]2CCCNC2)c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12
Reactant: CC(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CN1CCC[C@H](Cn2cc(C(=O)N3CCC4(CC3)OCc3ccccc34)c3ccc(Cl)cc32)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 1′-({6-chloro-1-[(3S)-piperidin-3-ylmethyl]-1H-indol-3-yl}carbonyl)-3H-spiro[2-benzofuran-1,4′-piperidine] in MeOH was treated with aq. H2CO (1.5 eq), AcOH (1.1 eq) and stirred for 15 min at room temperature, then treated with NaCNBH3 (1.1 eq) and stirred at room temperature for 1 h. Concentration and purification by preparative HPLC the desired product. ES-MS m/e (%): 478.2(M+H+).
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([C:13]([CH3:43])([CH3:42])[C:14]([N:16]([CH3:41])[C:17]2[C:18]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH3:40])=[CH:19][C:20]([N:23]3[CH2:27][C:26](=[O:28])[CH2:25][C@H:24]3[CH2:29][O:30]C(=O)C)=[N:21][CH:22]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C[O-].[Na+]>CO.O.[Cl-].[Na+].O>[F:45][C:2]([F:1])([F:44])[C:3]1[CH:4]=[C:5]([C:13]([CH3:42])([CH3:43])[C:14]([N:16]([C:17]2[CH:22]=[N:21][C:20]([N:23]3[CH2:27][C:26](=[O:28])[CH2:25][C@H:24]3[CH2:29][OH:30])=[CH:19][C:18]=2[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[CH3:40])[CH3:41])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: CC(=O)OC[C@@H]1CC(=O)CN1c1cc(-c2ccccc2C)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1ccccc1-c1cc(N2CC(=O)C[C@H]2CO)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 23.3 %

Procedure:
A solution of 60 mg (0.094 mmol) (S)-acetic acid 1-(5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-o-tolyl-pyridin-2-yl)-4-oxo-pyrrolidin-2-ylmethyl ester and a catalytic amount of sodium methylate in 2 ml methanol was stirred at room temperature for 30 min. The reaction mixture was diluted with water and brine and extracted with three portions of dichloromethane. The combined organic extracts were dried over sodium sulfate and concentrated in vacuo. Flash column chromatography gave 13 mg (23%) of the title compound as a light brown solid.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C1(C)C=CC(S(O)=O)=CC=1.[Na].[C-:22]#[N:23].[K+]>CS(C)=O.O>[N:5]1[C:4]2[NH:8][CH:9]=[CH:10][C:3]=2[C:2]([C:22]#[N:23])=[N:7][CH:6]=1
Reactant: [C-]#N
Reactant: Clc1ncnc2[nH]ccc12
Agent: Cc1ccc(S(=O)O)cc1
Agent: [K+]
Agent: [Na]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ncnc2[nH]ccc12
Temperature: 100 °C

Procedure:
Commercially available 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1 g, 6.51 mmol) was dissolved in DMSO (15 mL) then p-toluenesulfinic acid, sodium salt (1.16 g, 6.51 mmol) and KCN (635 mg, 9.76 mmol) were added. The reaction mixture was heated at 100° C. for 17 h, cooled to RT and diluted with water. The mixture was extracted with EtOAc. The organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo to give 7H-pyrrolo[2,3-d]pyrimidine-4-carbonitrile as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([NH:16][C:17]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=O)[CH:10]=2)=[C:4]([CH2:29][CH3:30])[N:3]=1.Cl.[OH-].[Na+]>O1CCCC1>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([NH:16][CH2:17][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:10]=2)=[C:4]([CH2:29][CH3:30])[N:3]=1
Reactant: CCCCCCCCCCC(=O)Nc1cc(-c2c(N)nc(N)nc2CC)ccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCCCCCCCNc1cc(-c2c(N)nc(N)nc2CC)ccc1Cl
Temperature: 60 °C
Reaction time: 24 h

Procedure:
Under a nitrogen atmosphere, a stirred solution of 40 mL of 1M borane-tetrahydrofuran complex was cooled to below 10° C., and a solution of 2.4 grams (0.006 mole) of 2,4-diamino-6-ethyl-5-(4-chloro-3-decylcarbonylaminophenyl)pyrimidine in 60 mL of tetrahydrofuran was added dropwise during about a 5 minute period. The reaction mixture temperature was maintained below 10° C. throughout the addition. Upon completion of addition, the reaction mixture was heated at 60° C. for about 18 hours. After this time, the reaction mixture was allowed to cool to ambient temperature, where it was stirred for about 24 hours. The reaction mixture was then made acidic with aqueous 2N hydrochloric acid, after which time it was stirred for about 15 minutes. The mixture was made basic with aqueous 10% sodium hydroxide, and then it was extracted with two 150 mL portions of ethyl acetate. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished using 10:1 methylene chloride and methanol. The product-containing fractions were combined and concentrated under reduced pressure, yielding when dried, 0.7 gram of 2,4-diamino-6-ethyl-5-(4-chloro-3 -undecylaminophenyl)pyrimidine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][N:8]([CH3:13])[CH:9]2[CH2:12][O:11][CH2:10]2)=[CH:5][C:4]([NH2:14])=[N:3]1.Br[C:16]1[C:17](=[O:24])[N:18]([CH3:23])[CH:19]=[C:20]([Br:22])[CH:21]=1>>[Br:22][C:20]1[CH:21]=[C:16]([NH:14][C:4]2[CH:5]=[C:6]([CH2:7][N:8]([CH3:13])[CH:9]3[CH2:10][O:11][CH2:12]3)[N:2]([CH3:1])[N:3]=2)[C:17](=[O:24])[N:18]([CH3:23])[CH:19]=1
Reactant: CN(Cc1cc(N)nn1C)C1COC1
Reactant: Cn1cc(Br)cc(Br)c1=O
Product: CN(Cc1cc(Nc2cc(Br)cn(C)c2=O)nn1C)C1COC1
Yield: 63 %

Procedure:
Following the procedure in Example 292c, and starting with 302c and 3,5-dibromo-1-methylpyridin-2(1H)-one afforded 302d in 63% yield. LCMS: (M+H)+ 383. 1H NMR (500 MHz, DMSO) δ 8.35 (s, 1H), 7.99 (d, J=2.5, 1H), 7.36 (d, J=2.5, 1H), 5.99 (s, 1H), 4.50 (t, J=7, 2H), 4.40 (t, J=6.5, 2H), 3.77 (s, 3H), 3.57 (m, 1H), 3.49 (s, 3H), 3.35 (s, 2H), 2.01 (s, 3H).
Reaction SMILES: CC([O:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:26](=[O:27])[C:14]3[CH:15]=[C:16]([C:23]([OH:25])=[O:24])[CH:17]=[C:18]([O:19]C(C)=O)[C:13]=3[C:11](=[O:12])[C:10]=12)=O.Cl>C([O-])([O-])=O.[Na+].[Na+]>[OH:19][C:18]1[C:13]2[C:11](=[O:12])[C:10]3[C:9](=[CH:8][CH:7]=[CH:6][C:5]=3[OH:4])[C:26](=[O:27])[C:14]=2[CH:15]=[C:16]([C:23]([OH:25])=[O:24])[CH:17]=1
Reactant: CC(=O)Oc1cccc2c1C(=O)c1c(OC(C)=O)cc(C(=O)O)cc1C2=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(O)c1cc(O)c2c(c1)C(=O)c1cccc(O)c1C2=O
Reaction time: 8 h

Procedure:
Diacerein (150 g, 0.41 mol) was stirred in 10% (w/w) Na2CO3 solution (4 L) resulting in a red mixture. After stirring overnight the mixture was acidified to pH2 with 5M HCl solution to give a yellow precipitate. This was filtered and dried in a vac-oven at 50° C. (168 g,>100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=[O:6].[Si]([C:15]#[N:16])(C)(C)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>C1COCC1.[I-].[Zn+2].[I-].O>[NH2:16][CH2:15][CH:5]([C:4]1[CH:7]=[CH:8][C:9]([F:10])=[C:2]([F:1])[CH:3]=1)[OH:6]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: C[Si](C)(C)C#N
Agent: [Al+3]
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Solvent: O
Product: NCC(O)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To a solution consisting of 3,4-difluorobenzaldehyde (3.85 g, 27.1 mmol), zinc iodide (104.9 mg, 0.329 mmol) and THF (5 mL) at 0° C. under nitrogen was added TMSCN (4.60 mL, 33.9 mmol). The resultant mixture was stirred for 3.5 h at 0° C. and then cannulated into a 0° C. suspension of LiAlH4 (1.41 g, 67.7 mmol) in THF (80 mL). The resultant mixture was allowed to gradually warm to rt with stirring for 21 h. The reaction mixture was then re-cooled to 0° C. and carefully treated with water (2.57 mL) followed by 15% aq. NaOH (2.57 mL) and lastly with water (7.7 mL). The resultant mixture was stirred for 1 h, the solids removed by vacuum filtration and the filtrate concentrated. The resulting crude product was purified by FCC(CH2Cl2/MeOH/NH3) to give the desired product.