Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:11]([CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1)[CH2:12][CH2:13][CH3:14])=O)C1C=CC=CC=1.[H][H]>CO.[OH-].[Pd+2].[OH-]>[CH2:12]([NH:11][CH2:15][CH:16]1[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:20][CH2:21]1)[CH2:13][CH3:14]
Reactant: CCCN(CC1CCN(C(=O)OC(C)(C)C)CC1)C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCCNCC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 91.9 %

Procedure:
To a solution of tert-butyl 4-(((benzyloxycarbonyl)(propyl)amino)methyl)piperidine-1-carboxylate (0.280 g, 0.717 mmol) in 7 mls of methanol was added palladium(II) hydroxide (0.200 g, 20 wt % Pd(OH)2 on carbon, Degussa type). This mixture was hydrogenated under a ballon of hydrogen for 1.5 hours, then filtered through GF/F filter paper and the filtrate concentrated. Obtained 0.169 g (92%) of the title compound and used directly without further purification.
Reaction SMILES: [C:1]([O:12][CH2:13][CH:14]=[CH2:15])(=[O:11])[CH2:2][NH:3][CH2:4][C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6].[C:16]1(=[O:22])[O:21][C:19](=[O:20])[CH2:18][CH2:17]1>C(Cl)(Cl)Cl>[CH2:13]([O:12][C:1]([CH2:2][N:3]([CH2:4][C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])[C:16]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[O:22])=[O:11])[CH:14]=[CH2:15]
Reactant: C=CCOC(=O)CNCC(=O)OCC=C
Reactant: O=C1CCC(=O)O1
Solvent: ClC(Cl)Cl
Product: C=CCOC(=O)CN(CC(=O)OCC=C)C(=O)CCC(=O)O
Reaction time: 24 h
Yield: 51 %

Procedure:
Compound 9 (4.0 g, 10.39 mmol), succinic anhydride (1.04 g, 10.39 mmol), and 4-di(methylamino)pyridine (1.90 g, 15.59 mmol) were dissolved in CHCl3 (30 mL) and stirred for 24 h. The solvent was evaporated in vacuo and the crude material was purified by silica gel chromatography (40-80% EtOAc in hexanes) to give the compound 10 (1.66 g, 51%). 1H NMR (400 MHz, CDCl3) δ 2.64 (t, J=5.8, 2H), 2.70 (t, J=5.8, 2H), 4.21 (d, J=6.2, 4H), 4.61 (d, J=6.2, 2H), 4.65 (d, J=6.2, 2H), 5.22-5.35 (m, 4H), 5.89 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:21])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:7][C:6]=1[C:22]1[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=1.Br[CH2:29][CH2:30][C:31]([F:34])([F:33])[F:32].C(N(CC)CC)C>CN(C=O)C>[CH3:20][O:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[C:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:1][CH2:29][CH2:30][C:31]([F:34])([F:33])[F:32])=[C:6]([C:22]2[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=2)[CH:7]=1)=[O:21]
Reactant: FC(F)(F)CCBr
Reactant: COc1cccc(C(=O)Nc2ccc(OCCN)c(-c3ccnn3C)c2)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cccc(C(=O)Nc2ccc(OCCNCCC(F)(F)F)c(-c3ccnn3C)c2)c1
Temperature: 150 °C
Yield: 2.3 %

Procedure:
A mixture of N-(4-(2-aminoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methoxybenzamide (14.5 mg, 81.9 μmol), 3-bromo-1,1,1-trifluoropropane (30 mg, 81.9 μmol) and triethylamine (34.2 μL, 246 μmol) in DMF was heated to 150° C. for 1 hour under microwave irradiation in a heavy-walled sealed tube. The crude product was purified by PLC. The proper fractions were collected and lyophilized to afford the title compound as a brown solid in 2.3% yield. LCMS m/z (%)=463 (M+H, 100). 1H NMR (400 MHz, MeOH-d4) δ 2.6 (m, 2H) 3.2 (dd, J=15.4, 7.8 Hz, 2H) 3.5 (m, 2H) 3.8 (s, 3H) 3.9 (s, 3H) 4.4 (m, 2H) 6.4 (d, J=2.0 Hz, 1H) 7.2 (dd, J=8.6, 3.5 Hz, 1H) 7.3 (d, J=9.1 Hz, 1H) 7.4 (t, J=8.1 Hz, 1H) 7.5 (m, 2H) 7.6 (d, J=2.0 Hz, 1H) 7.7 (d, J=2.5 Hz, 1H) 7.9 (dd, J=9.1, 2.5 Hz, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[CH2:8][C@@H:9]3[CH2:21][C@@H:10]3[C:11]=2[N:12]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][N:15]=2)[N:13]=1)=[O:5])C.[Li+].[OH-].Cl>O1CCOCC1.O>[Cl:20][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([N:12]2[C:11]3[C@H:10]4[CH2:21][C@H:9]4[CH2:8][C:7]=3[C:6]([C:4]([OH:5])=[O:3])=[N:13]2)[CH:19]=1
Reactant: CCOC(=O)c1nn(-c2cc(Cl)ccn2)c2c1C[C@@H]1C[C@H]21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1nn(-c2cc(Cl)ccn2)c2c1C[C@@H]1C[C@H]21
Temperature: 40 °C
Reaction time: 4 h

Procedure:
To a solution of (1aS,5aS)-2-(4-bromo-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ethyl ester (2.1 g, 6.0 mmol) in acetonitrile (30 mL) was added concentrated HCl (1.4 mL, 18.0 mmol). The reaction was stirred for 6 h at 80° C., and then diluted with H2O. The solid was filtered, washed with H2O, and dried to give (1aS,5aS)-2-(4-chloro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ethyl ester (1.7 g) which contained ˜20% of the hydrolyzed acid. The aforementioned ester was dissolved in dioxane (10 mL). After addition of 1 N LiOH (9.0 mL), the reaction was stirred for 4 h at 40° C. The reaction was cooled down to room temperature, diluted with H2O, and acidified with 4 N HCl to form a precipitate. The solid was filtered, washed with H2O, and dried to give the title compound. LCMS m/z=276.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:4][C@@H:5]1[CH2:9][N:8]([CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH2:7][C@H:6]1[NH:16][C:17](=[O:32])[CH2:18][NH:19][C:20](=[O:31])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1)[CH:2]=[CH2:3].[CH2:33](Br)[C:34]1C=CC=[CH:36][CH:35]=1.C(Br)C=C>>[CH2:1]([O:4][C@@H:5]1[CH2:9][N:8]([CH:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)[CH2:7][C@H:6]1[NH:16][C:17](=[O:32])[CH2:18][NH:19][C:20](=[O:31])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=1)[C:2]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: C=CCO[C@@H]1CN(C2CCOCC2)C[C@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Solvent: C=CCBr
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CN(C2CCOCC2)C[C@H]1OCc1ccccc1

Procedure:
The title compound was synthesized in similar fashion to rel-N-(2-{[(3R,4R)-4-(allyloxy)-1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide, benzyl bromide was substituted for allyl bromide and was isolated as a white solid. 1H-NMR (MeOD) δ: 1.51 (m, 2H), 1.82 (m, 2H), 2.40 (m, 1H), 2.58 (m, 1H), 2.76 (m, 1H), 3.02-3.14 (m, 2H), 3.40 (m, 2H), 3.91-3.98 (m, 3H), 4.05 (s, 2H), 4.41 (m, 1H), 4.60 (m, 2H), 7.26-7.38 (m, 5H), 7.70 (t, J=7.7 Hz, 1H), 7.87 (d, J=7.7 Hz, 1H), 8.15 (d, J=7.7 Hz, 1H), 8.23 (s, 1H) MS m/z: 506 (M+1).
Reaction SMILES: CN(C)C(=O)C[NH:5][C@:6]12[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:7]1[C@@H:8]1[C@@:21]([CH3:24])([CH2:22][CH2:23]2)[C@@:20]2([CH3:25])[C@@H:11]([C@:12]3([CH3:37])[C@@H:17]([CH2:18][CH2:19]2)[C:16]([CH3:27])([CH3:26])[C:15]([C:28]2[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1.Cl[CH2:47][C:48]([N:50]([CH2:53][CH3:54])[CH2:51][CH3:52])=[O:49]>>[CH2:51]([N:50]([CH2:53][CH3:54])[C:48](=[O:49])[CH2:47][NH:5][C@:6]12[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:7]1[C@@H:8]1[C@@:21]([CH3:24])([CH2:22][CH2:23]2)[C@@:20]2([CH3:25])[C@@H:11]([C@:12]3([CH3:37])[C@@H:17]([CH2:18][CH2:19]2)[C:16]([CH3:27])([CH3:26])[C:15]([C:28]2[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:35][CH:36]=2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1)[CH3:52]
Reactant: C=C(C)[C@@H]1CC[C@]2(NCC(=O)N(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CCN(CC)C(=O)CCl
Product: C=C(C)[C@@H]1CC[C@]2(NCC(=O)N(CC)CC)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(dimethylamino)-2-oxoethylamino)-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)benzoic acid using 2-chloro-N,N-diethylacetamide as alkylating reagent in Step 1. The product was isolated as a white solid (20 mg, 39%). LCMS: m/e 643.50 (M+H)+, 2.35 min (method 11). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.99 (d, J=8.28 Hz, 2H), 7.24 (d, J=8.28 Hz, 2H), 5.31 (d, J=4.52 Hz, 1H), 4.74 (d, J=1.76 Hz, 1H), 4.60 (s, 1H), 3.58-3.21 (m, 6H), 2.82-2.69 (m, 1H), 2.22-1.02 (m, 28H), 1.72 (s, 3H), 1.18 (s, 3H), 1.01 (s, 3H), 1.00 (s, 3H), 0.95 (s, 6H).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:9]=[C:8]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:7](I)=[C:6]([CH3:18])[N:5]=1)[CH3:2].[C:19]([O:23][CH2:24][CH3:25])(=[O:22])[CH:20]=[CH2:21].CCN(CC)CC>CC(N(C)C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:11]1([NH:10][C:8]2[C:7](/[CH:21]=[CH:20]/[C:19]([O:23][CH2:24][CH3:25])=[O:22])=[C:6]([CH3:18])[N:5]=[C:4]([NH:3][CH2:1][CH3:2])[N:9]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C=CC(=O)OCC
Reactant: CCNc1nc(C)c(I)c(NC2CCCCC2)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CCNc1nc(C)c(/C=C/C(=O)OCC)c(NC2CCCCC2)n1
Temperature: 100 °C
Reaction time: 12 h
Yield: 67.6 %

Procedure:
To a solution of 2-ethylamino-4-cyclohexylamino-5-iodo-6-methylpyrimidine (660 mg, 1.83 mmol) in DMA (7 mL) was added ethyl acrylate (458 mg, 4.58 mmol), Pd(OAc)2 (121 mg, 0.18 mmol), (o-Tol)3P (110 mg, 0.37 mmol), and Et3N (740 mg, 7.32 mmol). The mixture was then stirred at 100° C. for 12 h under N2. Standard workup and purification by column chromatography gave 411 mg (67% yield) of (E)-ethyl 3-(4-(cyclohexylamino)-2-(ethylamino)-6-methylpyrimidin-5-yl)acrylate
Reaction SMILES: Cl.[NH2:2]O.[Cl:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[OH:15])[O:11][C:10]([CH3:16])=[C:9]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:8]2=[O:25].O>N1C=CC=CC=1>[Cl:4][C:5]1[CH:6]=[C:7]([C:8]2[O:25][N:2]=[C:10]([CH3:16])[C:9]=2[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:12]([OH:11])=[CH:13][C:14]=1[OH:15]
Reactant: NO
Reactant: COc1ccc(-c2c(C)oc3cc(O)c(Cl)cc3c2=O)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(-c2c(C)noc2-c2cc(Cl)c(O)cc2O)cc1

Procedure:
Hydroxylamine hydrochloride (0.7 g, 10 mmol) was added to a suspension of 6-chloro-7-hydroxy-3-(4-methoxy-phenyl)-2-methyl-chromen-4-one [prepared analogously to Example 1, Step 2] (0.32 g, 1.0 mmol) in pyridine (4 ml) and the mixture heated under reflux for ˜6 hrs., to give a pale yellow solution. The solution was allowed to cool and water (20 ml) added. The mixture was extracted with diethyl ether (2×10 ml). The combined extracts were washed with water (2×20 ml) and saturated aqueous sodium chloride solution (10 ml). The solution was dried over anhydrous magnesium sulphate and concentrated. The crude products were purified by column chromatography, silica, eluting with ethyl acetate/hexane (1:1), to give 4-chloro-6-[4-(4-methoxy-phenyl)-3-methyl-isoxazol-5-yl]-benzene-1,3-diol as an off-white powder (0.103 g)
Reaction SMILES: [C:1]([NH:10][NH2:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[C:12](Cl)(=[O:21])[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O>[C:12]([NH:11][NH:10][C:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])(=[O:21])[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: NNC(=O)c1ccccc1O
Solvent: O
Product: O=C(C=Cc1ccccc1)NNC(=O)c1ccccc1O
Temperature: 20 °C
Reaction time: 9 h
Yield: 32.3 %

Procedure:
To 50 ml of N-dimethylacetamide were added 5.0 g of salicyloylhydrazine and 5.5 g of cinnamoyl chloride, and the mixture was stirred at 20° C for 9 hours. The reaction mixture was then poured into 2 liters of water, and the produced precipitate was collected by filtration and washed with water. The so obtained product was then recrystallized twice from acetic acid and dried under reduced pressure to yield 3 g of N-cinnamoyl-N'-salicyloylhydrazine as white crystals, m.p. 271° C. Analysis: Calculated for C16H14N2O3 ; C, 68.09%, H, 4.96%; N, 9.93%, Found: C, 68.08%; H, 4.81%; N, 9.08%.
Reaction SMILES: [CH3:1][C@@:2]12[C:22]([CH3:24])([CH3:23])[C@@H:5]([C:6]3[C:7](=[O:21])[N:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:17]([F:20])([F:19])[F:18])[NH:9][C:10]=31)[CH2:4][CH2:3]2.I[CH3:26].O>CN(C)C=O>[CH3:26][N:9]1[C:10]2[C@@:2]3([CH3:1])[C:22]([CH3:24])([CH3:23])[C@H:5]([CH2:4][CH2:3]3)[C:6]=2[C:7](=[O:21])[N:8]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([F:18])([F:19])[F:20]
Reactant: CI
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccccc3C(F)(F)F)c(=O)c12
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c2c(c(=O)n1-c1ccccc1C(F)(F)F)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Yield: 81.8 %

Procedure:
A mixture of (4S,7R)-7,8,8-trimethyl-2-(2-trifluoromethyl-phenyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 22; 710 mg, 2.1 mmol) and iodomethane (0.33 mL, 5.3 mmol) in N,N-dimethylformamide (5 mL) in a sealed tube was heated at 100° C. overnight. Water was added and the reaction mixture was extracted three times with ethyl acetate. The combined organic extracts were washed with water and brine, dried (magnesium sulfate), filtered, evaporated, and purified using an Analogix Intelliflash 280 system (Analogix, Inc., Burlington, Wis.) with an Analytical Sales Aspire 90 g column, eluting with 25-100% ethyl acetate/hexanes. Fractions homogeneous for the product were evaporated, dissolved in ethyl acetate and heated at reflux with activated charcoal for 10 min. The mixture was filtered through Celite® and evaporated to give (4S,7R)-1,7,8,8-tetramethyl-2-(2-trifluoromethyl-phenyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (602 mg, 81%) as a light yellow solid. ES(+)-MS (M+H) 351.
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:6]=1.[H-].[Na+].I[CH3:29]>CN(C=O)C.O>[F:1][C:2]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([N:11]([CH3:29])[C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17])[CH:6]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ncn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc([N+](=O)[O-])cc2F)ncn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
A solution of tert-butyl 6-(2-fluoro-4-nitrophenoxy)pyrimidin-4-ylcarbamate (Compound C of Example 6, 44 mg, 0.13 mmol) in anhydrous DMF (1 mL) was cooled in an ice bath and treated with 60% NaH (44 mg, 0.16 mmol) and stirred at the same temperature for 30 minutes. The reaction mixture was treated with iodomethane (10 μL, 0.15 mmol) and stirred at 0-5° C. for 10 min. The reaction mixture was allowed to warm to room temperature and stirred for 30 min. The mixture was diluted with H2O (10 mL) and extracted with EtOAc (2×10 mL). The combined extracts were dried (MgSO4) and concentrated in vacuo to give the product (35 mg, 74%) as a pale yellow solid. 1H NMR (DMSO-d6) δ 8.57 (d, 1H, J=1.1 Hz), 8.37 (dd, 1H, J=9.8, 3.0 Hz), 8.19 (ddd, 1H, J=9.1, 2.5, 1.0 Hz), 7.71 (dd, 1H, J=8.8, 8.8 Hz), 7.66 (s, 1H), 3.38 (s, 3H), 1.51 (s, 9H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.C[O:13][C:14](=[O:22])[CH:15]([CH3:21])[CH2:16][C:17]([O:19]C)=[O:18].[OH-].[Na+]>C1(C)C=CC=CC=1.CO>[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[C:16]([CH:15]([CH3:21])[C:14]([OH:22])=[O:13])[C:17]([OH:19])=[O:18])=[CH:6][CH:5]=1
Reactant: COC(=O)CC(C)C(=O)OC
Reactant: O=Cc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C(=O)O)C(=Cc1ccc(Cl)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.3 %

Procedure:
After careful addition of absolute methanol (0.1 mL) to a suspension of sodium hydride (60% in mineral oil, 16 g, 0.40 mol) in anhydrous toluene (200 mL), a solution of 4-chloro-benzaldehyde (28 g, 0.20 mol) and 2-methyl-succinic acid dimethyl ester (48 g, 0.30 mol) in anhydrous toluene (100 mL) was added dropwise at room temperature under a stream of nitrogen. After being stirred at room temperature for 2 hours, the resulting mixture was diluted by addition of 2 N sodium hydroxide (200 mL) dropwise. The mixture was heated to 80° C., and stirred at this temperature for 2 hours. After cooling to room temperature, the aqueous layer was separated, washed with ethyl acetate (100 mL×3), then acidified with 2 N hydrochloric acid to pH 2 and extracted with ethyl acetate (150 mL×3). The combined organic layers were dried over sodium sulfate, and concentrated in vacuo. The residue was precipitated from ethyl acetate/petroleum ether (10:1) to give 2-(4-chloro-benzylidene)-3-methyl-succinic acid (13.4 g, 26%) as a yellow solid.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=2[C:9]=1[S:10]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].[CH2:30]([CH:32]1[O:34][CH2:33]1)Br>CC(C)=O>[CH2:1]([C:5]1[O:6][C:7]2[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=2[C:9]=1[S:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:30][CH:32]2[O:34][CH2:33]2)=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH2:2][CH2:3][CH3:4]
Reactant: BrCC1CO1
Reactant: CCCCc1oc2ccccc2c1S(=O)(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCc1oc2ccccc2c1S(=O)(=O)c1ccc(OCC2CO2)cc1

Procedure:
2-n-Butyl-3-(4-hydroxyphenylsulfonyl)benzofuran (1.5 g., 0.0045 mol.) was dissolved in 40 ml. of dry acetone containing 2.5 g. (0.018 mol.) of potassium carbonate and 2.46 g. (0.018 mol.) of epibromohydrin. The mixture was refluxed for ca. 16 hours then filtered. The solvent and excess epibromohydrin were removed in vacuo to give 2-n-butyl-3-[4-(2,3-epoxypropoxy)phenylsulfonyl]benzofuran.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][CH2:10][CH:11]([F:13])[F:12])=[CH:4][CH:3]=1.O[C:15]1[CH2:19][O:18][C:17](=[S:20])[CH:16]=1>C(O)(=O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:10][CH:11]([F:13])[F:12])[C:15]2[CH2:19][O:18][C:17](=[S:20])[CH:16]=2)=[CH:4][CH:3]=1
Reactant: OC1=CC(=S)OC1
Reactant: FC(F)CNCc1ccc(Cl)nc1
Solvent: CC(=O)O
Product: FC(F)CN(Cc1ccc(Cl)nc1)C1=CC(=S)OC1
Temperature: 25 °C
Reaction time: 336 h
Yield: 29.1 %

Procedure:
105 mg (0.506 mmol) of N-[(6-chloropyridin-3-yl)methyl]-2,2-difluoroethanamine (which can be prepared according to: WO 2007/115644 A1, WO 2008/009360 A2) were added to 20 mg (0.169 mMol) of 4-hydroxyfuran-2(5H)-thione (known from: R. Labruère et al., Synthesis 4163-4166, 2006) in 0.5 ml of acetic acid, and the mixture was stirred at room temperature for 14 days. Concentration under reduced pressure and purification of the residue by preparative HPLC (RP18, CH3CN—H2O) gave 15 mg (yield: 28.8% of theory) of 4-{[(6-chloropyridin-3-yl)methyl](2,2-difluoroethyl)amino}furan-2(5H)-thione.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][OH:7].[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17](F)[C:14]=1[C:15]#[N:16]>CN(C=O)C>[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([O:7][CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[Br:3])[C:14]=1[C:15]#[N:16]
Reactant: N#Cc1c(F)cccc1F
Reactant: OCc1ccccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(F)cccc1OCc1ccccc1Br
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 83 %

Procedure:
To a cold (ice water) suspension of sodium hydride (222 mg; 5.0 mmol) in anhydrous DMF (4 mL) is added a solution of 2-bromobenzyl alcohol (941 mg; 5.0 mmol) in anhydrous DMF (5 mL) over 10 minutes. After allowing to room temperature over 45 minutes, this solution is added to a cold (ice water) stirred solution of 2,6-difluorobenzonitrile (703 mg; 5.0 mmol) in anhydrous DMF (3 mL), and allowed to room temperature over 4 hours. The reaction mixture is poured into ice water with vigorous stirring and the resulting solid is filtered, washed with water, and dried under vacuum at 40° C. for 3 hours to give 1.27 grams of 2-fluoro-6-(2-bromobenzyloxy)-benzonitrile.
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([I:9])[C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16](O)=[O:17])=[C:12]([N+:19]([O-:21])=[O:20])[CH:11]=1.S(Cl)([Cl:24])=O>>[I:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([I:9])[C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([Cl:24])=[O:17])=[C:12]([N+:19]([O-:21])=[O:20])[CH:11]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(-c2c(I)cc(I)cc2I)cc1[N+](=O)[O-]
Product: O=C(Cl)c1ccc(-c2c(I)cc(I)cc2I)cc1[N+](=O)[O-]

Procedure:
2′,4′,6′-triiodo-3-nitrobiphenyl-4-carboxylic acid (6) is reacted with thionyl chloride to yield 2′,4′,6′-triiodo-3-nitrobiphenyl-4-carbonyl chloride (7).
Reaction SMILES: [O:1]=[C:2]([NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)[CH2:3][N:4]([CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][N:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[CH:22][C:21]2=[O:30])[CH2:14][CH2:13]1)C(=O)OC(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[O:30]=[C:21]1[CH:22]=[N:23][C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:20]1[CH2:19][CH2:18][N:15]1[CH2:16][CH2:17][CH:12]([NH:4][CH2:3][C:2]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)=[O:1])[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)N(CC(=O)Nc1ccccn1)C1CCN(CCn2c(=O)cnc3ccccc32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CNC1CCN(CCn2c(=O)cnc3ccccc32)CC1)Nc1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
To 3 mL of a dichloromethane solution containing 0.26 g of tert-butyl (2-oxo-2-(pyridin-2-ylamino)ethyl)(1-(2-(2-oxoquinoxalin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 3 mL of trifluoroacetic acid was added and stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, chloroform and water were added, and adjusted to pH 11 with 20% aqueous sodium hydroxide solution. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 0.20 g of N2-(1-(2-(2-oxoquinoxalin-1(2H)-yl)ethyl)piperidin-4-yl)-N-(pyridin-2-yl)glycinamide as a light brown oil.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][O:11][C@@H:10]([CH3:15])[C@@H:9]1[C:16]([OH:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:23][CH2:24]O>>[CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][O:11][C@@H:10]([CH3:15])[C@@H:9]1[C:16]([O:18][CH2:23][CH3:24])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H]1OCC(=O)N(Cc2ccccc2)[C@H]1C(=O)O
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)[C@H]1[C@H](C)OCC(=O)N1Cc1ccccc1
Temperature: 20 °C
Reaction time: 72 h
Yield: 61.4 %

Procedure:
A round-bottomed flask equipped with a magnetic stirrer was added (2S,3R)-4-benzyl-2-methyl-5-oxomorpholine-3-carboxylic acid (1 g, 4.01 mmol), EtOH (20 ml), thionyl chloride (1.155 ml, 16.05 mmol). The reaction was stirred at 20° C. for 72 hours. Concentrate in vacuo to afford a crude oil. The oil was purified by silica gel column chromatography (eluting with 20% EtOAc in Hexanes using the Moritex SI-60 size 60-half column). The resultant fractions were collected and concentrated in-vacuo to afford (2S,3R)-ethyl 4-benzyl-2-methyl-5-oxomorpholine-3-carboxylate (683 mg, 2.46 mmol, 61.4% yield) as a white solid. MS [M+H] found 278.