Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[C:11]([OH:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].CN(C1C=CC(N=NC2C=CC(S(O)(=O)=O)=CC=2)=CC=1)C.Cl>O1CCCC1.O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH3:13])=[C:11]([OH:17])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1O
Agent: CN(C)c1ccc(N=Nc2ccc(S(=O)(=O)O)cc2)cc1
Agent: Cl
Agent: [BH3-]C#N
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(OCc2ccccc2)cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-benzyloxy-2-hydroxybenzaldehyde (2.28 g, 10.0 mmol, prepared by the method of Example 18 below) and sodium cyanoborohydride (2.0 g, 15.9 mmol) in tetrahydrofuran (60 mL) was added methyl orange as an indicator, giving the solution a yellow color; 1N aqueous HCl solution (15 mL) was added slowly, keeping the solution orange. The mixture was stirred overnight at room temperature. Water was added, and the mixture was extracted with ethyl acetate three times. The combined organic phase was washed with water and brine, dried (MgSO4) and concentrated. The residue was purified by flash chromatography eluting with 0-40% ethyl acetate in hexanes to give 5-benzyloxy-2-methyl-phenol. (Yield 0.64 g).
Reaction SMILES: [F:1][C:2]1[CH:39]=[CH:38][C:5]([C:6]([NH:8][C@@:9]([C:24]2[CH:29]=[C:28]([O:30][C:31]([F:36])([F:35])[CH:32]([F:34])[F:33])[CH:27]=[C:26]([F:37])[CH:25]=2)([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)=[CH:4][C:3]=1[C:40]([F:43])([F:42])[F:41].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:53])=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:39]=[CH:38][C:5]([C:6](=[S:53])[NH:8][C@@:9]([C:24]2[CH:29]=[C:28]([O:30][C:31]([F:36])([F:35])[CH:32]([F:34])[F:33])[CH:27]=[C:26]([F:37])[CH:25]=2)([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][C:3]=1[C:40]([F:43])([F:42])[F:41]
Reactant: O=C(N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(F)c(C(F)(F)F)c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Fc1ccc([C@@](Cc2ccccc2)(NC(=S)c2ccc(F)c(C(F)(F)F)c2)c2cc(F)cc(OC(F)(F)C(F)F)c2)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
To a stirred solution of (R)-4-fluoro-N-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamide (105 mg, 0.17 mmol), prepared as described in Procedure 3, 4, 5, 6 and 7, in toluene (5.2 mL) was added Lawesson's reagent (83 mg, 0.20 mmol). The reaction mixture was heated at 110° C. After 8 h, the reaction mixture was concentrated and the residue was purified by ISCO column chromatography (EtOAc/hexane 0-100%, SiO2) to provide (R)-4-fluoro-N-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-(trifluoromethyl)benzothioamide (Example 315, 89 mg, 83% yield) as a yellow oil. 1H NMR (500 MHz, CDCl3) δ ppm 7.92 (s, 1H), 7.74-7.72 (m, 1H), 7.68-7.66 (m, 1H), 7.22-6.86 (m, 11H), 6.72 (d, J=5 Hz, 2H), 5.92-5.70 (m, 1H), 4.36 (d, J=15 Hz, 1H), 3.82 (d, J=10 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ ppm 195 (C═S); LC/MS: RT=4.393 min [M+H] 632.4 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeCN/H2O over 4 minutes containing 0.1% NH4OAc; 4 mL/min, monitoring at 220 nm).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([NH:11]C(=O)OC(C)(C)C)[CH2:7][CH2:6]1.FC(F)(F)C(O)=O>>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:6][CH2:7][CH:8]([NH2:11])[CH2:9][CH2:10]1
Reactant: COCCN1CCC(NC(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Product: COCCN1CCC(N)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 37.8 %

Procedure:
A mixture of tert-butyl 1-(2-methoxyethyl)piperidin-4-ylcarbamate (0.842 g, 3.26 mmol) and 2,2,2-trifluoroacetic acid (2.51 ml, 32.6 mmol) was stirred for 15 minutes at ambient temperature. The mixture was concentrated in vacuo, using toluene (2×10 mL) to azeotrope residual TFA. The crude TFA salt of the product was converted to the free base using Biotage Flash 40M flash chromatography, eluting with 10% MeOH (containing 7N NH3) in DCM (500 mL), followed by 20% MeOH (containing 7N NH3) in DCM (500 mL). The product was obtained as an oil (195 mg, 37%).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([O:14][C:15]([N:17]([CH2:29][C:30]([NH:32][NH2:33])=[O:31])[CH:18]1[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:19]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].[CH2:34]([O:41][N:42]1[C:48](=[O:49])[N:47]2[CH2:50][C@H:43]1[CH2:44][CH2:45][CH:46]2[C:51](O)=[O:52])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:34]([O:41][N:42]1[C:48](=[O:49])[N:47]2[CH2:50][C@H:43]1[CH2:44][CH2:45][C@H:46]2[C:51]([NH:33][NH:32][C:30](=[O:31])[CH2:29][N:17]([C:15]([O:14][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:16])[CH:18]1[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:19]1)=[O:52])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC(C)(C)OC(=O)N1CC(N(CC(=O)NN)C(=O)OC(C)(C)C)C1
Reactant: O=C(O)C1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
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: CC(C)(C)OC(=O)N1CC(N(CC(=O)NNC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.3 %

Procedure:
DIPEA (14 g, 0.11 mol) was added to a 0° C. solution of tert-butyl 3-(tert-butoxycarbonyl(2-hydrazinyl-2-oxoethyl)amino)azetidine-1-carboxylate (15 g, 0.044 mol), (5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carboxylic acid (10 g, 0.036 mol) and HATU (15 g, 0.04 mol) in CH2Cl2 (250 mL). The mixture was allowed to warm to rt then was stirred at rt for 2 hrs. The mixture was quenched with saturated sodium chloride (50 mL) and the organic layer was separated. The water layer was extracted with EtOAc (3×). The combined organic layer was washed with saturated sodium chloride (2×), dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (gradient elution 0˜50% EtOAc/petroleum ether) to afford tert-butyl 3-((2-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)hydrazinyl)-2-oxoethyl)(tert-butoxycarbonyl)amino)azetidine-1-carboxylate (18.5 g, 86%). ESI-MS (EI+, m/z): 603.3 [M+H]+.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[O:15][C@@H:14]([CH2:19][N:20]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:21][C@H:22]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:13][CH2:12]3)O1.C([O-])([O-])=O.[Na+].[Na+].Br[C:54]1[CH:69]=[CH:68][C:57]([C:58]([O:60][CH2:61][C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)=[O:59])=[C:56]([NH:70][CH2:71][CH2:72][CH2:73][CH3:74])[CH:55]=1>C1(C)C=CC=CC=1.O1CCCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:71]([NH:70][C:56]1[CH:55]=[C:54]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[O:15][C@@H:14]([CH2:19][N:20]([CH2:21][C@H:22]([O:31][Si:32]([C:35]([CH3:37])([CH3:38])[CH3:36])([CH3:34])[CH3:33])[CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:13][CH2:12]3)[CH:69]=[CH:68][C:57]=1[C:58]([O:60][CH2:61][C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=1)=[O:59])[CH2:72][CH2:73][CH3:74]
Reactant: CC1(C)OB(c2ccc3c(c2)CC[C@H](CN(Cc2ccccc2)C[C@@H](COc2ccccc2)O[Si](C)(C)C(C)(C)C)O3)OC1(C)C
Reactant: CCCCNc1cc(Br)ccc1C(=O)OCc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCCCNc1cc(-c2ccc3c(c2)CC[C@H](CN(Cc2ccccc2)C[C@@H](COc2ccccc2)O[Si](C)(C)C(C)(C)C)O3)ccc1C(=O)OCc1ccccc1
Temperature: 85 °C
Reaction time: 3 h
Yield: 42 %

Procedure:
Argon gas was bubbled through a solution of (2S)-N-{[(2R)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-chromen-2-yl]methyl}-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-N-(phenylmethyl)-3-(phenyloxy)-1-propanamine (Example 88, 92 mg, 0.14 mmol) in toluene (1.25 mL), tetrahydrofuran (0.25 mL), and aqueous Na2CO3 (0.50 mL of a 2M solution) for 10 minutes. Pd(dppf)Cl2 (10 mg, 0.014 mmol, 0.1 eq.) and phenylmethyl 4-bromo-2-(butylamino)benzoate (Example 193, 52 mg, 0.14 mmol, 1.0 eq.) were added, and argon was bubbled through the mixture for an additional 5 minutes before the mixture was stirred vigorously at 85° C. for 3 hours. The reaction mixture was cooled and filtered through a pad of Celite® with the aid of ethyl acetate. The filtrate was transferred to a separatory funnel where the water layer was removed. The organic layer was dried (MgSO4) and concentrated in vacuo to a crude oil. The crude was purified by flash chromatography on silica gel eluted on a gradient from 100:0 to 90:10 hexanes/ethyl acetate to provide the title compound as a colorless oil (47 mg, 42%): 1H NMR (300 MHz, CDCl3) δ7.95 (d, 1 H)7.69 (t, 1 H), 7.43-7.27 (m, 8 H), 7.23-7.19 (m, 6 H), 6.89 (t, 1 H), 6.84-6.80 (m, 3H), 6.75 (s, 1 H), 6.70 (d, 1 H), 5.29 (s, 2 H), 4.17-4.07 (m, 3 H), 3.83-3.66 (m, 3 H), 3.23 (q, 2 H), 2.93-2.64 (m, 6 H), 2.01-1.96 (m, 1 H), 1.72-1.63 (m, 3 H), 1.50-1.41 (m, 2 H), 0.95 (t, 3 H), 0.84 (s, 9 H), 0.07 (s, 3 H), 0.03 (s, 3 H); MS m/z 799.3 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]([CH3:15])=[CH:13][C:12]([OH:16])=[CH:11][C:10]1=[O:17].C1C(=O)N([Cl:25])C(=O)C1>ClCCl>[Cl:25][C:11]1[C:10](=[O:17])[N:9]([C:3]2[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[C:14]([CH3:15])=[CH:13][C:12]=1[OH:16]
Reactant: Cc1cc(O)cc(=O)n1-c1c(F)cccc1F
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: Cc1cc(O)c(Cl)c(=O)n1-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 79.2 %

Procedure:
To a mixture of 1-(2,6-difluorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one (0.30 g, 1.26 mmol) in dichloromethane (5 mL) was added NCS (2.52 g, 1.90 mmol). The reaction mixture stirred at room temperature under nitrogen for 4.5 hours. The suspension was cooled in ice bath, filtered, and the solid was rinsed with fresh dichloromethane to afford the desired product (0.271 g, 79%) as a white solid. 1H-NMR (CD3OD, 400 MHz) δ 7.58 (m, 1H), 7.22 (m, 2H), 6.20 (s 1H), 2.00 (s, 3H); ES-HRMS m/z 272.0287 (M+H calculated for C12H9NO2F2Cl requires 272.0290).
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[O:18][C:19]3[CH:25]=[C:24]([C:26]([OH:28])=O)[CH:23]=[CH:22][C:20]=3[N:21]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:29].C(Cl)CCl.Cl.[CH3:38][NH:39][CH3:40]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:38][N:39]([CH3:40])[C:26]([C:24]1[CH:23]=[CH:22][C:20]2[N:21]=[C:17]([C:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3](=[O:30])[C:2]([CH3:32])([CH3:31])[CH3:1])=[C:7]([CH3:29])[CH:8]=3)([CH2:15][CH3:16])[CH2:13][CH3:14])[O:18][C:19]=2[CH:25]=1)=[O:28]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1nc2ccc(C(=O)O)cc2o1
Reactant: CNC
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1nc2ccc(C(=O)N(C)C)cc2o1
Temperature: 25 °C
Yield: 78.4 %

Procedure:
2-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzooxazole-6-carboxylic acid (150 mg, 0.343 mmol) in CH2Cl2 (5.0 mL) is treated with DMAP (125 mg, 1.03 mmol) and EDC (99 mg, 0.514 mmol). The mixture is stirred for 15 m at RT, and dimethylamine hydrochloride (42 mg, 0.514 mmol) is added. The reaction is stirred for 18 h and quenched with aqueous NH4Cl (5.0 mL). The organic layer is loaded onto a silica gel column and purified with 50% EtOAc/Hex to afford the title compound (125 mg, 79%). MS (ES) m/e: 465.3 (M+1).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[N:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:17][CH2:18][CH2:19]I>C(#N)C>[F:17][CH2:18][CH2:19][N:2]1[C:3]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:5]=[N:1]1
Reactant: FCCI
Reactant: CCOC(=O)c1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)c1ccnn1CCF
Temperature: 20 °C
Reaction time: 18 h
Yield: 41.1 %

Procedure:
To a solution of ethyl 1H-pyrazole-3-carboxylate (0.77 g) (available from ABCR) in acetonitrile (30 ml) was added cesium carbonate (1.79 g) and the mixture stirred for 5 min when 1-fluoro-2-iodoethane (0.96 g) was added and the mixture stirred at 20° C. for 18 h. The mixture was evaporated and the residue taken up in water (30 ml) and DCM (30 ml) separated by hydrophobic frit and concentrated to ˜5 ml, placed on an SPE cartridge (50 g silica) and eluted with a gradient of ethyl acetate in cyclohexane to give the Ethyl 1-(2-fluoroethyl)-1H-pyrazole-5-carboxylate (0.42 g) as a colourless oil.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])=[CH:14][CH:13]=2)[N:3]=1.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>CN1C(=O)CCC1.C(Cl)Cl>[N:20]1([C:18]([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:4]3[N:3]=[C:2]([N:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:10]=[CH:9][C:5]=3[C:6]([NH2:8])=[O:7])=[CH:13][CH:14]=2)=[O:19])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: C1CNCCN1
Reactant: NC(=O)c1ccc(Cl)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: NC(=O)c1ccc(N2CCNCC2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Yield: 63.3 %

Procedure:
A solution of 6-chloro-2-(4-(morpholine-4-carbonyl)phenylamino)nicotinamide (100 mg, 0.277 mmol) and piperazine (477 mg, 5.54 mmol) in NMP (2 mL) was heated to 120° C. overnight. The reaction mixture was diluted with CH2Cl2, washed with satd NaHCO3, separated, and concentrated. The residue was purified by MPLC chromatography (ISCO, 8% NH4OH/MeOH/CH2Cl2, 40 g silica gel column) to give 72 mg of 2-(4-(morpholine-4-carbonyl)phenylamino)-6-(piperazin-1-yl)nicotinamide as a white solid. LCMS: (M+H)+=411.35. 1H NMR (400 MHz, CDCl3) δ ppm 11.20 (1H, s), 7.70 (2H, d, J=8.56 Hz), 7.54 (1H, d, J=9.06 Hz), 7.38 (2H, d, J=8.56 Hz), 6.04 (1H, d, J=8.81 Hz), 5.58 (2H, s), 3.58-3.78 (12H, m), 2.92-3.01 (4H, m).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:4](=[O:34])[CH2:3]1.[CH2:35]([N:42]1[C:46]([CH2:47]Br)=[CH:45][C:44]([CH3:49])=[N:43]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CN(C=O)C.C1(C)C=CC=CC=1>[CH2:35]([N:42]1[C:46]([CH2:47][CH:3]2[C:2](=[O:1])[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[O:11])[C:7]3[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=3[N:5]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:4]2=[O:34])=[CH:45][C:44]([CH3:49])=[N:43]1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Reactant: Cc1cc(CBr)n(Cc2ccccc2)n1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3cc(C)nn3Cc3ccccc3)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Reaction time: 0.08 h
Yield: 60 %

Procedure:
To a stirring solution of 300 mg (0.66 mmol) of 2-(2,4-Dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl) acetamide, prepared as in Intermediate 4, in 5 mL of DMF at 0° C. is added 1.57 mL (0.79 mmol, 1.2 equiv) of a 0.5M solution of KN(TMS)2 in toluene. The resulting solution is stirred 5 min, and a solution of 190 mg (0.72 mmol, 1.1 equiv.) of 1-Benzyl-5-bromomethyl-3-methyl-1H-pyrazole, prepared as in Intermediate 56, in 2 mL of DMF is added. The resulting solution is stirred for 18 h at RT then quenched with 5 mL of H2O. The reaction mixture is poured into 50 mL of EtOAc and extracted with H2O (2×50 mL). The organic layer is separated, dried (MgSO4), and the solvents removed in vacuo. Purification by silica gel flash column chromatography using hexane/EtOAc 1/2 as eluent afforded 254 mg of the title compound as a white solid: mp 117°-120° C.; 1H NMR (CDCl3, 400 MHz) δ7.37-7.02 (m, 15H), 6.94 (m, 2H), 6.85 (d, 1H, J=7.4), 5.80(s, 1H), 5.30 (dd, 2H, J=16.1, 30.9), 4.98 (m, 1H), 4.19 (dd, 2H, J=15.6, 76.0), 3.83 (s, 3H), 3.43 (t, 1H, J=6.7), 3.25 (ddd, 1H, J=7.1, 16.0, 40.5), 2.20 (s, 3H), 1.06 (m, 6H); low resolution MS (FAB)m/e 642 (MH+), 641 (M+); Anal. (C39H39N5O4) Calcd. C, 72.99; H, 6.13; N, 10.91 Found C, 72.86; H, 6.11; N, 10.96.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:45])[C@@H:4]([NH:23][C:24](=[O:44])[C:25]1[C:30]([Cl:31])=[CH:29][C:28]([O:32][Si](C(C)C)(C(C)C)C(C)C)=[CH:27][C:26]=1[Cl:43])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:22])[C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:21])=[CH:8][CH:7]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:45])[C@@H:4]([NH:23][C:24](=[O:44])[C:25]1[C:26]([Cl:43])=[CH:27][C:28]([OH:32])=[CH:29][C:30]=1[Cl:31])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:22])[C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:21])=[CH:10][CH:11]=1
Reactant: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)c1c(Cl)cc(O[Si](C(C)C)(C(C)C)C(C)C)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)c1c(Cl)cc(O)cc1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.2 %

Procedure:
To a solution of (S)-3-[4-(2,6-dichlorobenzoylamino)phenyl]-2-(2,6-dichloro-4-triisopropylsilanyloxy-benzoylamino)propionic acid methyl ester (6.76 g, 9.48 mmol) in THF (150 mL) was added a solution of TBAF (14.22 mL, 14.22 mmol, 1M) in THF at 0° C. The resulting solution was slowly warmed to room temperature and stirred for 15 h. Then, the reaction mixture was diluted with water and the organic compound was extracted into ethyl acetate (2×150 mL). The combined organic layer was washed with brine solution and dried over anhydrous MgSO4. Filtration and concentration gave the crude residue which was dissolved in ethyl acetate in hot conditions and then diluted with hexanes. The resulting solids were collected by filtration and washed with hexanes. After drying in air, 5.23 g (99%) of (S)-3-[4-(2,6-dichlorobenzoylamino)phenyl]-2-(2,6-dichloro-4-hydroxy-benzoylamino)propionic acid methyl ester was obtained as a white solid. ES(+)-HRMS m/e calcd. for C24H18Cl4N2O5 (M−H)− 552.9897, obsd. 552.9897.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].N[C@H:6](C=O)CCSC.CC(C)=O.NC(N)=O.[Cl-:21].[OH:22][CH2:23][CH2:24][N+:25]([CH3:28])([CH3:27])[CH3:26]>[Cl-].OCC[N+](C)(C)C.[O-2].[Zn+2].[Fe].[Ni].[Ti]>[NH2:1][C:2]([NH2:4])=[O:3].[Cl-:21].[OH:22][CH2:23][CH2:24][N+:25]([CH3:28])([CH3:27])[CH3:26].[CH4:6]
Reactant: CSCC[C@H](N)C=O
Agent: [Fe]
Agent: [Ni]
Agent: [Ti]
Solvent: CC(C)=O
Product: C
Temperature: 80 °C

Procedure:
Zinc oxide and lead compounds can be dissolved in 2:1 urea-choline chloride and the respective metals subsequently electrodeposited onto a suitable cathode. Oxides of Fe, Al, Si and Ca were found to be almost totally insoluble in the above ionic liquid. Urea-choline chloride ionic liquid was prepared by combining urea (0.02 moles) with choline chloride (0.01 moles) in a beaker and heating at 80° C. Arc furnace dust (0.5 g) was added to the resulting clear colourless liquid and the mixture was heated at 80° C. for 1 hour. After 1 hour a brown suspension was obtained which was transferred to an electrochemical cell. Metal electrodeposition was achieved using a nickel cathode and a titanium anode (both electrodes were 50 mm by 10 mm and 1 mm thick) and applying a potential difference of 3.5 V for 1 hour. Prior to electrodeposition the electrodes were gently abraded with glass paper and cleaned with acetone. After 1 hour of electrodeposition the nickel cathode was removed from the brown suspension, washed with acetone and dried. A thick charcoal coloured deposit was obtained. The electrodeposited material was analysed using Energy Dispersive Analysis by X-rays. The results of the analysis revealed the presence of lead (77%), zinc (16%) and copper (7%). There was no trace of iron in the deposit thus showing that zinc oxide and iron (III) oxide can be separated and harmful lead compounds removed from arc furnace dust.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:10]([O:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](O)=[O:24])=[O:16])([CH3:13])([CH3:12])[CH3:11].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[C:10]([O:14][C:15](=[O:16])[NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](=[O:24])[NH:9][CH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)O
Reactant: NCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCCCC(=O)NCCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Phenethylamine (340 μL, 4.3 mmol), 6-tert-butoxycarbonylamino-hexanoic acid (1.0 g, 4.3 mmol) and 1-hydroxybenzotriazole (700 mg, 5.1 mmol) were dissolved under nitrogen in N,N-dimethylformamide and cooled to 0° C. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride was added and the mixture stirred overnight, allowing to warm to room temperature. The mixture was partitioned between water and isopropyl acetate. The organics were washed with 0.5 M citric acid, then saturated sodium hydrogen carbonate, dried over sodium sulfate and evaporated to dryness. The residue was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[I:9]I.C(=O)([O-])[O-].[Ca+2].CCOCC>O>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([I:9])[CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: II
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: CCOCC
Product: Nc1ccc(F)cc1I

Procedure:
A mixture of 22 g. of 4-fluoroaniline, 50 g. of iodine, 25 g. of calcium carbonate, 75 ml. of ether and 75 ml. of water is heated at reflux for 48 hours. The ether is removed by distillation and the excess iodine is destroyed by addition of sodium thiosulfate. Steam distillation and recrystallization from petroleum ether gives 4-fluoro-2-iodoaniline.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][CH:14]([C:17](=[O:37])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][Si:25]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])[C:19]=3[O:35][CH3:36])[CH2:13][CH2:12]2)=O)=[CH:4][CH:3]=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:11]2[CH2:12][CH2:13][CH:14]([CH:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][Si:25]([CH:26]([CH3:28])[CH3:27])([CH:32]([CH3:33])[CH3:34])[CH:29]([CH3:30])[CH3:31])[C:19]=3[O:35][CH3:36])[OH:37])[CH2:15][CH2:16]2)=[CH:4][CH:3]=1
Reactant: COc1c(O[Si](C(C)C)(C(C)C)C(C)C)cccc1C(=O)C1CCN(C(=O)Cc2ccc(F)cc2)CC1
Solvent: Cc1ccccc1
Product: COc1c(O[Si](C(C)C)(C(C)C)C(C)C)cccc1C(O)C1CCN(CCc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(4-Fluoro-phenyl)-1-[4-(2-methoxy-3-triisopropylsilanyloxy-benzoyl)-piperidin-1-yl]-ethanone, Example 1A (262 g, 0.496 mol) in toluene (3.8 L) at −38° C. add (R)-methyloxoazaborolidine (150 mL, 0.15 mol, of 1M solution in toluene), follow with the addition of borane dimethylsulfide complex (750 mL of a 2M solution in toluene, 1.5 mol), over a 2 h period at −30° C. Stir between −25° C. to -28° C. overnight and then allow the reaction to warm to ambient temperature over a 2 h period. Slowly add MeOH (500 mL) over a1 h period and then concentrate the solution to obtain 363 g of yellow oil. Add MeOH (1.8 L) to the oil and concentrate under reduced pressure at 80° C. to obtain 341 g of a yellow oil. Purify the oil by plug filtration through silica gel eluting with 1:1 MeOHI/CHCI3. Combine and concentrate the desired fractions to obtain 250 g of product. Further purify the product by column chromatography over silica gel eluting with 1:3 EtOAc/hexane (20 L), 1:1 EtOAc/hexane (20 L) and 1:1 CHCl3/MeOH (40 L). Collect and concentrate like fractions to obtain 214 g of oil. Dissolve the oil in CHCl3 (500 mL)/toluene (600 mL), dry (MgSO4) and concentrate to obtain 207 g of the title compound as a foam.