Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-])=O)([CH3:5])[CH3:4]>C(O)C.[Pd]>[OH:1][CH2:2][C:3]([NH:6][C:7]1[C:8]([NH2:13])=[CH:9][CH:10]=[CH:11][CH:12]=1)([CH3:5])[CH3:4]
Reactant: CC(C)(CO)Nc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(CO)Nc1ccccc1N
Reaction time: 2 h
Yield: 98 %

Procedure:
N-(1-Hydroxy-2-methylprop-2-yl)-2-nitroaniline (10 g) in ethanol (200 ml) was hydrogenated over 5% palladium on charcoal (0.5 g) at 50 p.s.i. for 2 hours. The reaction was filtered and the solvent removed under vacuum to yield N-(1-hydroxy-2-methylprop-2-yl)benzene 1,2-diamine (8.4 g, 98%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:13][C:14](=[O:16])[CH3:15])=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][C:9](=[CH2:12])[C:10]=2[CH:11]=1.[OH:17]C1C(OS(C2C=CC(C)=CC=2)(=O)=O)=C(I)C=CC=1.[Na+].[Cl-]>CO.O>[CH3:1][C:2]1[C:3]([NH:13][C:14](=[O:16])[CH3:15])=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][C:12](=[O:17])[CH2:9][C:10]=2[CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2c(O)cccc2I)cc1
Reactant: C=C1CCCc2cc(NC(C)=O)c(C)cc21
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(=O)Nc1cc2c(cc1C)CC(=O)CCC2
Reaction time: 0.25 h
Yield: 68.1 %

Procedure:
In a 50 L mechanically stirred vessel, N-(3-methyl-5-methylene-5,6,7,8-tetrahydronaphthalen-2-yl)acetamide (76) (710 g, 3.30 mol) was suspended in MeOH (22.5 L) and water (1.875 L). A solution of hydroxy(tosyloxy)iodobenzene (1.30 kg, 3.30 mol) in MeOH (3.50 L) was added maintaining the internal temperature below about 20° C. After completion of addition, the solution was stirred for about 15 min and then poured into saturated aqueous NaCl (35 L). The aqueous mixture was extracted with DCM (2×12 L). The combined organic layers were washed with 5 N aqueous HCl (3.50 L), dried with Na2SO4, filtered, and concentrated to afford N-(3-methyl-6-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)acetamide (77) (520 g, 68% yield). 1H NMR (300 MHz, DMSO): δ 9.24 (s, 1H), 7.20 (s, 1H), 6.98 (s, 1H), 3.68 (s, 2H), 2.88 (m, 2H), 2.52 (m, 2H), 2.16 (s, 3H), 2.04 (s, 3H), 1.82 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5]([N+:8]([O-])=O)=[CH:6][CH:7]=1>C(O)(=O)C.[Zn]>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[OH:11]
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: [Zn]
Solvent: CC(=O)O
Product: Nc1ccc(F)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.7 %

Procedure:
A suspension of 3-fluoro-6-nitrophenol (500 mg, 3.18 mmol) and zinc (2.10 g, 31.8 mmol) in acetic acid (7.3 mL) was stirred overnight at room temperature. The reaction mixture was filtered through celite and washed with DCM. After evaporation and distillation under vacuum (2.10−2 mbar) of the solvents, the residue was dissolved in DCM. The organic phase was washed with a saturated solution of NaHCO3 and brine, dried over MgSO4, filtered and evaporated. The crude residue was purified by flash chromatography (DCM/MeOH 99.5:0.5) to yield 177 mg (1.39 mmol, 44%) of 2-amino-5-fluorophenol as an orange solid.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)[C:4]=1[CH3:16].[C:19]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)#[N:20].C1COCC1.N1CCCCC1>C(N(CC)CC)C>[CH3:16][C:4]1[C:5]([C:8]2[S:12][C:11]([C:13]([N:24]3[CH2:25][CH2:26][CH:21]([C:19]#[N:20])[CH2:22][CH2:23]3)=[O:15])=[CH:10][CH:9]=2)=[N:6][O:7][C:3]=1[C:2]([F:1])([F:18])[F:17]
Reactant: N#CC1CCNCC1
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Solvent: C1CCOC1
Solvent: C1CCNCC1
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccc(C(=O)N3CCC(C#N)CC3)s2)noc1C(F)(F)F
Yield: 61 %

Procedure:
Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and 4-cyanopiperidine by the method described in Example 2 Method B reversing the order of addition such that solid acid chloride was added to a THF solution of triethylamine and piperidine derivative. The reaction mixture was evaporated to a solid, triturated and filtered with the aid of water, then washed with a 1 N aqueous hydrochloric acid solution followed by water. The solid was air dried then chromatographed on a short column of silica gel with EtOAc as eluant to afford product as a colorless solid (91 mg, 61%). 1H NMR (CDCl3) 1.91-2.06 (m, 4 H), 2.37 (d, J=1.3, 3 H), 2.97-3.03 (m, 1 H), 3.71-3.79 (m, 2 H), 3.90-3.98 (m, 2 H), 7.34 (d, J=4.0, 1 H), 7.47 (d, J=4.0, 1 H). 13C NMR 7.9, 26.5, 28.9, 43.6, 114.8, 118.7 (q, J=271), 120.8, 128.1, 129.5, 131.7, 139.4, 155.2 (q, J=40), 157.8, 162.9. 19F NMR −63.2. LC/MS 6.18 min, [M+1]+ 370.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:5]([C:6]([NH:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(N(C(C)C)C(C)C)C>CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[CH3:9][NH:8][C:6](=[O:7])[C:5]1[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:11][C:2]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[N:3][CH:4]=1
Reactant: CNC(=O)c1cnc(Cl)cc1-c1ccccc1C
Reactant: C1COCCN1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cnc(N2CCOCC2)cc1-c1ccccc1C
Temperature: 25 °C
Yield: 92.8 %

Procedure:
A mixture of 1.00 g (3.84 mmol) 6-chloro-N-methyl-4-o-tolyl-nicotinamide, 0.37 ml (4.22 mmol) morpholine, 2.0 ml (12 mmol) N-ethyldiisopropylamine and a catalytic amount of 4-(N,N-dimethylamino)-pyridine was heated at 100° C. over night. After cooling to room temperature the mixture was dissolved in ethyl acetate and washed with two portions of water. The combined aqueous layers were extracted with 3 portions of dichloromethane. Drying with sodium sulfate and concentration gave 1.23 g of the crude product. Flash column chromatography afforded 1.11 g (92.9%) of the title compound as an off-white solid. M.p. 156-158° C.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[C@@H:3]([CH3:5])[OH:4].C[Si:10](O)(O)[OH:11]>>[SiH3:10][OH:11].[NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[C@@H:3]([CH3:5])[OH:4]
Reactant: C[Si](O)(O)O
Agent: C[C@@H](O)[C@H](N)C(=O)O
Product: O[SiH3]

Procedure:
1 liter of aqueous solution of the complex was prepared by mixing 500 ml containing 5.6 g of threonine with 500 ml of a solution of 4.4 g of methylsilanetriol; the solution contained 1.3 g Si per liter, that is to say 1 mol of CH3Si(OH)3 for 1 mol of ##STR8##
Reaction SMILES: [Cl:1][C:2]([Cl:8])=[CH:3][CH:4]=[C:5]([CH3:7])[CH3:6].Br[CH:10]([C:16]#[N:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[Ca+2].[Cl-].[Ca+2].[Cl-]>C(O)C>[C:16]([C:10]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:4]([CH:3]=[C:2]([Cl:8])[Cl:1])[C:5]1([CH3:7])[CH3:6])#[N:17]
Reactant: CCOC(=O)C(Br)C#N
Reactant: CC(C)=CC=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Product: CCOC(=O)C1(C#N)C(C=C(Cl)Cl)C1(C)C
Reaction time: 6 h
Yield: 68.7 %

Procedure:
A mixture of 1,1-dichloro-4-methylpenta-1,3-diene (30.2 parts), ethyl bromocyanoacetate (38.4 parts), calcium carbonate (20 parts), cuprous chloride (0.2 part) and calcium chloride (22.2 parts) in ethanol (100 parts by volume) is heated to reflux temperature and held at 78°-84° C. for 6 hours. The ethanol is distilled off under reduced pressure and the residue is stirred with a mixture of toluene (100 parts by volume), water (150 parts) and concentrated hydrochloric acid (100 parts by volume). The mixture is filtered from extraneous matter, the residue is washed with toluene and the filtrate and washings are combined. The toluene layer is separated and washed with water. The crude ethyl 1-cyano-3-(2',2'-dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylate is isolated by removal of the toluene under reduced pressure. The product has a strength of 74.6% and a cis-cyano/trans-cyano ratio of 86.1:13.9. The yield is 68.7%.
Reaction SMILES: Cl.[O:2]1[C:6]2[C:7]([O:11][CH:12]3[CH2:15][NH:14][CH2:13]3)=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[CH:3]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.Cl.[O:47]=[C:48]1[NH:57][C:56]2[N:55]=[CH:54][C:53](/[CH:58]=[CH:59]/[C:60](O)=[O:61])=[CH:52][C:51]=2[CH2:50][CH2:49]1>CN(C)C=O.O.C(OCC)(=O)C>[O:2]1[C:6]2[C:7]([O:11][CH:12]3[CH2:15][N:14]([C:60](=[O:61])/[CH:59]=[CH:58]/[C:53]4[CH:52]=[C:51]5[C:56](=[N:55][CH:54]=4)[NH:57][C:48](=[O:47])[CH2:49][CH2:50]5)[CH2:13]3)=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[CH:3]1
Reactant: c1cc(OC2CNC2)c2occc2c1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCc2cc(/C=C/C(=O)N3CC(Oc4cccc5ccoc45)C3)cnc2N1
Reaction time: 8 h

Procedure:
3-(Benzofuran-7-yloxy)-azetidine hydrochloride (190 mg, 0.84 mmol), EDCI (161 mg, 0.84 mmol), HOBt (113 mg, 0.84 mmol) and diisopropylethylamine (240 μL, 1.40 mmol) were successively added to a solution of (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-acrylic acid hydrochloride (143 mg, 0.56 mmol) in dimethylformamide (14 mL) at room temperature. The reaction mixture was stirred overnight. The reaction mixture was then diluted by addition of ethyl acetate (40 mL) and water (40 mL). The aqueous phase was separated and extracted with ethyl acetate (2×40 mL). The combined organic phases were washed with a saturated solution of sodium chloride (3×40 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel using dichloromethane/methanol (1:0 to 95:5) as eluent. After trituration in diethyl ether and acetone, the title compound was obtained as a white solid (80 mg, 37%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OCCOC)=O)=N\C(OCCOC)=O.[CH2:36]([O:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][C:46]=1[OH:47])[C:42]#[N:43])[CH3:37].[CH2:48]([NH:50][C:51]([C:53]1[CH:54]=[N:55][C:56]([N:59]2[CH2:64][CH2:63][CH2:62][C@H:61](O)[CH2:60]2)=[N:57][CH:58]=1)=[O:52])[CH3:49]>C1COCC1.CCOCC>[C:42]([C:41]1[CH:44]=[CH:45][C:46]([O:47][C@@H:61]2[CH2:62][CH2:63][CH2:64][N:59]([C:56]3[N:57]=[CH:58][C:53]([C:51]([NH:50][CH2:48][CH3:49])=[O:52])=[CH:54][N:55]=3)[CH2:60]2)=[C:39]([O:38][CH2:36][CH3:37])[CH:40]=1)#[N:43]
Reactant: CCOc1cc(C#N)ccc1O
Reactant: CCNC(=O)c1cnc(N2CCC[C@H](O)C2)nc1
Agent: COCCOC(=O)/N=N/C(=O)OCCOC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCNC(=O)c1cnc(N2CCC[C@@H](Oc3ccc(C#N)cc3OCC)C2)nc1
Temperature: 22.5 °C
Reaction time: 16 h

Procedure:
A solution of triphenylphosphine (65 mg, 0.25 mmol) in THF (1 mL) and a solution of bis(2-methoxyethyl) (E)-diazene-1,2-dicarboxylate (56 mg, 0.24 mmol) in THF (1 mL) were added sequentially to a solution of 3-ethoxy-4-hydroxybenzonitrile (26 mg, 0.16 mmol) and (S)—N-ethyl-2-(3-hydroxypiperidin-1-yl)pyrimidine-5-carboxamide (40 mg, 0.16 mmol) in THF (2 mL) at 20-25° C. The reaction mixture was stirred at 20-25° C. for 16 hours. The mixture was diluted with ether (30 mL), and was washed sequentially with aqueous 1N NaOH solution (1 mL) and brine (1 mL). The organic phase was dried over MgSO4, filtered, and concentrated to provide a crude residue, which was purified via preparative HPLC to afford (R)-2-(3-(4-cyano-2-ethoxyphenoxy)piperidin-1-yl)-N-ethylpyrimidine-5-carboxamide. HPLC: Waters XBridge dC18 4.6×50 mm, 5 μm, 95% water/5% acetonitrile linear to 5% water/95% acetonitrile over 4.0 min, 0.03% NH4OH modifier, 2 mL/min; retention time 2.60 min. MS (ES+) 396.1 (M+H).
Reaction SMILES: [Na].[CH2:2]([CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH3:4].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32]>C(O)C>[C:26]1(=[O:27])[N:22]([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:5]([CH2:2][CH2:3][CH3:4])([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:23](=[O:32])[C:24]2=[CH:31][CH:30]=[CH:29][CH:28]=[C:25]12
Reactant: CCCC(C(=O)OCC)C(=O)OCC
Reactant: O=C1c2ccccc2C(=O)N1CCCCCBr
Agent: [Na]
Solvent: CCO
Product: CCCC(CCCCCN1C(=O)c2ccccc2C1=O)(C(=O)OCC)C(=O)OCC
Yield: 41 %

Procedure:
Sodium (0.5 g) was dissolved in ethanol (7 ml) and diethyl propylmalonate (4.4 g) was added to the solution. The resulting mixture was heated under reflux for 15 minutes. To the mixture was added N-(5-bromopentyl)phthalimide (6.4 g) and the mixture was further heated under reflux for 4 hours. Then, ethanol was removed by distillation. The residue was treated with ether and filtered. The filtrate was concentrated and the residue was chromatographed on silica gel column. A fraction eluted with 5% methanol in chloroform was recrystallized from a mixture of ether and hexane to give colorless crystals of diethyl 2-(5-phthalimidopentyl)-2-propylmalonate (m.p. 51°-52° C., yield 3.7 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[CH2:26]([O:33][C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=1B(O)O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[CH2:26]([O:33][C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=1[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Reactant: OB(O)c1ccc(F)cc1OCc1ccccc1
Solvent: CN(C)C=O
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccc(F)cc1OCc1ccccc1

Procedure:
The title compound was prepared in analogy to example 25, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 2-benzyloxy-4-fluorophenylboronic acid (CAS RN 848779-87-3) and using DMF as reaction solvent. Off-white solid (29%). MS (ESI): m/z=549.0 [M+H]+.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[C:15]2[CH:16]=[C:17]([CH:20]=[C:21](Br)[CH:22]=2)[CH:18]=[O:19])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.B1([C:32]2[CH:37]=[CH:36][CH:35]=[N:34][CH:33]=2)OCC(C)(C)CO1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[C:15]2[CH:16]=[C:17]([CH:20]=[C:21]([C:32]4[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=4)[CH:22]=2)[CH:18]=[O:19])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1cc(Br)cc(-c2c3ccccc3cc3ccccc23)c1
Reactant: CC1(C)COB(c2cccnc2)OC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cc(-c2cccnc2)cc(-c2c3ccccc3cc3ccccc23)c1

Procedure:
7.9 g (21.9 mmol) of 3-(anthracen-9-yl)-5-bromobenzaldehyde, 5 g (24.4 mmol of pyridine-3-boronic acid neopentylglycol ester, 0.85 g (3 mol %) of tetrakis(triphenylphosphine) palladium (0), and 5.17 g (48.8 mmol) of sodium carbonate were dissolved in 90 ml of tetrahydrofuran/H2O in a volume ratio of 2/1. The solution was reacted at 80° C. for 12 hours. The acquired reactant was extracted with ethyl acetate and treated under reduced pressure to remove the solvent. The extract was separated through a column, obtaining 7.24 g (Y=91%) of a white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]([NH2:12])[CH:9]=[CH:10][CH:11]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([NH:23][CH2:24][C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([NH:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:29]([NH:12][C:8]3[CH:9]=[CH:10][CH:11]=[C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)[CH:7]=3)=[O:30])=[CH:32][CH:33]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: Nc1cccc(-c2cccs2)c1
Reactant: COc1ccc(NCc2ccc(C(=O)O)cc2)cc1OC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc(NCc2ccc(C(=O)Nc3cccc(-c4cccs4)c3)cc2)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 24.9 %

Procedure:
To a stirred solution of 31 (122 mg, 0.696 mmol), acid 4 (182 mg, 0.633 mmol) and BOP (308 mg, 0.696 mmol) in DMF (4 ml) was added B3N (265 μl, 1.90 mmol). The reaction was stirred 3 h at room temperature under nitrogen, quenched with H2O and evaporated. The residue was extracted with ethyl acetate, washed with saturated solutions of NH4Cl, NaHCO3 and brine. The organic layer was dried over anhydrous MgSO4 and concentrated in vacuum to form a material which was purified by flash chromatography (eluent 40% EtOAc in hexane) to give the title compound 32 (70 mg, 25%) as a yellow solid. 1H NMR: (DMSO) δ (ppm): 10.25 (s, 1H), 8.09-8.08 (m, 1H), 7.73 (ddd, J=7.6, 3.7, 3.7 Hz, 1H), 7.54 (dd, J=5.1, 1.0 Hz, 1H), 7.49 (d, J=8.2 Hz, 2H), 7.45 (dd, J=3.7, 1.2 Hz, 1H), 7.42-7.32 (m, 2H), 7.13 (dd, J=5.1, 3.7 Hz, 1H), 6.64 (d, J=8.6 Hz, 1H), 6.31 (d, J=2.5 Hz, 1H), 6.00-5.97 (m, 2H), 4.31 (d, J=6.1 Hz, 2H), 3.65 (s, 3H), 3.59 (s, 3H). MS: (calc), 444.2; (obt.) 445.5 (MH)+.
Reaction SMILES: S(=O)(=O)(O)O.[CH:6]([OH:15])([C:11]([F:14])([F:13])[F:12])[C:7]([F:10])([F:9])[F:8].C[O:17][CH:18](O)[C:19]([F:22])([F:21])[F:20]>>[C:19]([CH:18]([O:15][CH:6]([C:11]([F:14])([F:13])[F:12])[C:7]([F:10])([F:9])[F:8])[OH:17])([F:22])([F:21])[F:20]
Reactant: COC(O)C(F)(F)F
Reactant: OC(C(F)(F)F)C(F)(F)F
Agent: O=S(=O)(O)O
Product: OC(OC(C(F)(F)F)C(F)(F)F)C(F)(F)F
Temperature: 0 °C

Procedure:
This reaction was carried out in essentially the same manner as described in Example 1 using charges of sulfuric acid (175 g), (CF3)2CHOH (70.6 g, 0.42 mole, Synquest Labs) and trifluoroacetaldehyde methyl hemiacetal (Alfa Aesar, 50 g, 90% purity, 0.346 mole). In this case the receiver was cooled in an ice water bath to about 0° C. to avoid solidification of the alcohol. The receiver had gained 8.6 g in weight and this solution was used without purification in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.C(=O)(O)[O-].[Na+].Br[CH2:15][C:16]([C:18]1[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=1)=O>C(O)C>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:15]=[C:16]([C:18]3[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=3)[N:1]=2)[CH:4]=1
Reactant: Cc1ccc(N)nc1
Reactant: CCOC(=O)c1ccc(C(=O)CBr)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1ccc(-c2cn3cc(C)ccc3n2)cc1
Reaction time: 19 h

Procedure:
67 g (0.62 mole) of 2-amino-5-methylpyridine, 86 g (1.02 mole) of sodium bicarbonate and 143 g (0.527 mole) of ethyl 4-(2-bromoacetyl)benzoate are introduced into 1 l of ethanol. The mixture is brought to reflux for 3 hours and left standing for 19 hours, and the solid formed is recovered by filtration, washed copiously with water and dried. It is recrystallized in a dichloromethane/methanol mixture. M.p. 228°-230° C.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:4]1.C(N(CC)CC)C.ClCCl.Cl[S:24]([C:27]1[CH:28]=[C:29]([CH:39]=[CH:40][CH:41]=1)[C:30]([O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])=[O:31])(=[O:26])=[O:25]>N1C=CC=CC=1>[CH3:12][O:11][C:9]([C@H:6]1[CH2:5][CH2:4][C@H:3]([NH:2][S:24]([C:27]2[CH:28]=[C:29]([CH:39]=[CH:40][CH:41]=2)[C:30]([O:32][CH2:33][CH2:34][Si:35]([CH3:36])([CH3:37])[CH3:38])=[O:31])(=[O:25])=[O:26])[CH2:8][CH2:7]1)=[O:10]
Reactant: C[Si](C)(C)CCOC(=O)c1cccc(S(=O)(=O)Cl)c1
Reactant: COC(=O)[C@H]1CC[C@H](N)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: COC(=O)[C@H]1CC[C@H](NS(=O)(=O)c2cccc(C(=O)OCC[Si](C)(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 604 mg of methyl trans-4-aminocyclohexane carboxylate hydrochloride, 0.90 mL of triethylamine, and 10 mL of dichloromethane was stirred at room temperature for 30 minutes, and 10 mL of pyridine and 1.00 g of 2-(trimethylsilyl)ethyl 3-(chlorosulfonyl)benzoate were added thereto in this order, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and to the residue was added an aqueous citric acid solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 1.27 g of 2-(trimethylsilyl)ethyl 3-{[trans-4-(methoxycarbonyl)cyclohexyl]sulfamoyl}benzoate as a colorless oily substance.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.FC(F)(F)C(O)=O.[CH2:39]([O:41][C:42](=[O:58])[N:43]([CH3:57])[NH:44][C:45](=[O:56])[C@@H:46]1[CH2:50][CH2:49][CH2:48][N:47]1[C:51](=[O:55])[C@H:52]([CH3:54])[NH2:53])[CH3:40]>O1CCCC1.C(Cl)(Cl)Cl>[CH2:39]([O:41][C:42](=[O:58])[N:43]([CH3:57])[NH:44][C:45](=[O:56])[C@@H:46]1[CH2:50][CH2:49][CH2:48][N:47]1[C:51](=[O:55])[C@H:52]([CH3:54])[NH:53][C:14](=[O:16])[C@H:12]([CH3:13])[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[CH3:40]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCOC(=O)N(C)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)N
Agent: CC(C)COC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)N(C)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OCc1ccccc1
Reaction time: 0.17 h

Procedure:
To a solution of 0.005 mole of carbobenzyloxyalanine in 100 ml of dry tetrahydrofuran which has been cooled to -20° to -30° is added 1 ml of N-methylmorpholine and then 1 ml of isobutyl-chloroformate. After stirring for 10 minutes there is added 0.005 mole of alanylprolyl-2-azaalanine ethyl ester trifluoroacetic acid salt, 60 ml of chloroform and 1 ml of N-methylmorpholine. The reaction mixture is stirred overnight at room temperature, concentrated in vacuo, the residue treated with ethylacetate and the insoluble material removed by filtration. The filtrate is concentrated in vacuo and the residue chromatographed on a silica gel. Elution with ethyl acetate gives carbobenzyloxyalanylalanylprolyl-2-azaalanine ethyl ester.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.[Cl:24][C:25]1[CH:26]=[C:27]([OH:32])[CH:28]=[CH:29][C:30]=1[CH3:31]>>[Cl:23][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:32][C:27]2[CH:28]=[CH:29][C:30]([CH3:31])=[C:25]([Cl:24])[CH:26]=2)=[N:3][CH:4]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cl)cc1
Reactant: Cc1ccc(O)cc1Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Oc2ccc(C)c(Cl)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from methyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 48) and 3-chloro-4-methylphenol: 1H-NMR (CDCl3) δ 8.54 (1H, d, J=2.6 Hz), 8.15 (1H, d, J=2.6 Hz), 8.07 (1H, d, J=7.3 Hz), 8.01 (2H, d, J=8.4 Hz), 7.43 (2H, d, J=8.4 Hz), 7.32 (1H, d, J=8.4 Hz), 7.20 (1H, d, J=2.5 Hz), 6.97 (1H, dd, J=8.4, 2.5 Hz), 5.37 (1H, dq, J=7.3, 7.1 Hz), 3.91 (3H, s), 2.41 (3H, s), 1.59 (3H, d, J=7.1 Hz); MS (ESI) m/z 459 (M+H)+, 457 (M−H)−.