Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1([CH3:22])[O:9][C:8](=[O:10])[NH:7][C:6]2[CH:11]=[CH:12][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)=[CH:14][C:5]1=2)[CH:2]=[CH2:3].ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[CH2:1]([C:4]1([CH3:22])[O:9][C:8](=[O:10])[NH:7][C:6]2[CH:11]=[CH:12][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)=[CH:14][C:5]1=2)[C:2]1[CH:3]=[CH:2][CH:1]=[CH:4][CH:3]=1
Reactant: C=CCC1(C)OC(=O)Nc2ccc(-c3cccc(Cl)c3)cc21
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CC1(Cc2ccccc2)OC(=O)Nc2ccc(-c3cccc(Cl)c3)cc21
Reaction time: 0.17 h
Yield: 58.9 %

Procedure:
A mixture of 1-(4-amino-3′-chloro-biphenyl-3-yl)-1-benzyl-ethanol (prepared from 1-(4-amino-3′-chloro-biphenyl-3-yl)-ethanone and benzylmagnesium bromide according to Procedure C, 0.14 g, 0.42 mmol) and triphosgene (0.04 g, 0.14 mmol) in dry THF (10 mL) was stirred under a blanket of nitrogen for 10 minutes. Upon completion of the reaction, the THF was removed and the residue purified via flash chromatography (silica gel, 35% ethyl acetate/hexane) to give 4-benzyl-6-(3-chloro-phenyl)-4-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one (0.045 g, 30%) as an off-white solid: mp 187-188° C.; 1H-NMR (DMSO-d6) δ10.1 (s, 1H), 7.70 (t, 1H, J=2.3 Hz), 7.6 (d, 1H, J=8.0 Hz), 7.58-7.53 (m, 2H), 7.46 (t, 1H, J=8.0 Hz), 7.38 (d, 1H, J=8.0 Hz), 7.22-7.17 (m, 3H), 7.06-7.0 (m, 2H), 6.84 (d, 1H, J=9.14 Hz), 3.24 (d, 1H, J=14.3 Hz), 3.06 (d, 1H, J=14.3 Hz), 1.68 (s, 3H); MS (ESI) m/z 364 ([M+H]+, 100%); Anal. Calc. For C22H18ClNO2: C,72.63; H, 4.99; N, 3.85. Found: C, 71.82; H,5.09; N,3.58.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([Cl:9])[C:7]=1F.[F:14][C:15]1[CH:23]=[C:22]2[C:18]([CH:19]=[CH:20][NH:21]2)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[N:21]1[C:22]2[C:18](=[CH:17][CH:16]=[C:15]([F:14])[CH:23]=2)[CH:19]=[CH:20]1
Reactant: Fc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: Fc1ccc2cc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc2ccn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)c2c1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
To a solution of 3,5-dichloro-4-fluorobenzotrifluoride (34.5 g) in dimethylformamide (250 ml) was added 6-fluoroindole (34.5 g) and potassium carbonate (20.4 g). The mixture was heated at 90° C. for 6 hours and then left to stir for 16 hours at room temperature. The reaction was diluted with water (1000 ml) and extracted with hexane (1000 ml). The organic fraction was separated and evaporated to dryness to give the title compound as a colourless liquid. δ(CDCl3): 7.80 (2H,s), 7.62 (1H,dd), 7.20 (1H,d), 6.96 (1H,dt), 6.76 (1H,d), 6.62 (1H,dd.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([N:21]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH2:22]3)=[O:20])=[CH:15][CH:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[C:35]1C=CC(C(N2CCC(C3C=NC=CC=3)C2)=O)=[CH:37][C:36]=1[O:54]C(C)C>>[CH:36]([O:54][C:14]1[CH:15]=[C:16]([C:19]([N:21]2[CH2:25][CH2:24][CH:23]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[CH2:22]2)=[O:20])[CH:17]=[CH:18][C:13]=1[C:5]1[CH:4]=[C:3]([C:2]([F:1])([F:32])[F:33])[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=1)([CH3:37])[CH3:35]
Reactant: CC(C)Oc1cc(C(=O)N2CCC(c3cccnc3)C2)ccc1Br
Reactant: O=C(c1ccc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1)N1CCC(c2cccnc2)C1
Product: CC(C)Oc1cc(C(=O)N2CCC(c3cccnc3)C2)ccc1-c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
Compound 5b was prepared following procedures similar to those described for the preparation of compound 1a, substituting 5a for i-21a. m/z (ES) 523 (MH)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([C:9]1[CH:10]=[C:11]([CH:15]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=2)[CH2:16][C:17]([OH:19])=O)[CH:12]=[CH:13][CH:14]=1)#[N:8].[CH3:30][NH2:31].Cl>C(Cl)Cl.O.C(OCC)(=O)C>[C:28]([C:25]1[CH:24]=[CH:23][C:22]([CH2:21][CH2:20][CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([C:7]#[N:8])[CH:10]=2)[CH2:16][C:17]([NH:31][CH3:30])=[O:19])=[CH:27][CH:26]=1)#[N:29]
Reactant: CN
Reactant: N#Cc1ccc(CCC(CC(=O)O)c2cccc(C#N)c2)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: CNC(=O)CC(CCc1ccc(C#N)cc1)c1cccc(C#N)c1
Reaction time: 2 h
Yield: 46 %

Procedure:
Part A. Oxalyl chloride was added to a solution of 3-(3-cyanophenyl)-5-(4-cyanophenyl)pentanoic acid (0.25 gm, 0.82 mmol) in 10 mLs methylene chloride under a nitrogen atmosphere at ambient temperature. The reaction was stirred for 2 hrs and was concentrated in vacuo to give a semi solid residue. The residue was taken up in 5 mLs methylene chloride and 40% methyl amine in water (5 mLs) was added. The reaction was stirred vigorously for 2 hrs and then was partioned between 1N HCl and ethyl acetate. The organic layer was washed with water, brine dried over magnesium sulfate and concentrated to give the crude product as a semisolid. The residue was purified by flash chromatography on silica gel (100 mLs) eluting methylene chloride:ethyl acetate (v:v, 80:20) to give 4-(cyano)-beta-(3-cyanophenyl)-N-methylbenzenepentanamide as a semisolid 0.120 gm (46%) MS 335(M+NH4) 1H NMR (CDCl3): 7.6-7.4(m, 6H), 7.17(d, 2H), 5.3(m, 1H), 3.27(m, 1H), 2.67(d, 2H), 2.55-2.35(m, 4H), 2.07(m, 1H), 1.95(m, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[C:21]([CH3:24])[S:22][CH:23]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[N:28]1([C:33]2[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=2)[CH:32]=[CH:31][CH:30]=[N:29]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(Cl)Cl.N.CN(C=O)C>[N:28]1([C:33]2[CH:40]=[CH:39][C:36]([C:37]3[NH:8][C:5]4=[N:6][CH:7]=[C:2]([Br:1])[C:3]([N:12]5[CH2:17][CH2:16][N:15]([CH2:18][C:19]6[N:20]=[C:21]([CH3:24])[S:22][CH:23]=6)[CH2:14][CH2:13]5)=[C:4]4[N:9]=3)=[CH:35][CH:34]=2)[CH:32]=[CH:31][CH:30]=[N:29]1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: Cc1nc(CN2CCN(c3c(Br)cnc(N)c3[N+](=O)[O-])CC2)cs1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nc(CN2CCN(c3c(Br)cnc4[nH]c(-c5ccc(-n6cccn6)cc5)nc34)CC2)cs1
Temperature: 85 °C
Yield: 24.9 %

Procedure:
To a mixture of 5-bromo-4-(4-((2-methylthiazol-4-yl)methyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.050 g, 0.12 mmol), EtOH (2.3 mL) and DMF (0.2 mL), 4-(1H-pyrazol-1-yl)-benzaldehyde (0.023 g, 0.13 mmol) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.36 mL, 0.36 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH v/v 96:4 to give the title compound as a off-white solid (0.016 g, 25%); 1H-NMR (500 Mz, DMSO-d6): δ 2.63-2.71 (m, 7H), 3.65 (s, 2H, NCH2), 3.66-3.72 (m, 4H), 6.59-6.62 (m, 1H), 7.33 (s, 1H, thiazole 5-H), 7.81 (d, J=2.0 Hz, 1H), 8.03 (d, J=9.0 Hz, 2H, ArH, C6H4), 8.25 (s, 1H, imidazo[4,5-b]pyridine 5-H), 8.30 (d, J=8.5 Hz, 2H, ArH, C6H4), 8.61 (d, J=2.5 Hz, 1H), 13.54 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z) 3.41 min—535/537 [(M+H)+, Br isotopic pattern]. ESI-HRMS: Found: 535.1028, calculated for C24H24BrN8S (M+H)+: 535.1039.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]([CH2:13][OH:14])[CH2:11][OH:12])=[CH:4][CH:3]=1.[C:15](OC)(=[O:17])[CH3:16]>>[C:15]([O:14][CH2:13][C@@H:10]([CH2:11][OH:12])[CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)(=[O:17])[CH3:16]
Reactant: COC(C)=O
Reactant: OCC(CO)CCc1ccc(Br)cc1
Product: CC(=O)OC[C@@H](CO)CCc1ccc(Br)cc1

Procedure:
To a solution of 4.6 g of 4-(4-bromophenyl)-2-(hydroxymethyl)butanol in 300 ml of methyl acetate was added 33.1 g of the above PPL preparation. The mixture was stirred while the progress of the reaction was monitored by HPLC method A. When the consumption of diol was complete, the mixture was immediately filtered and the filtrate was concentrated to an oil under vacuum. The oil was purified by flash chromatography on 200 g of silica with 3:1 ethyl acetate: hexane to obtain 4.82 g of the desired product as an oil. The 1-naphthyl carbamate derivative of a small portion of the product was prepared and analyzed by HPLC method B to determine that the product was 99% R and 1% S; the R isomer eluted at 9.4 minutes, and the S isomer at 12.6 minutes.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:7])[NH:5][CH:6]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:12](Cl)(=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>[N+](C1C=CC=CC=1)([O-])=O>[CH3:1][C:2]1[NH:3][C:4](=[O:7])[NH:5][C:6]=1[C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: Cc1c[nH]c(=O)[nH]1
Reactant: CCCCCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: CCCCCC(=O)c1[nH]c(=O)[nH]c1C
Temperature: 75 °C
Reaction time: 5 h
Yield: 31 %

Procedure:
A flask equipped with mechanical stirrer, reflux condenser and nitrogen inlet, was charged with 5.0 g (0.051 mol) of 4-methyl-4-imidazolin-2-one in 40 ml of nitrobenzene and cooled to ice-bath temperature. Aluminum chloride (27.1 g, 0.204 mol) was added portionwise. The reaction was heated to 75° C. and 7.55 g (0.056 mol) of hexanoyl chloride was added dropwise over 1 hour. Heating was continued for an additional 5 hours whereupon all starting material had been consumed as evidenced by tlc analysis (silica gel, methanol/ethyl acetate 1:4, phosphomolybdic acid visualization). The reaction was poured onto 100 ml of ice containing 7.5 g of sodium carbonate dissolved in 25 ml of water. The reaction mixture was stirred rapidly while 100 ml of ether were added. The resulting solids were isolated by filtration to afford after drying 5.2 g of crude ketone. The crude solids were recrystallized from 50 ml of water/ethanol 1:1 to afford 3.1 g (31%) of homogeneous title product; m.p. 221°-223° C.; IR (KBr) cm-1 : 3178 (s), 3153 (s), 3106 (s), 1746 (s), 1714 (s), 1657 (s), 1644 (s), 1611 (s); 1H-NMR (DMSO-d6): 10.17 (s, 2, N--H), 2.5 (m), 2.27 (s, 3), 1.34 (m, 6), 0.86 (t, 3); 13C-NMR (DMSO-d6): 188.5, 152.4, 118.9, 129.4, 38.8, 31.0, 23.4, 22.0, 13.8, 11.7; mass spectrum (70 eV) m/e 196 (parent), 140 (C6H8N2O2, base), 125 (C5H5N2O2).
Reaction SMILES: [NH:1]([CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:2]([NH2:4])=[S:3].C([O-])(=O)C.[Na+].Br[CH:22]([CH:25]=O)[CH:23]=[O:24]>C1COCC1.C(O)(=O)C>[CH:23]([C:22]1[S:3][C:2]([NH:1][CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[N:4][CH:25]=1)=[O:24]
Reactant: CC(C)(C)OC(=O)NCCCNC(N)=S
Reactant: O=CC(Br)C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCNc1ncc(C=O)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 33 %

Procedure:
To a solution of material from Example 59 (3.4 g, 10.20 mmol) in a mixture of THF (30 mL) and acetic acid (5.00 mL) is added sodium acetate (1.004 g, 12.24 mmol) followed by 2-bromomalonaldehyde (1.540 g, 10.20 mmol). The resulting mixture is stirred at room temp for 18 h, then filtered thru a ground glass frit and the filtrate is concentrated in vacuo. The resulting residue treated with EtOAc, filtered thru a ground glass frit and the filtrate is extracted with sodium bicarbonate, water, brine, dried over Na2SO4, filtered and evaporated to dryness. The residue is purified by BIOTAGE® Silica gel chromatography on an 80 g Thompson Single Step silica cartridge using a linear gradient from 30% EtOAc/hexanes to 100% EtOAc over 11.25 column volumes to give 960 mg (29.7%) of the title compound as a yellow solid. LC/MS (Condition A): ret. T=2.92 min, (M+Na)+ 308.13. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.64 (1 H, s), 8.83-8.98 (1 H, m), 8.06 (1 H, s), 6.89 (1 H, t, J=5.40 Hz), 3.31 (2 H, d, J=5.27 Hz), 2.99 (2 H, q, J=6.69 Hz), 1.69 (2 H, t, J=7.03 Hz), 1.39 (9 H, s).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:17]1([S:23]([NH:26][C:27](=[O:49])[C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[C:30]([NH:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)=[CH:39][CH:38]=3)[CH:29]=2)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])O.[K+]>CN(C)C=O>[C:17]1([S:23]([NH:26][C:27](=[O:49])[C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:8](=[O:15])[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:30]([NH:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)=[CH:39][CH:38]=3)[CH:29]=2)(=[O:24])=[O:25])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc(C(=O)NS(=O)(=O)c2ccccc2)cc1NCc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(=O)NS(=O)(=O)c2ccccc2)cc1NCc1ccc(-c2ccccc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 64 %

Procedure:
Triethylamine (0.115 g) and 0.200 g of benzoyl chloride were added to a solution of 0.500 g of N-benzenesulfonyl-4-amino-3-(biphenyl-4-ylmethylamino)benzamide in 5 ml of N,N-dimethylformamide. The mixture was stirred at room temperature for 15 hours. A potassium hydrogencarbonate aqueous solution was added thereto to stop the reaction. The solvent was distilled off under reduced pressure. The residue was dissolved in a mixture of water and methanol, and the solution was adjusted to a pH of from 5 to 6 with 10% hydrochloric acid. The crystals precipitated were collected, and were dried to obtain 0.393 g of crude N-benzenesulfonyl-4-benzoylamino-3-(biphenyl-4-ylmethylamino)benzamide. This crude product was converted to 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-phenylbenzimidazole [(246), 0.270 g] in the same manner as in Example 183.
Reaction SMILES: C([O-])(C)C.[NH2:5][C:6]1[N:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[C:7]=1[C:8](NNS(C1C=CC=CC=1)(=O)=O)=[O:9].C(O)CO.C(=O)([O-])[O-].[Na+].[Na+].O>C(Cl)(Cl)Cl>[NH2:5][C:6]1[N:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[C:7]=1[CH:8]=[O:9]
Reactant: Cc1cc(C)c(C(=O)NNS(=O)(=O)c2ccccc2)c(N)n1
Agent: CC(C)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: OCCO
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)c(C=O)c(N)n1
Temperature: 160 °C

Procedure:
N1 -(2-amino-4,6-dimethylnicotinoyl)-N2 -benzenesulfonyl hydrazine isopropanolate (62.0 g., 0.163 mole) is divided into two portions. To each portion, ethylene glycol (300 ml.) is added and the mixture heated to 160° C. prior to the addition of anhydrous sodium carbonate (30 g.) in one portion with vigorous stirring. The mixture is allowed to cool and then is poured into water. The two runs are combined and the product isolated by extraction with chloroform. Following recrystallization from carbon tetrachloride the product melts at 152°-158° C. Further recrystallization from the same solvent raises the melting point to 162°-166° C.
Reaction SMILES: C(OCC)(=O)C.[OH:7][C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[NH:11][C:12](=[O:15])[CH:13]=[CH2:14].[CH2:19]([N:37]=[C:38]=[O:39])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>C(N(CC)CC)C>[CH2:19]([NH:37][C:38]([O:7][C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[NH:11][C:12](=[O:15])[CH:13]=[CH2:14])=[O:39])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: C=CC(=O)Nc1cccc(O)c1
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1cccc(OC(=O)NCCCCCCCCCCCCCCCCCC)c1
Temperature: 20 °C

Procedure:
A reaction vessel is charged with 100 parts of ethyl acetate, 16.3 parts of 3'-hydroxyacrylanilide, 29.5 parts of octadecyl isocyanate and one part of triethylamine. The reaction mixture is heated at reflux for about 1 hour, cooled to 20°C and filtered. The solids are washed with ethyl acetate and air dried to give 40.5 parts of 3'-(octadecylcarbamoyloxy)acrylanilide, m.p. 124°-126°C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.[C:22]([OH:25])(=[O:24])[CH3:23].C([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][C:29]1=O)C>>[Cl:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[C:29]3[CH:30]([CH2:23][C:22]([OH:25])=[O:24])[CH2:31][CH2:32][CH2:33][C:28]=3[C:15]3[C:10]2=[CH:11][CH:12]=[C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:14]=3)=[CH:5][CH:4]=1
Reactant: CCC1CCCCC1=O
Reactant: CC(=O)O
Reactant: CC(C)(C)c1ccc(N(N)Cc2ccc(Cl)cc2)cc1
Agent: Cl
Product: CC(C)(C)c1ccc2c(c1)c1c(n2Cc2ccc(Cl)cc2)C(CC(=O)O)CCC1

Procedure:
Following the procedure of Example 1, but using 1-(4-chlorobenzyl)-1-(4-tert-butylphenyl)hydrazine hydrochloride and ethyl2-cyclohexanone acetate as starting materials, the title compound was prepared.
Reaction SMILES: [CH:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]([OH:16])=O)=[C:6]1[CH3:17])([CH2:3][CH3:4])[CH3:2].C1C=C2N=NN(O)C2=CC=1.N.C(N(CC)CC)C.[NH2:36][CH2:37][C:38]1[C:39]([OH:46])=[N:40][C:41]([CH3:45])=[CH:42][C:43]=1[CH3:44]>ClCCl>[CH:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]([NH:36][CH2:37][C:38]2[C:39]([OH:46])=[N:40][C:41]([CH3:45])=[CH:42][C:43]=2[CH3:44])=[O:16])=[C:6]1[CH3:17])([CH2:3][CH3:4])[CH3:2]
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: CCC(C)n1c(C)c(C(=O)O)c2ccccc21
Agent: N
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(C)n1c(C)c(C(=O)NCc2c(C)cc(C)nc2O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.1 %

Procedure:
A mixture of 1-sec-butyl-2-methyl-1H-indole-3-carboxylic acid (97 mg, 0.42 mmol), 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (121 mg, 0.63 mmol), N-hydroxybenzotrizole (85 mg, 0.63 mmol) and triethylamine (127.26 mg, 1.26 mmol) in dichloromethane (30 mL) was stirred for 30 minutes at room temperature. Then to the mixture, 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (63.8 mg, 0.42 mmol) was added. The resulting mixture was stirred at room temperature for 12 hours. Then the mixture was washed with water (20 mL×3). The organic layer was concentrated to give a residue which was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give 1-sec-butyl-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-2-methyl-1H-indole-3-carboxamide (57 mg, 30%). LRMS (M+H+) m/z: calcd 365.2. found 365. HPLC purity (214 nm): 99%. 1H.NMR (300 MHz, CD3OD): δ 7.72-7.69 (m, 1H), 7.53 (d, J=7.2 Hz, 1H), 7.11-7.06 (m, 2H), 6.10 (s, 1H), 4.53-4.51 (m, 3H), 2.62 (s, 3H), 2.41 (s, 3H), 2.24 (s, 3H), 1.95-1.93 (m, 2H), 1.59 (d, J=6.9 Hz, 3H), 0.72 (t, J=7.5 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH2:11][CH2:12][NH:13]C(=O)OC)=[CH:4][CH:3]=1.[OH-].[K+].O.NN>C(O)CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][O:10][CH2:11][CH2:12][NH2:13])=[CH:6][CH:7]=1
Reactant: COC(=O)NCCOCCc1ccc(F)cc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: NCCOCCc1ccc(F)cc1
Temperature: 25 °C

Procedure:
The product of step d) (8.0 g) was dissolved in ethylene glycol and to this was added potassium hydroxide (48 g) and hydrazine hydrate (8.3 ml). The stirred mixture was heated to 140° for 4 hours then allowed to cool to room temperature overnight. The mixture was then diluted with water and extracted with diethyl ether (×3). The combined organic extracts were washed with brine, dried (MgOS4) and filtered. The volatiles were removed in vacuo to give the subtitle compound (5.36 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH:9]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=2)[C:10]([F:13])([F:12])[F:11])[N:5]=[CH:4]N=1.B([C:25]1[CH:36]=[CH:35][C:28]([CH2:29][C@@H:30]([C:32]([OH:34])=[O:33])[NH2:31])=[CH:27][CH:26]=1)(O)O.[C:37](#N)C.C(=O)([O-])[O-].[Na+].[Na+]>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.O>[NH2:31][CH:30]([CH2:29][C:28]1[CH:35]=[CH:36][C:25]([C:2]2[CH:7]=[C:6]([O:8][CH:9]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=3)[C:10]([F:13])([F:12])[F:11])[N:5]=[CH:4][CH:37]=2)=[CH:26][CH:27]=1)[C:32]([OH:34])=[O:33]
Reactant: N[C@@H](Cc1ccc(B(O)O)cc1)C(=O)O
Reactant: Fc1ccc(C(Oc2cc(Cl)ncn2)C(F)(F)F)cc1F
Reactant: CC#N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: NC(Cc1ccc(-c2ccnc(OC(c3ccc(F)c(F)c3)C(F)(F)F)c2)cc1)C(=O)O
Temperature: 150 °C
Yield: 21 %

Procedure:
An Emrys process vial (2-5 ml) for microwave was charged with 4-chloro-6-[1-(3,4-difluoro-phenyl)-2,2,2-trifluoro-ethoxy]-pyrimidine (33 mg, 0.1 mmol), 4-borono-L-phenylalanine (31 mg, 0.15 mmol), 1 ml of acetonitrile and 0.7 ml of water. Aqueous sodium carbonate (0.3 ml, 1M) was added to above solution followed by 5 mol % of dichlorobis(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated to 150° C. for 5 minutes by microwave. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol, then purified with Prep-LC to give 10 mg of 2-amino-3-(4-{6-[1-(3,4-difluoro-phenyl)-2,2,2-trifluoro-ethoxy]-pyridin-4-yl}-phenyl)-propionic acid, yield 21%. 1H-NMR (400 MHz, CD3OD): δ 3.11 (m, 1H), 3.27 (m, 1H), 4.19 (dd, 1H), 6.78 (q, 1H), 7.26 (m, 2H), 7.35 (d, 3H), 7.49 (m, 2H), 8.02 (d, 2H), 8.66 (s, 1H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[I:8].[CH3:9][Si:10]([C:13]#[CH:14])([CH3:12])[CH3:11]>>[CH3:9][Si:10]([CH3:12])([CH3:11])[C:13]#[C:14][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[I:8]
Reactant: Ic1ccccc1I
Reactant: C#C[Si](C)(C)C
Product: C[Si](C)(C)C#Cc1ccccc1I
Yield: 54 %

Procedure:
The title compound was synthesized as a yellow oil in 54% yield using 1,2-diiodobenzene and (trimethylsilyl)acetylene as the starting materials according to Method A of the above-described General Synthesis Procedures I.
Reaction SMILES: F[C:2]1(F)[O:6][C:5]2[CH:7]=CC=CC=2[O:3]1.C([Li])CCC.C[N:18]([CH2:20][CH2:21]N(C)C)C.[O:25]1[CH2:29]C[CH2:27][CH2:26]1>>[CH2:5]([O:6][C:2](=[O:3])[C:21](=[CH:29][O:25][CH2:26][CH3:27])[C:20]#[N:18])[CH3:7]
Reactant: CN(C)CCN(C)C
Reactant: FC1(F)Oc2ccccc2O1
Reactant: C1CCOC1
Agent: [Li]CCCC
Product: CCOC=C(C#N)C(=O)OCC

Procedure:
7.9 g (50 mmol) of 2,2-difluoro-1,3-benzodioxole are metellated according to Example 2 at -15° C. with 35 ml (55 mmol) of n-butyllithium (1.60M in hexane) and 6.5 g (55 mmol) of TMEDA in 60 ml of boxate. To the 2,2-difluoro-1,3-benzodioxol-4-yllithium which precipitates there is added at -20° C., over a period of 30 minutes, a solution of 9.3 g (55 mmol) of ethoxymethylenecyanoacetic acid ethyl ester in 30 ml of tetrahydrofuran, an orange-red turbid solution being formed during the reaction, which is exothermic. After stirring for 20 minutes at -15° C., the solution is hydrolysed with 50 ml of 2N hydrochloric acid. The aqueous phase is extracted twice with 80 ml of diethyl ether each time. The organic solutions are washed twice with 50 ml of water each time, dried over MgSO4 and concentrated to dryness by evaporation in a vacuum rotary evaporator. The residue is crystallised from ethanol/water 4:1, affording 10.1 g (72%) of colourless platelets of m.p. 87°-88° C.