Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([C:13]2[CH:14]=[N:15][NH:16][CH:17]=2)[C:5]([O:11][CH3:12])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[H-].[Na+].Cl[CH2:22][C:23]#[N:24]>CN(C)C=O>[C:8]([C:6]1[C:5]([O:11][CH3:12])=[C:4]([C:13]2[CH:17]=[N:16][N:15]([CH2:22][C:23]#[N:24])[CH:14]=2)[C:3]([CH3:18])=[C:2]([Cl:1])[CH:7]=1)(=[O:10])[CH3:9]
Reactant: N#CCCl
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1-c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c(C(C)=O)cc(Cl)c(C)c1-c1cnn(CC#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.2 %

Procedure:
To a solution of 1-[5-chloro-2-methoxy-4-methyl-3-(1H-pyrazol-4-yl)phenyl]ethanone (0.13 g, 0.49 mmol) in N,N-dimethylformamide (2 mL) was added sodium hydride (60% in oil, 0.014 g, 0.59 mmol) at 0° C. The mixture was stirred for 1 hour at room temperature, followed by the addition of chloroacetonitrile (0.037 mL, 0.59 mmol) at 0° C. The reaction was stirred at room temperature for 1 hour, quenched with water and extracted with ethyl acetate. The organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified on silica gel (eluting with 0-40% of ethyl acetate in hexanes) to afford the desired product (0.1 g, 67%). LCMS calculated for C15H15ClN3O2 (M+H)+: m/z=304.1. found: 304.1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH2:21][CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH:17]=[C:16](Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:28])[CH3:2].[C:30]1([C:36]#[CH:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(OC(=O)COC1C=CC(SC2C=C(C#CC3C=CC(CO)=CC=3)C=C(OCCC3C=CC(Cl)=CC=3)C=2)=CC=1C)C>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:15]=[C:16]([C:37]#[C:36][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:17]=[C:18]([O:20][CH2:21][CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH:19]=2)=[CH:9][C:8]=1[CH3:28])[CH3:2]
Reactant: C#Cc1ccccc1
Reactant: CCOC(=O)COc1ccc(Sc2cc(Br)cc(OCC(CC)CC)c2)cc1C
Agent: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(CO)cc3)cc(OCCc3ccc(Cl)cc3)c2)cc1C
Product: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccccc3)cc(OCC(CC)CC)c2)cc1C

Procedure:
The title product was prepared from {4-[3-Bromo-5-(2-ethyl-butoxy)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (200 mg; 0.42 mmol), (phenyl acetylene (170 mg; 1.66 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 170 mg (82%). HPLC-MS: m/z: 502.9 (M)+; Rt: 3.32 min.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][C:19]1([CH3:25])[CH3:24])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CCN(C(C)C)C(C)C.[Cl:35][C:36]1[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=1)[C:39](Cl)=[O:40]>CCOC(C)=O>[CH2:8]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:39](=[O:40])[C:38]2[CH:42]=[CH:43][CH:44]=[C:36]([Cl:35])[CH:37]=2)[CH2:20][C:19]1([CH3:25])[CH3:24])=[O:17])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: CC1(C)CNCCN1C(=O)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CC1(C)CN(C(=O)c2cccc(Cl)c2)CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3.00 g (8.28 mmol) 2,2-dimethyl-piperazine-1-carboxylic acid benzyl ester trifluoroacetate in 50 mL EtOAc was added 3.50 mL (20.3 mmol) DIPEA followed by 1.07 mL (8.28 mmol) 3-chloro-benzoyl chloride dropwise at RT. The reaction mixture was stirred at RT for 1 h. Then the suspension was washed with water. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][CH:19]=2)=[N:9][S:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)=O.O[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])=[C:29]([CH3:40])[C:28]=1[CH3:41]>>[CH2:24]([C:21]1[CH:22]=[CH:23][C:18]([C:8]2[C:7]([CH2:6][O:5][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[C:29]([CH3:40])[C:28]=3[CH3:41])=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[S:10][N:9]=2)=[CH:19][CH:20]=1)[CH3:25]
Reactant: CCc1ccc(-c2nsc(-c3ccccc3)c2COS(C)(=O)=O)cc1
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Product: CCc1ccc(-c2nsc(-c3ccccc3)c2COc2ccc(CCC(=O)O)c(C)c2C)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 1 following Steps 2-6 by coupling of (3-(4-ethylphenyl)-5-phenylisothiazol-4-yl)methyl methanesulfonate and ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate to afford the desired product as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 7.73 (d, J=8.1 Hz, 2H), 7.58-7.59 (m, 2H), 7.42 (t, J=3.0 Hz, 3H), 7.22 (s, 2H), 6.94 (d, J=8.4 Hz, 1H), 6.63 (d, J=8.4 Hz, 1H), 4.83 (s, 2H), 2.97 (t, J=8.4 Hz, 2H), 2.60-2.70 (m, 2H), 2.28 (s, 3H), 2.24 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C29H29NO3S, 472.2 (M+H). found 472.2.
Reaction SMILES: [N:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=2)[CH:7]([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1.ClCCl.[Cl:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31](Cl)=[O:32])[CH:27]=[CH:28][CH:29]=1>C(N(CC)CC)C>[Cl:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31]([NH:16][C:13]2[CH:14]=[CH:15][C:10]([CH:6]([N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)[CH:7]([CH3:9])[CH3:8])=[CH:11][C:12]=2[N+:17]([O-:19])=[O:18])=[O:32])[CH:27]=[CH:28][CH:29]=1
Reactant: O=C(Cl)Cc1cccc(Cl)c1
Reactant: CC(C)C(c1ccc(N)c([N+](=O)[O-])c1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(c1ccc(NC(=O)Cc2cccc(Cl)c2)c([N+](=O)[O-])c1)n1ccnc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To a stirred solution of 13 parts of 4-[1-(1H-imidazol-1-yl)-2-methylpropyl]-2-nitrobenzenamine in 195 parts of dichloromethane was added a solution of 19 parts of 3-chlorobenzeneacetyl chloride in 65 parts of dichloromethane. After stirring for 4 hours at room temperature, 10.1 parts of N,N-diethylethanamine were added. The reaction mixture was washed with water, dried, filtered and evaporated, yielding 39 parts (100%) of 3-chloro-N-[4-[1-(1H-imidazol-1-yl)-2-methylpropyl]-2-nitrophenyl]benzeneacetamide as an oily residue (interm. 100).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:16][C:15]=2[N+:25]([O-:27])=[O:26])=[CH:10][CH:9]=1.Br[CH2:29][C:30]1[C:35]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[C:34]([O:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:33]([C:51]([F:54])([F:53])[F:52])=[CH:32][CH:31]=1.O>CC(C)=O>[C:47]([O:46][C:44]([O:43][C:34]1[C:33]([C:51]([F:52])([F:53])[F:54])=[CH:32][CH:31]=[C:30]([CH2:29][O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:16][C:15]=3[N+:25]([O-:27])=[O:26])=[CH:10][CH:9]=2)[C:35]=1[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:45])([CH3:48])([CH3:49])[CH3:50]
Reactant: COC(=O)Cc1ccc(-c2ccc(O)cc2)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)Oc1c(C(F)(F)F)ccc(CBr)c1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)Cc1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(OC(=O)OC(C)(C)C)c3C(=O)OC(C)(C)C)cc2)c([N+](=O)[O-])c1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Potassium carbonate (147 mg, 1.06 mmol) was added to a solution of methyl (4′-hydroxy-2-nitro-1,1′-biphenyl-4-yl)acetate (203 mg, 0.71 mmol) obtained in Example (37-1) and tert-butyl 6-(bromomethyl)-2-[(tert-butoxycarbonyl)oxy]-3-(trifluoromethyl)benzoate (330 mg, 0.781 mmol) obtained in Example (28-5) in acetone (15 ml), and the mixture was stirred at 70° C. for 8 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was successively washed with water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was subjected to silica gel column chromatography (eluting solvent: hexane/ethyl acetate=4/1) to give crude tert-butyl 2-[(tert-butoxycarbonyl)oxy]-6-[({4′-[(methoxycarbonyl)methyl]-2′-nitro-1,1′-biphenyl-4-yl}oxy)methyl]-3-(trifluoromethyl)benzoate.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[OH:15][C:16]1([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:28]=3)[CH:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:19]3[CH2:20][CH2:21][C:16]([OH:15])([C:22]4[CH:31]=[CH:30][C:29]5[C:24](=[CH:25][CH:26]=[C:27]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:28]=5)[CH:23]=4)[CH2:17][CH2:18]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: CCCCCCOc1ccc2cc(C3(O)CCNCC3)ccc2c1
Product: CCCCCCOc1ccc2cc(C3(O)CCN(C[C@H](O)COc4cccc5[nH]ccc45)CC3)ccc2c1
Yield: 56.9 %

Procedure:
Beginning with 0.232 gm (1.2 mMol) (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 0.400 gm (1.2 mMol) 4-hydroxy-4-(6-hexyloxynaphth-2-yl)piperidine, 0.353 gm (56%) of the title compound were recovered as a white solid by the procedure described in Example 9.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:15]=[C:14]3[C:9]([CH:10]=[CH:11][CH:12]=[C:13]3[NH2:16])=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.Cl.Cl[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]Cl.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(O)CCC>[CH:1]1([CH2:4][O:5][C:6]2[CH:15]=[C:14]3[C:9]([CH:10]=[CH:11][CH:12]=[C:13]3[N:16]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[CH:8][CH:7]=2)[CH2:2][CH2:3]1
Reactant: Nc1cccc2ccc(OCC3CC3)cc12
Reactant: ClCCNCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCCCO
Product: c1cc(N2CCNCC2)c2cc(OCC3CC3)ccc2c1
Reaction time: 10 h

Procedure:
A mixture of 7.7 g (0.036 mol) of 7-(cyclopropylmethoxy)naphthalene-1-amine, 6 g (0.036 mol) of bis(2-chloroethyl)amine hydrochloride, 50 ml of butanol and approximately 50 mg of potassium iodide is heated at reflux for 10 h under a nitrogen atmosphere. 2.5 g (0.018 mol) of potassium carbonate are added and heating at reflux is continued for 10 h, and then, twice, a further 1.25 g (0.009 mol) of potassium carbonate are added and the mixture is heated at reflux for 10 h. The butanol is evaporated. The residue is taken up in 100 ml of dichloromethane and 50 ml of 10% sodium hydroxide solution. The mixture is stirred in the presence of carbon black and filtered. The organic phase is separated and dried over magnesium sulphate. The solvent is evaporated under reduced pressure and the residue is purified by chromatography on a column of silica gel, eluting with a 90:10 mixture of dichloromethane/methanol. After evaporation of the solvent, 4.2 g of an oily product are obtained which is used as it is in the following step.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C@H:20]2[O:24][N:23]=[C:22]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[CH2:21]2)=[O:19])=[CH:13][CH:12]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[OH:10][CH:3]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18]([C@H:20]2[O:24][N:23]=[C:22]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[CH2:21]2)=[O:19])=[CH:15][CH:16]=1
Reactant: O=C(c1ccccc1)c1ccc(NC(=O)[C@@H]2CC(c3cccnc3)=NO2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C(Nc1ccc(C(O)c2ccccc2)cc1)[C@@H]1CC(c2cccnc2)=NO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
) NaBH4 (0.054 mol) was added to a solution of compound (3) (0.054 mol) in methanol (300 ml). The reaction mixture was stirred overnight at RT. The precipitate was filtered off, washed with CH3OH and DIPE, then dried, yielding 18 g (89%) of (5S)-4,5-dihydro-N-[4-(hydroxyphenylmethyl)phenyl]-3-(3-pyridinyl)-5-isoxazolecarboxamide (compound 499).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19](=[O:22])(=[O:21])[NH2:20])=[CH:15][CH:14]=2)[C:10]#N)=[CH:5][C:4]=1[CH3:23].O=[CH:25][C:26](=C)[CH3:27]>>[CH3:27][C:26]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH3:23])[CH:5]=2)[N:12]([C:13]2[CH:18]=[CH:17][C:16]([S:19](=[O:22])(=[O:21])[NH2:20])=[CH:15][CH:14]=2)[CH:25]=1
Reactant: C=C(C)C=O
Reactant: COc1ccc(C(C#N)Nc2ccc(S(N)(=O)=O)cc2)cc1C
Product: COc1ccc(-c2cc(C)cn2-c2ccc(S(N)(=O)=O)cc2)cc1C

Procedure:
Following a procedure similar to that described in Example 1(iii), but using α-(4-methoxy-3-methylphenyl)-α-(4-sulfamoylanilino)acetonitrile [prepared as described in step (ii) above] and methacrolein as starting materials, the title compound was obtained as a pale yellow powder (yield 39%), melting at 149-151° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([NH:9][C:10](=[O:12])[CH3:11])=[CH:4][N:3]=1.C([O-])(=O)C.[K+].C(OC(=O)C)(=O)C.[N:25](OCCC(C)C)=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:9]([C:10](=[O:12])[CH3:11])[N:25]=[CH:8][C:6]=2[N:7]=1
Reactant: CC(C)CCON=O
Reactant: CC(=O)Nc1cnc(Cl)nc1C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: CC(=O)n1ncc2nc(Cl)ncc21
Yield: 77.3 %

Procedure:
A solution of N-(2-chloro-4-methylpyrimidin-5-yl)acetamide (9 g, 46.06 mmol, 1.00 equiv, 95%), potassium acetate (3.3 g, 32.95 mmol, 0.72 equiv, 98%), acetic anhydride (17.27 g, 165.78 mmol, 3.60 equiv) and isoamyl nitrite (13.6 g, 116.24 mmol, 2.52 equiv, 98%) in chloroform (180 mL) was reflux overnight. The resulting mixture was washed with water, dried over anhydrous sodium sulfate and concentrated under vacuum to give 7 g (73%) of 1-[5-chloro-1H-pyrazolo[4,3-d]pyrimidin-1-yl]ethan-1-one as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[O:8][C:9]3[C:14]([C@@:15]4([CH2:19][O:18][C:17]([NH2:20])=[N:16]4)[C:4]=2[CH:3]=1)=[CH:13][C:12](B1OC(C)(C)C(C)(C)O1)=[CH:11][CH:10]=3.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:38][C:39]1[C:44](I)=[C:43]([F:46])[CH:42]=[CH:41][N:40]=1>O1CCOCC1.O.CCOC(C)=O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[F:38][C:39]1[C:44]([C:12]2[CH:13]=[C:14]3[C@@:15]4([CH2:19][O:18][C:17]([NH2:20])=[N:16]4)[C:4]4[CH:3]=[C:2]([C:15]5[CH2:14][CH2:9][O:8][CH2:5][CH:4]=5)[N:7]=[CH:6][C:5]=4[O:8][C:9]3=[CH:10][CH:11]=2)=[C:43]([F:46])[CH:42]=[CH:41][N:40]=1
Reactant: Fc1ccnc(F)c1I
Reactant: CC1(C)OB(c2ccc3c(c2)[C@@]2(COC(N)=N2)c2cc(Cl)ncc2O3)OC1(C)C
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: NC1=N[C@@]2(CO1)c1cc(-c3c(F)ccnc3F)ccc1Oc1cnc(C3=CCOCC3)cc12
Temperature: 100 °C

Procedure:
A 20 mL glass microwave reaction vessel was charged with (S)-3-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine (0.251 g, 0.608 mmol), potassium phosphate (0.269 g, 1.266 mmol), 2,4-difluoro-3-iodopyridine (0.122 g, 0.506 mmol) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II) (0.036 g, 0.051 mmol) in dioxane (3.2 mL) and water (0.8 mL). The reaction mixture was heated at 100° C. for 30 min in microwave reactor. After cooling the rt the mixture was diluted with EtOAc and water. The aqueous layer was washed twice with saturated Na2CO3. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude residue was purified by silica gel chromatography (2-10% MeOH—CH2Cl2) to provide the desired product as a brown residue.
Reaction SMILES: [C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]([NH:19]C(=O)OC(C)(C)C)[C:9]([N:11]([CH2:13][C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)[CH3:12])=[O:10])=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:19][C@@H:8]([CH2:7][C:4]1[CH:3]=[CH:2][C:1]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:6][CH:5]=1)[C:9]([N:11]([CH2:13][C:14]1[O:15][CH:16]=[CH:17][CH:18]=1)[CH3:12])=[O:10]
Reactant: CN(Cc1ccco1)C(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(Cc1ccco1)C(=O)[C@@H](N)Cc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-tert-butyl 3-(biphenyl-4-yl)-1-((furan-2-ylmethyl)(methyl)amino)-1-oxopropan-2-ylcarbamate (614 mg) in CH2Cl2 (6 mL) was added TFA (3 mL). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and azeotroped (three times) with toluene and dried under high vacuum. The crude (S)-2-amino-3-(biphenyl-4-yl)-N-(furan-2-ylmethyl)-N-methylpropanamide TFA salt (721 mg) was used for next step without further purification. HPLC retention time=1.37 minutes (condition B); MS (m+1)=335.0.
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:24][C:25](O)=[O:26])[C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:5]=2.[Br:28][C:29]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:30]=1[CH2:31][NH:32][CH2:33][CH2:34][N:35]([CH3:37])[CH3:36].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:20]([O:19][C:17]([C:6]1[CH:5]=[C:4]2[C:9]([C:10]([CH:11]3[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]3)=[C:2]([Br:1])[N:3]2[CH2:24][C:25]([N:32]([CH2:31][C:30]2[CH:38]=[C:39]([Cl:42])[CH:40]=[CH:41][C:29]=2[Br:28])[CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])=[O:26])=[CH:8][CH:7]=1)=[O:18])([CH3:21])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CC(=O)O)c2c1
Reactant: CN(C)CCNCc1cc(Cl)ccc1Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)CCN(Cc1cc(Cl)ccc1Br)C(=O)Cn1c(Br)c(C2CCCCC2)c2ccc(C(=O)OC(C)(C)C)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
To a solution of [2-bromo-6-(tert-butoxycarbonyl)-3-cyclohexyl-1H-indol-1-yl]acetic acid (from Step 7, 1 eq) in DCM (0.07 M), N′-(2-bromo-5-chlorobenzyl)-N,N-dimethylethane-1,2-diamine (from Step 3, 2.1 eq), DIPEA (3 eq) and HATU (2 eq) were added and the mixture stirred at RT overnight. The solution was diluted with DCM and washed with HCl (1 N), a saturated aqueous solution of NaHCO3 and brine, dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound (56%) that was used in the next step without further purification; MS (ES+) m/z 710 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=2)[N:9]([CH2:11][CH2:12][CH3:13])[CH:10]=1)=[O:5])[CH3:2].[C:22]([N:41]1[C:45]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=2B(O)O)=[N:44][N:43]=[N:42]1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=3[C:45]3[N:41]([C:22]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:42]=[N:43][N:44]=3)=[CH:17][CH:16]=2)[N:9]([CH2:11][CH2:12][CH3:13])[CH:10]=1)=[O:5])[CH3:2]
Reactant: OB(O)c1ccccc1-c1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCn1cc(C(=O)OCC)nc1Cc1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCn1cc(C(=O)OCC)nc1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 105 °C
Reaction time: 3 h
Yield: 71.1 %

Procedure:
2-(4-Bromobenzyl)-1-propyl-1H-imidazole-4-carboxylic acid ethyl ester (300.0 mg, 854.1 μmol) and [2-(1-trityl-1H-tetrazol-5-yl)phenyl]boronic acid (1.1 g, 2.6 mmol) were combined with 1,1′-bis(diphenylphosphino)ferrocene-palladium(ii)dichloride dichlorometh (244 mg, 299 μmol), dicesium carbonate (974 mg, 3.0 mmol), toluene (11 mL, 100 mmol), and water (2.2 mL, 119.6 mmol), and stirred under nitrogen at 105° C. for 3 hours. The mixture was cooled to room temperature. Water (50 mL) was added, the mixture was extracted with EtOAc (2×50 mL), washed with saturated aqueous NaCl (50 mL), dried over MgSO4, filtered and concentrated. The product was then purified by column chromatography (0-60% EtOAc in Hexanes) to yield 1-propyl-2-[2′-(1-trityl-1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-1H-imidazole-4-carboxylic acid ethyl ester (400 mg).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([N:17]([O:19][CH3:20])[CH3:18])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:21][NH:22][CH3:23]>C(O)C>[CH3:21][N:22]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([N:17]([O:19][CH3:20])[CH3:18])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)[CH3:23]
Reactant: CNC
Reactant: CON(C)C(=O)c1ccc(-c2ccc(CBr)cc2)cc1
Solvent: CCO
Product: CON(C)C(=O)c1ccc(-c2ccc(CN(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 52 %

Procedure:
1.95 g of 4'-bromomethyl-N-methoxy-N-methyl-4-biphenylcarboxamide was treated with 20 mL of a 33% solution of dimethylamine in ethanol, stirred at room temperature for 24 hours, the reaction mixture was evaporated, the residue was dissolved in 50 mL of ethyl acetate and washed with 50 mL of sodium hydroxide solution and with 50 mL of a saturated sodium chloride solution. The organic phases were dried over magnesium sulphate and evaporated. The crude product was chromatographed on 100 mL of silica gel with methylene chloride/methanol 9:1. There was obtained 1.16 g (52%) of 4'-[(dimethylamino)methyl]-N-methoxy-N-methyl-4-biphenylcarboxamide as a colorless solid with a m.p. of 42°-43° C.
Reaction SMILES: [C:1]1([O:9][CH3:10])[C:2](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O:3][CH3:4].[I:11]I>C(O)C>[I:11][C:7]1[CH:8]=[C:1]([O:9][CH3:10])[C:2]([O:3][CH3:4])=[CH:5][CH:6]=1
Reactant: COc1ccccc1OC
Reactant: II
Solvent: CCO
Product: COc1ccc(I)cc1OC
Yield: 70 %

Procedure:
A solution of veratrole (28.0 ml, 0.22M) in 95% ethanol (75 ml) was heated to 60° C. and, while stirring, was treated with iodine (50 g, 0.197M) and yellow mercuric oxide (30.0 g, 0.1385M). The iodine and mercuric oxide were added alternately in small portions over a period of 1.5 hours. After the addition was complete, the cooled mixture was filtered through Celite and concentrated. The residue was taken up in Et2O and again filtered. The Et2O solution was washed with solutions of sodium thiosulfate, 2N NaOH, saturated NaCl, dried over anhydrous K2CO3 and evaporated. The residue was distilled under reduced pressure to give 40.88 g, bp 110°-112° C. (2 mm) pure 4-iodoveratrole [70% yield, literature: Gutzke et al., J. Org. Chem. 22, 1271 (1957), bp 80°-85° C. (1 mm)]. NMR (CDCl3) δ 3.80 ppm (s, 6H, (2x) OCH3), 6.57 (d, 1H, ArH6), 7.20 (m, 2H, ArH3 and ArH5).