Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C([O-])(=O)C.[Na+].[Br:22]Br>C(O)(=O)C>[Br:22][C:14]1[S:13][C:12]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[C:2]([Cl:1])[CH:3]=2)=[N:16][CH:15]=1
Reactant: BrBr
Reactant: CC(C)Oc1ccc(-c2nccs2)cc1Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)Oc1ccc(-c2ncc(Br)s2)cc1Cl
Temperature: 20 °C

Procedure:
To a solution of 2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazole (D70) (1.5 g) and sodium acetate (0.970 g) in acetic acid (10 mL) stirred at room temperature was added a solution of Br2 (0.31 ml) in acetic acid (1 mL) dropwise during 30 min. The reaction mixture was stirred at 20° C. until start material was consumed completely. The reaction mixture was basified with 2M NaOH. The resulting solution was diluted with ethyl acetate. The mixture was washed with brine. The organic phase was dried over anhydrous sodium sulphate and evaporated in vacuo. The crude product was purified by column chromatography to give 5-bromo-2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazole (D71) (1.2 g). MS (ES): C12H11BrClNOS requires 332. found 333.0 (M+H+).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C@@:11]2([CH3:22])[C:15](=[O:16])[N:14]([CH2:17][C:18]([OH:20])=[O:19])[C:13](=[O:21])[NH:12]2)=[CH:7][CH:6]=1)#[N:4].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([C@@:11]2([CH3:22])[C:15](=[O:16])[N:14]([CH2:17][C:18]([O:20][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:19])[C:13](=[O:21])[N:12]2[CH2:3][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[CH:9][CH:10]=1)#[N:4]
Reactant: BrCc1ccccc1
Reactant: C[C@@]1(c2ccc(C#N)cc2)NC(=O)N(CC(=O)O)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@]1(c2ccc(C#N)cc2)C(=O)N(CC(=O)OCc2ccccc2)C(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
7.73 g (160.8 ,, mol) of sodium hydride were added to a solution of 20 g (73.1 mmol) of ((S)-4-(4-cyanophenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetic acid in 120 ml of absolute DMF with ice-cooling. After stirring at room temperature for 30 min, 19 ml (160.8 mmol) of benzyl bromide were added. The reaction mixture was stirred at room temperature for 2 h, allowed to stand overnight, the solvent was removed in vacuo and the residue was chromatographed on silica gel using heptane/ethyl acetate (2:1). 11.43 g (35%) of 8.1 were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[CH3:37][S:38]([CH2:41][CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)(=[O:40])=[O:39]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:47]3[CH2:48][CH2:49][N:44]([CH2:43][CH2:42][CH2:41][S:38]([CH3:37])(=[O:39])=[O:40])[CH2:45][CH2:46]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:31])([CH3:30])[C:32]#[N:33])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)CCCN1CCNCC1
Product: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1

Procedure:
2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-1-[4-(3-methanesulfonyl-propyl)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-3-ethoxy-phenyl)-2-methyl-propionitrile was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (example 12j) and 1-(3-methanesulfonyl-propyl)-piperazine (example 16e) in an analogous manner as described in example 25. LR-MS: 710.4 [(M+H)+]
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C([O-])(=O)C.[K+].C(OC(=O)C)(=O)C.C1OCCOCCOCCOCCOCCOC1.[N:40](OCCC(C)C)=O>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:4]2[C:3]=1[CH:9]=[N:40][NH:5]2
Reactant: CC(C)CCON=O
Reactant: Cc1c(N)cccc1Br
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: Brc1cccc2[nH]ncc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 39.6 %

Procedure:
To a solution of 3-bromo-2-methyl aniline (0104) (0.50 g, 2.69 mmol) in chloroform (5 mL) was added potassium acetate (0.28 g, 2.82 mmol). The mixture was cooled with ice-water bath and then acetic anhydride (0.50 mL, 5.37 mmol) was added to it. Ice-water bath was then removed and the resulting mixture was stirred at room temperature for 10 minutes after which time a white gelatinous solid formed. 18-Crown-6 (0.14 g, 0.54 mmol) was then added followed by isoamyl nitrite (0.80 mL, 5.90 mmol). The mixture was then heated under reflux for 18 hours. The reaction mixture was allowed to cool, and was partitioned between chloroform (3×10 mL) and saturated aqueous sodium hydrogen carbonate (10 mL). The combined organic extracts were washed with brine (10 mL), dried over Na2SO4, filtered and evaporated to give a crude product which was purified by column chromatography (ethyl acetate in petroleum ether, 10% v/v) to give 1-(4-bromoindrazol-1-yl)-ethanone (0105) as an orange solid (0.31 g, 49%), and 4-bromo-1H-indazole (0106-3) as a pale orange solid (0.21 g, 40%). Compound 0105: LCMS: 239 [M+1]+; 1H NMR (400 Hz, CDCl3) δ 2.80 (s, 3H), 7.41 (t, J=6.8 Hz, 1H), 7.50 (d, J=6.0 Hz, 1H), 8.15 (s, 1H), 8.40 (d, J=6.8 Hz, 1H). Compound 0106: LCMS: 197 [M+1]+; 1H NMR (400 Hz, CDCl3) δ 7.25 (t, J=6.0 Hz, 1H), 7.34 (d, J=6.4 Hz, 1H), 7.46 (d, J=6.8 Hz, 1H), 8.12 (s, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@H:11]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[CH:15]=2)=[CH:2]1.C([O-])=O.[NH4+]>CO.[Pd]>[NH2:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[O:13][CH2:12][C@@H:11]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:27])[CH3:28])[CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: CC(C)(C)OC(=O)N[C@H](COc1cccc([N+](=O)[O-])c1)Cc1c[nH]c2ccccc12
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H](COc1cccc(N)c1)Cc1c[nH]c2ccccc12
Temperature: 25 °C
Yield: 87.4 %

Procedure:
A solution of Example 20A (247 mg, 0.600 mmol), ammonium formate (400 mg, 6.34 mmol) and 10% Pd/C (25 mg) in methanol (10 mL) was heated to reflux for 30 minutes, cooled to room temperature, filtered through diatomaceous earth (Celite®), and concentrated. The concentrate was purified by flash column chromatography on silica gel with ethyl acetate/hexanes (1:1) to provide the desired product (200 mg, 87%). MS (DCI/NH3) m/e 382 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:16])[CH2:7]P(OCC)(OCC)=O)[CH3:4].O[CH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:25]=2)[C:20](=[O:31])[N:19]1[CH2:32][C:33]([F:36])([F:35])[F:34].CC(=O)OCC>COCCOC>[CH2:3]([O:5][C:6](=[O:16])[CH2:7][CH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([S:27]([CH3:30])(=[O:28])=[O:29])[CH:25]=2)[C:20](=[O:31])[N:19]1[CH2:32][C:33]([F:34])([F:36])[F:35])[CH3:4]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CS(=O)(=O)c1ccc2c(c1)C(O)N(CC(F)(F)F)C2=O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1c2cc(S(C)(=O)=O)ccc2C(=O)N1CC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.56 g of a 60% suspension of NaH in mineral oil were suspended in 20 ml of DME. Afterwards, 2.8 ml of (diethoxy-phosphoryl)-acetic acid ethyl ester were added dropwise at ambient temperature and the mixture stirred for 1 h at that temperature. A solution prepared of 3-hydroxy-5-methanesulfonyl-2-(2,2,2-trifluoro-ethyl)-2,3-dihydro-isoindol-1-one using 30 ml of DME was then added and the mixture was heated up to reflux. The mixture was refluxed for 4 h and then allowed to cool to ambient temperature. 300 ml of EA were added and the mixture was washed 3 times using 100 ml of saturated aqueous NaHCO3 solution each time. The aqueous layer was then extracted twice using 100 ml of EA each time. The combined EA layers were dried over Na2SO4 and the solvent was removed in vacuo. Chromatography on silica gel using MTB yielded 1.1 g of a colorless oil (Rf (MTB)=0.40; MS (DCI): 380 (M+1)+).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:15]=[C:14]([C@@H:16]4[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]4)[NH:13][N:12]=3)[CH:9]=2)[N:4]([C:29]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:3]=1.[N:48]1[CH:53]=[CH:52][C:51](B(O)O)=[CH:50][CH:49]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[N:48]1[CH:53]=[CH:52][C:51]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]4[N:15]=[C:14]([C@@H:16]5[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]5)[NH:13][N:12]=4)[CH:9]=3)[N:4]([C:29]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:3]=2)=[CH:50][CH:49]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](c2nc(-c3ccc4c(c3)c(Br)nn4C(c3ccccc3)(c3ccccc3)c3ccccc3)n[nH]2)C1
Reactant: OB(O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](c2nc(-c3ccc4c(c3)c(-c3ccncc3)nn4C(c3ccccc3)(c3ccccc3)c3ccccc3)n[nH]2)C1
Yield: 86.8 %

Procedure:
Stirred a mixture of (R)-tert-butyl 3-(3-(3-bromo-1-trityl-1H-indazol-5-yl)-1H-1,2,4-triazol-5-yl)piperidine-1-carboxylate (500 mg, 0.72 mmol), pyridine 4-boronic acid (150 mg, 1.22 mmol), PdCl2dppf (30 mg, 0.036 mmol) and Cesium carbonate (400 mg, 1.23 mmol) in dioxane (9 mL) and water (1 mL) at 100° C. in a microwave oven for 2 hours. After cooling, diluted with water (50 ml), then extracted with DCM (100 ml). The combined organic layer was dried (Na2SO4), filtered and evaporated to yield crude product, which chromatographed on silica gel eluting with 30% v/v EtOAc/Hexanes to yield (R)-tert-butyl 3-(3-(3-(pyridin-4-yl)-1-trityl-1H-indazol-5-yl)-1H-1,2,4-triazol-5-yl)piperidine-1-carboxylate as a white solid (430 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=1[O:14][CH2:15][CH:16]1[CH2:18][O:17]1.[CH3:23][NH:24][CH3:25]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=1[O:14][CH2:15][CH:16]([OH:17])[CH2:18][N:24]([CH3:25])[CH3:23]
Reactant: Clc1ccccc1CCCCc1ccccc1OCC1CO1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)CC(O)COc1ccccc1CCCCc1ccccc1Cl
Yield: 80 %

Procedure:
Following a procedure similar to that described in Example 1(b), 860 mg of 2-{2-[4-(2-chlorophenyl)butyl]phenoxymethyl}oxirane [prepared as described in step (a) above] dissolved in 20 ml of tetrahydrofuran were treated with 4 ml of 50% by volume aqueous dimethylamine. The crude product thus obtained was purified as described in Example 1(b), to give 790 mg (yield 80%) of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([N:8]([CH:29]1[CH2:37][C:36]2[C:31](=[CH:32][C:33]([CH2:40][CH3:41])=[C:34]([CH2:38][CH3:39])[CH:35]=2)[CH2:30]1)[CH2:9][C@@H:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:14]([N+:26]([O-])=O)[CH:13]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.C1(C)C=CC=CC=1.O=[Pt]=O>[NH2:26][C:14]1[CH:13]=[C:12]([C@@H:10]([OH:11])[CH2:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:29]2[CH2:30][C:31]3[C:36](=[CH:35][C:34]([CH2:38][CH3:39])=[C:33]([CH2:40][CH3:41])[CH:32]=3)[CH2:37]2)[CH:17]=[CH:16][C:15]=1[O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCc1cc2c(cc1CC)CC(N(Cc1ccccc1)C[C@H](O)c1ccc(OCc3ccccc3)c([N+](=O)[O-])c1)C2
Agent: O=[Pt]=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCc1cc2c(cc1CC)CC(N(Cc1ccccc1)C[C@H](O)c1ccc(OCc3ccccc3)c(N)c1)C2
Reaction time: 6 h

Procedure:
(R)-2-[Benzyl-(5,6-diethyl-indan-2-yl)-amino]-1-(4-benzyloxy-3-nitro-phenyl)-ethanol (3.00 g) is dissolved in THF (50 mL) and toluene (50 mL). A catalytic amount of PtO2 is added and the solution is stirred under an atmosphere of H2. The reaction is shown to be complete by TLC after 6 hours. The catalyst is filtered off and the solvent is removed in vacuo. The product is not purified further. TLC (silica, n-hexane/ethyl acetate 1:1 Rf=0.75).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4]=1[C:13]([OH:15])=O.C(Cl)(=O)C([Cl:19])=O>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4]=1[C:13]([Cl:19])=[O:15]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc2c(c1C(=O)O)CCCC2
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc2c(c1C(=O)Cl)CCCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-methoxy-5,6,7,8-tetrahydro-1-naphthalenecarboxylic acid (0.20 g, 0.97 mmol) in DCM (5 mL) was added oxalyl chloride (0.11 mL, 1.21 mmol) and 1 drop of DMF. The mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo and the 2-methoxy-5,6,7,8-tetrahydro-1-naphthalenecarbonyl chloride was used without purification.
Reaction SMILES: CN(C)C=[N:4][S:5]([C:8]1[N:9]([CH3:21])[N:10]=[C:11]2[C:16]=1[C:15]([O:17][CH2:18][CH2:19][F:20])=[CH:14][CH:13]=[CH:12]2)(=[O:7])=[O:6].Cl>C(O)C>[F:20][CH2:19][CH2:18][O:17][C:15]1[C:16]2[C:11]([CH:12]=[CH:13][CH:14]=1)=[N:10][N:9]([CH3:21])[C:8]=2[S:5]([NH2:4])(=[O:6])=[O:7]
Reactant: CN(C)C=NS(=O)(=O)c1c2c(OCCF)cccc2nn1C
Agent: Cl
Solvent: CCO
Product: Cn1nc2cccc(OCCF)c2c1S(N)(=O)=O
Yield: 84.8 %

Procedure:
A mixture comprising 3.4 g of N1,N1 -dimethyl-N2 -{[4-(2-fluoroethoxy)-2-methyl-2H-indazol-3-yl]sulfonyl}formamidine, 5 ml of concentrated hydrochloric acid and 50 ml of ethanol, was refluxed for 12 hours. Disappearance of the starting material was confirmed by TLC, and then ethanol was distilled off. Water was added to the residue, whereupon the formed crystals were collected by filtration and washed with water and IPE to obtain 2.4 g (yield: 85%) of the desired product. Melting point: 178°-180° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:36])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:14][C:12]1[C:11]([C:15]([F:17])([F:16])[F:18])=[CH:10][C:9]2[NH:19][C:20](=[O:36])[CH2:21][C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[CH:24]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccccn3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccccn3)c1)=N2

Procedure:
The title compound was prepared from {5-methyl-2-[3-oxo-3-(3-pyridin-2-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M42) (245 mg, 0.476 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (162 mg).
Reaction SMILES: [C:1]([O:10]C1C=CC=CC=1)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1>>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:1](=[O:10])[C:2]2[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=2)[OH:4])=[CH:19][CH:20]=1
Reactant: O=C(Oc1ccccc1)c1ccccc1O
Reactant: COc1ccc(N)cc1
Product: COc1ccc(NC(=O)c2ccccc2O)cc1

Procedure:
The 4′-methoxy-salicylanilide was prepared by condensing phenyl salicylate with 4-aminoanisole then purified as described in Example 2a. The mixture of ligands was then prepared from 4′-methoxy-salicylanilide and 1,1′-bi-2-naphthol using the procedure described in Example 5a. 31P NMR (121.77 MHz): several peaks between 116-118 ppm.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([O:12][CH3:13])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[CH:2].[CH2:14]([O:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=1)[CH3:15]>C(N(CC)CC)C.[Cu]I.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>[CH3:13][O:12][C:9]1([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[C:2][C:21]3[CH:22]=[CH:23][C:18]([C:17]([O:16][CH2:14][CH3:15])=[O:25])=[CH:19][CH:20]=3)=[CH:4][CH:5]=2)[CH2:10][CH2:11]1
Reactant: C#Cc1ccc(C2(OC)CC2)cc1
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(C3(OC)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
Using General Procedure F; 1-ethynyl-4-(1-methoxycyclopropyl)-benzene (Intermediate 61, 100.0 mg, 0.47 mmol) and ethyl-4-iodo benzoate (Reagent A, 141.0 mg, 0.51 mmol) in triethyl amine (6 mL) was treated with copper(I)iodide (30.0 mg, 0.16 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (109 mg, 0.16 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-5% EtOAc-hexanes) afforded 135.0 mg (90%) of the title compound as an orange solid.
Reaction SMILES: C[Li].C(NC(C)C)(C)C.[CH3:10][N:11]([CH3:21])[C:12](=[O:20])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:22][Si:23]([CH3:26])([CH3:25])Cl>C(OCC)C>[CH3:21][N:11]([C:12]([O:20][Si:23]([CH3:26])([CH3:25])[CH3:22])=[CH:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH3:10]
Reactant: CN(C)C(=O)Cc1ccccc1
Reactant: C[Si](C)(C)Cl
Agent: [Li]C
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Product: CN(C)C(=Cc1ccccc1)O[Si](C)(C)C
Temperature: -70 °C
Reaction time: 8 h
Yield: 20.3 %

Procedure:
Methyllithium in diethyl ether (140 ml of 1.8 M solution, 0.25 mol) was added dropwise to a solution of 27.6 g (0.27 mol) of diisopropylamine in 40 ml of dry diethyl ether. The reaction mixture was cooled to -70° C. and a solution of 26.1 g (0.16 mol) of N,N-dimethylbenzeneacetamide in 75 ml of diethyl ether was added dropwise. The reaction mixture was warmed to 0° C. and 46 ml (0.36 mol) of trimethylchlorosilane were added dropwise. The reaction mixture was stirred at 25° C. overnight, the solid was filtered off, and the filtrate was distilled to give 7.65 g of β-(N,N-dimethylamino)-β-trimethylsiloxystyrene as a light yellow oil: bp 75°-78° C. (0.5 mm); 1H NMR (CDCl3) δ 2.18 ppm (s, 6H), 4.83 ppm (s, 1H), 6.7-7.6 ppm (m, 5H) and 0.04 ppm (s, 9H). Anal. Calcd. for C13H21NOSi: C, 66.33; H, 8.99; N, 5.95; Found: C, 66.47; H, 9.11; N, 5.78.
Reaction SMILES: C(Cl)Cl.[CH2:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[N:25]3[C:21](=[CH:22][CH:23]=[N:24]3)[N:20]=[C:19]3[C:15]=2[CH2:16][CH2:17][N:18]3[OH:26])=[CH:9][CH:8]=1)[CH3:5].[C:27](OC(=O)C)(=[O:29])[CH3:28]>C(N(CC)CC)C>[C:27]([O:26][N:18]1[CH2:17][CH2:16][C:15]2[C:19]1=[N:20][C:21]1[N:25]([C:14]=2[NH:13][C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:4][CH3:5])=[CH:12][CH:11]=2)[N:24]=[CH:23][CH:22]=1)(=[O:29])[CH3:28]
Reactant: CCOc1ccc(Nc2c3c(nc4ccnn24)N(O)CC3)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1ccc(Nc2c3c(nc4ccnn24)N(OC(C)=O)CC3)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a methylene chloride (0.5 mL) solution containing 8-(4-ethoxyphenylamino)-6,7-dihydro-1,4,5,8a-tetraaza-s-indacen-5-ol (2.8 mg), triethylamine (50 μL) and acetic anhydride (50 μL) were added. After this solution was stirred at room temperature for 30 min, the solvent was concentrated, and the residue was purified with PTLC (70% ethyl acetate-hexane) to obtain the title compound (2.3 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][C:13](=[O:17])[NH:14]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[O:18]=[C:19]1[C:24]2=[CH:25][NH:26][C:27]([CH:28]=O)=[C:23]2[CH2:22][CH2:21][O:20]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([C:12](=[CH:28][C:27]4[NH:26][CH:25]=[C:24]5[C:19](=[O:18])[O:20][CH2:21][CH2:22][C:23]=45)[C:13](=[O:17])[NH:14]3)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Reactant: O=C1Cc2ccc(-c3ccc(F)cc3)cc2N1
Product: O=C1Nc2cc(-c3ccc(F)cc3)ccc2C1=Cc1[nH]cc2c1CCOC2=O

Procedure:
6-(4-Fluoro-phenyl)-1,3-dihydro-indol-2-one was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][CH:7]=1.[C:18]([C:20]([OH:27])([CH2:24][CH2:25]C)[CH2:21][CH2:22]C)#[CH:19].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(N(CC)CC)C.CN(C=O)C.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.[Cu]I>[CH2:18]([C:20]([OH:27])([CH2:24][CH3:25])[CH2:21][CH2:22][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][CH:7]=1)[CH3:19]
Reactant: O=C(NCCCc1cccc(Br)c1)C(F)(F)F
Reactant: C#CC(O)(CCC)CCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(O)(CC)CCc1cccc(CCCNC(=O)C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a degassed solution of N-(3-(3-bromophenyl)propyl)-2,2,2-trifluoroacetamide (10) (2.29 g, 7.4 mmol) and 4-ethynylheptan-4-ol (2.4 g, 18.5 mmol) in triethylamine (2 mL) and DMF (18 mL) was added PdCl2(PPh3)2 (0.130 g, 0.185 mmol), P(o-Tol)3 (0.113 g, 0.37 mmol), and CuI (0.070 g, 0.37 mmol). The resulting mixture was degassed and stirred under argon at 90° C. overnight. The mixture was cooled to room temperature and the solids were removed by filtration through Celite. The filtrate was partitioned between diethyl ether and water and the combined organics were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (6 to 50% EtOAc-hexanes gradient) gave N-(3-(3-(3-ethyl-3-hydroxypentyl)phenyl)propyl)-2,2,2-trifluoroacetamide (12) as an amber oil. Yield (2.6 g, 95%): 1H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 7.18-7.29 (m, 4H), 3.16 (q, J=7.2 Hz, 2H), 2.56 (t, J=7.2 Hz, 2H), 1.76 (quint, J=7.2 Hz, 2H), 1.53-1.67 (m, 8H), 0.97 (t, J=7.2 Hz, 6H).
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][C:8]([C:11]1[N:12]=[C:13]([CH2:21][CH2:22][CH3:23])[NH:14][C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])([CH3:10])[CH3:9].Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[C:33]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:28][CH:27]=1.O>CN(C)C(=O)C>[C:41]([O:40][C:38]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[C:29]1[CH:30]=[CH:31][C:26]([CH2:25][N:14]2[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:11]([C:8]([OH:7])([CH3:10])[CH3:9])[N:12]=[C:13]2[CH2:21][CH2:22][CH3:23])=[CH:27][CH:28]=1)=[O:39])([CH3:44])([CH3:43])[CH3:42]
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OCC)[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reaction time: 0.17 h
Yield: 91.7 %

Procedure:
3.00 g of potassium t-butoxide were added, whilst ice-cooling, to a solution of 6 g of ethyl 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate (prepared as described in Preparation 9) in 40 ml of N,N-dimethylacetamide, and the resulting mixture was stirred for 10 minutes, after which a solution of 9.00 g of t-butyl 4'-bromomethylbiphenyl -2-carboxylate in 40 ml of N,N-dimethylacetamide was added. After the reaction mixture had been stirred at room temperature for 1 hour and then at 50° C. for 2 hours, it was mixed with water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure, after which the residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 11.6 g of the title compound as a solid, softening at above 85° C.