Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC=CC=1.[CH2:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl[CH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18]1.OS(O)(=O)=O>O>[CH2:8]([NH:15][CH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: ClC1CCc2ccccc21
Reactant: NCc1ccccc1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(CNC2CCc3ccccc32)cc1
Temperature: 90 °C
Yield: 72.5 %

Procedure:
A mixture of 272 ml of toluene and 199.5 g benzylamine was prepared and heated to 90° C. The chlorindan was added dropwise to the mixture over a 30 minute period. The reaction mixture was heated to 115° C. for ten hours. The reaction mixture was cooled to ambient temperature and 300 ml of water was added. The resulting heterogeneous mixture was then brought to pH 2.2 by the addition of 33% H2SO4. The phases were separated and the organic layer discarded. The pH of the aqueous layer was adjusted to pH 6.0 prior to extraction with 300 ml of toluene. A further 100 ml of toluene was then added and the aqueous phase discarded. The toluene was removed under vacuo from the combined organic layer leaving 104.3 g racemic N-benzyl-1-aminoindan base as an oil (72.5% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:43]=[CH:42][C:6]([CH2:7][N:8]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:24][C:25]4[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)=[N:18][CH:19]=[C:20]([CH:23]=3)[CH:21]=[O:22])[N:10]=2)=[CH:5][CH:4]=1.[C-]#N.[Na+].[CH3:47][S:48]([N:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)(=[O:50])=[O:49]>C1COCC1.[O-2].[Mn+4].[O-2]>[CH3:41][O:40][C:37]1[CH:36]=[CH:35][C:34]([CH2:33][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:43][CH:42]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:23]=[C:20]([C:21]([N:54]4[CH2:55][CH2:56][N:51]([S:48]([CH3:47])(=[O:50])=[O:49])[CH2:52][CH2:53]4)=[O:22])[CH:19]=[N:18][C:17]=3[NH:24][C:25]3[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[N:10]=2)=[CH:39][CH:38]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C=O)cnc3Nc3ccc(OC)nc3)n2)cc1
Reactant: CS(=O)(=O)N1CCNCC1
Agent: [Mn+4]
Agent: [C-]#N
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(=O)N4CCN(S(C)(=O)=O)CC4)cnc3Nc3ccc(OC)nc3)n2)cc1
Reaction time: 72 h
Yield: 27.5 %

Procedure:
A mixture of 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)nicotinaldehyde (Example 144, 1.00 g, 1.731 mmol), activated manganese (IV) oxide (<5 micron; 4.52 g, 51.9 mmol), sodium cyanide (0.053 mL, 1.731 mmol) and 1-(methylsulfonyl)piperazine (0.711 g, 4.33 mmol) in THF (15 mL) was stirred rapidly under nitrogen for 72 h. The reaction was filtered through Celite® (diatomaceous earth) rinsing with 10% MeOH/DCM followed by EtOAc. The filtrate was concentrated and adsorbed onto 5 g silica gel and passed through an 80 g column using 20-100% EtOAc/hexanes to give (5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)(4-(methylsulfonyl)piperazin-1-yl)methanone (0.352 g, 0.476 mmol, 27.5% yield) as a yellow foam. m/z (ESI, +ve ion) 740 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 12.02 (s, 1H); 8.91 (d, J=2.3 Hz, 1H); 8.42 (d, J=2.5 Hz, 1H); 8.29 (d, J=2.5 Hz, 1H); 7.90 (dd, J=8.8, 2.7 Hz, 1H); 7.11-7.24 (m, 4H); 6.80-6.94 (m, 4H); 6.75 (d, J=9.0 Hz, 1H); 4.85 (s, 2H); 4.82 (s, 2H); 3.95 (s, 3H); 3.82 (s, 3H); 3.80 (s, 3H); 3.71-3.78 (m, 4H); 3.17-3.25 (m, 4H); 2.70 (s, 3H); 2.60 (s, 3H).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[NH:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH:7]=[CH:6]1.[C:14](Cl)(=[O:19])[C:15]#[C:16][CH2:17][CH3:18].C(=O)([O-])O.[Na+]>ClCCl>[NH:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14](=[O:19])[C:15]#[C:16][CH2:17][CH3:18])=[CH:6]1
Reactant: CCC#CC(=O)Cl
Reactant: c1cnc2[nH]ccc2c1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC#CC(=O)c1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
2.1 5.6 g (42.0 mmol) of aluminium trichloride are added to a solution of 1.0 g (8.47 mmol) of pyrrolo[2,3-b]pyridine in 100 ml of dichloromethane, and the mixture is stirred at room temperature for 2 h. 52 ml (0.2 M, 10.09 mmol) of pent-2-ynoyl chloride dissolved in dichloromethane are then slowly added dropwise to the reaction solution. The mixture is left to stir at room temperature for a further 16 h. Saturated sodium hydrogencarbonate solution is added to the reaction mixture until neutral, and the aluminium salt precipitate is filtered off with suction. The aqueous phase is separated off and extracted twice with dichloromethane. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated. The residue is employed in the next reaction without further purification. 1-(1H-Pyrrolo[2,3-b]pyridin-3-yl)pent-2-yn-1-one (74% purity) is obtained as colourless oil; ESI 199.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][C:5]=1[F:11].Cl.[CH3:14][NH:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([N:15]([CH3:16])[CH3:14])=[CH:6][C:5]=1[F:11]
Reactant: CNC
Reactant: COC(=O)c1ccc(F)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(N(C)C)cc1F
Temperature: 55 °C
Reaction time: 5 h
Yield: 55 %

Procedure:
To a stirred solution of 3.87 g (22.5 mmol) 2.4-difluoro-benzoic acid methyl ester (Apollo) and 60.0 ml dimethylsulphoxid were added 2.23 g (27.0 mmol) dimethylamine hydrochloride and 6.54 g (47.3 mmol) potassium carbonate. The reaction mixture was stirred for 5 h at 55° C. in an autoclave and was reduced with high vacuum rotation evaporator at 65° C. The residue was diluted with dichloromethane, washed twice with water. The combined water phases were extracted with dichloromethane. The combined dichloromethane phases were washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The oily crude was purified by column chromatography and the desired product 4a was obtained in 55% yield (2.44 g, 12.4 mmol).
Reaction SMILES: CN(C=O)C.[NH2:6][C:7]1[C:8]2[C:32]([CH3:39])([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:31](=[O:40])[NH:30][C:9]=2[N:10]=[C:11]([NH:13]/[N:14]=[C:15](/[C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=2Br)\[CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])[N:12]=1.CNCCNC>CCOC(C)=O.[Cu]I>[NH2:6][C:7]1[C:8]2[C:32]([CH3:39])([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:31](=[O:40])[NH:30][C:9]=2[N:10]=[C:11]([N:13]2[C:23]3[C:22](=[CH:27][C:26]([Cl:28])=[CH:25][CH:24]=3)[C:15]([CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:14]2)[N:12]=1
Reactant: CC1(c2ccccc2)C(=O)Nc2nc(N/N=C(\CCC(F)(F)F)c3cc(Cl)ccc3Br)nc(N)c21
Agent: [Cu]I
Agent: CNCCNC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(c2ccccc2)C(=O)Nc2nc(-n3nc(CCC(F)(F)F)c4cc(Cl)ccc43)nc(N)c21

Procedure:
A DMF (3 mL) solution of the crude intermediate from Step C (77 mg, 0.135 mmol), copper (I) iodide (25.7 mg, 0.135 mmol), and N,N′-dimethylethylenediamine (14.3 mg, 0.162 mmol) was stirred at ambient temperature for 1 hour. The reaction mixture was diluted with EtOAc and washed with 10% aqueous NH4OH solution (2×), water (3×), and brine. The organic phase was JO dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by reverse phase HPLC using a water/acetonitrile (with 0.1% TFA) gradient. The isolated material was converted to the free base by suspending in EtOAc, washing with aqueous saturated NaHCO3 solution (2×) and brine. The solution was dried over anhydrous MgSO4, filtered, concentrated. The residue was purified by silica gel chromatography using a hexanes/EtOAc gradient to give the indicated compound as a racemic mixture. The enantiomers were separated on a ChiralPak IB column using 7% EtOH/heptane as eluent to give the indicated compound. Data is given for the faster eluting enantiomer. 1H NMR (500 MHz, DMSO-d6): δ (ppm) 11.23 (1H, s), 8.86 (1H, d, J=9.1 Hz), 8.07 (1H, d, J=2.1 Hz), 7.52 (1H, dd, J=9.0, 2.1 Hz), 7.37-7.25 (5H, m), 6.75 (2H, s), 3.30-3.20 (2H, m), 2.88-2.76 (2H, m), 1.79 (3H, s). m/z=487.1 (M+H).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[C:6]([N+:12]([O-:14])=[O:13])[CH:7]=[CH:8][C:9]=1[CH2:10][CH3:11])#[N:2].Cl[CH2:16][C:17]1[C:18]([CH2:23]Cl)=[CH:19][CH:20]=[CH:21][CH:22]=1.CS(C)=O.CC(C)([O-])C.[K+]>O.C(OCC)(=O)C>[C:1]([C:3]1([C:4]2[CH:5]=[C:6]([N+:12]([O-:14])=[O:13])[CH:7]=[CH:8][C:9]=2[CH2:10][CH3:11])[CH2:23][C:18]2[C:17](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:16]1)#[N:2]
Reactant: ClCc1ccccc1CCl
Reactant: CCc1ccc([N+](=O)[O-])cc1CC#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCc1ccc([N+](=O)[O-])cc1C1(C#N)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 29.5 %

Procedure:
To a mixture of the compound (3.0 g) obtained in Example 25a, α,α′-dichloro-o-xylene (4.15 g) and dimethyl sulfoxide (200 ml), potassium t-butoxide (3.55 g) was added and after stirring the resulting mixture at room temperature for 3 h, ethyl acetate and water were added. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure to give the titled compound (1.36 g) (yield, 29%).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[C:10](F)=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[CH2:5][CH2:4]1)[CH3:2].C([OH:22])C#CC.CC(C)([O-])C.[K+].Cl>CS(C)=O>[CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[C:10]([OH:22])=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CC#CCO
Reactant: CCN1CCC(c2cccc(C#N)c2F)CC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: CCN1CCC(c2cccc(C#N)c2O)CC1
Temperature: 125 °C

Procedure:
To a solution of 3-(1-ethylpiperidin-4-yl)-2-fluorobenzonitrile (10 mg, 0.031 mmol) in dimethylsulfoxide (1 ml) was added 2-butyn-1-ol (4.3 mg, 0.062 mmol) and potassium-tert-butoxide (7 mg, 0.063 mmol). The mixture was heated to 125° C. in a sealed tube under microwave radiation for 120 s. Aqueous hydrochloric acid (10%, 10 ml) was added and the aqueous phase was washed with diethyl ether (2×20 ml). The aqueous phase was basified by addition of sodium hydroxide (5 M, 5 ml) and extracted with ethyl acetate (3×20 ml). The combined organic phase was dried (MgSO4) and evaporated under reduced pressure to give the title compound. MS m/z (relative intensity, 70 eV) 230 (M+, 60), 229 (24), 216 (23), 215 (bp) 110 (30).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19]CC3C=CC=CC=3)=[C:15]([O:27][CH3:28])[CH:14]=2)=[O:12])[CH:2]=1>FC(F)(F)C(O)=O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([O:27][CH3:28])[CH:14]=2)=[O:12])[CH:2]=1
Reactant: COc1cc(C(=O)c2cnc3ccccc3c2)ccc1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)c2cnc3ccccc3c2)ccc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
11.0 g of 4-(benzyloxy)-3-methoxyphenyl (3-quinolinyl) ketone are treated with 50 ml of trifluoroacetic acid, whereupon the mixture is stirred at room temperature for 2 hours. After distillation of the trifluoroacetic acid, the residue is treated twice with 50 ml of ethanol each time and the solvent is distilled each time. The oil obtained crystallizes upon treatment with ethanol. After recrystallization from ethanol, there is obtained 4-hydroxy-3-methoxyphenyl (3-quinolinyl) ketone in the form of yellowish crystals of m.p. 196°-197°.
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:6]=[N:5]1)[CH2:2][CH3:3].Cl[C:19]1[N:24]=[N:23][C:22]([N:25]2[CH2:30][CH2:29][CH:28]([N:31]3[C:39]4[C:34](=[CH:35][CH:36]=[C:37]([F:40])[CH:38]=4)[CH2:33][CH2:32]3)[CH2:27][CH2:26]2)=[CH:21][CH:20]=1>>[F:40][C:37]1[CH:38]=[C:39]2[C:34]([CH2:33][CH2:32][N:31]2[CH:28]2[CH2:29][CH2:30][N:25]([C:22]3[N:23]=[N:24][C:19]([C:7]4[CH:6]=[N:5][N:4]([CH2:1][CH2:2][CH3:3])[CH:8]=4)=[CH:20][CH:21]=3)[CH2:26][CH2:27]2)=[CH:35][CH:36]=1
Reactant: Fc1ccc2c(c1)N(C1CCN(c3ccc(Cl)nn3)CC1)CC2
Reactant: CCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CCCn1cc(-c2ccc(N3CCC(N4CCc5ccc(F)cc54)CC3)nn2)cn1

Procedure:
The title compound was prepared following the procedure as described in Example 1, Method A, reacting 1-propylpyrazole-4-boronic acid pinacol ester and 1-(1-(6-chloropyridazin-3-yl)piperidin-4-yl)-6-fluoroindoline.
Reaction SMILES: Br[C:2]1[C:7]2[CH:8]=[C:9]([CH2:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][N:13]3[C:18]([C:20]3[N:21]=[C:22]([CH3:32])[S:23][C:24]=3[C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:19])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C[CH2:34][N:35](C1C=CC(C(C2C(S([O-])(=O)=O)=CC(S([O-])(=O)=O)=C(O)C=2)=C2C=CC(=[N+](CC)CC)C=C2)=CC=1)CC.CCN(C1C=CC(C(C2C(S([O-])(=O)=O)=CC(S([O-])(=O)=O)=C(O)C=2)=C2C=CC(=[N+](CC)CC)C=C2)=CC=1)CC.[Ca+2].[Cu]C#N>>[C:34]([C:2]1[C:7]2[CH:8]=[C:9]([CH2:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][N:13]3[C:18]([C:20]3[N:21]=[C:22]([CH3:32])[S:23][C:24]=3[C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:19])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1)#[N:35]
Reactant: Cc1nc(C(=O)N2CCCCC2Cc2cc3c(Br)cccc3o2)c(-c2ccc(F)cc2)s1
Reactant: CCN(CC)c1ccc(C(=C2C=CC(=[N+](CC)CC)C=C2)c2cc(O)c(S(=O)(=O)[O-])cc2S(=O)(=O)[O-])cc1
Agent: N#C[Cu]
Agent: [Ca+2]
Product: Cc1nc(C(=O)N2CCCCC2Cc2cc3c(C#N)cccc3o2)c(-c2ccc(F)cc2)s1

Procedure:
The title compound (80 mg) was prepared from (RS)-1-[2-(4-bromo-benzofuran-2-ylmethyl)-piperidin-1-yl]1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone, E131 (400 mg) and copper(I)cyanide according to a procedure similar to that described for Example 67.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH:13]2[CH2:15][CH2:14]2)=[C:11]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][N:20]=[C:19]3[NH2:25])[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[CH:30](=O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C)C=O>[CH2:30]([NH:25][C:19]1[C:18]2[C:22](=[CH:23][CH:24]=[C:16]([C:11]3[N:10]=[N:9][N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:12]=3[CH:13]3[CH2:15][CH2:14]3)[CH:17]=2)[NH:21][N:20]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Nc1n[nH]c2ccc(-c3nnn(Cc4ccccc4)c3C3CC3)cc12
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: c1ccc(CNc2n[nH]c3ccc(-c4nnn(Cc5ccccc5)c4C4CC4)cc23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 89B (18.3 mg, 0.05 mmol) in dimethylformamide (2 mL) was added acetic acid (15 mg, 0.25 mmol) and benzaldehyde (6.4 mg, 0.06 mmol). The reaction mixture was stirred at room temperature overnight. Sodium triacetoxyborohydride (NaBH(OAc)3, 32 mg, 0.15 mmol) was added to the mixture. The reaction was stirred at room temperature for 3 hours, concentrated and purified by reverse phase-HPLC (CH3CN/H2O/NH4OAc) to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 13.09 (s, 1H), 9.24 (s, 1H), 8.02-8.10 (m, 3H), 7.84-7.90 (m, 1H), 7.49-7.67 (m, 4H), 7.25-7.45 (m, 5H), 5.70 (s, 2H), 3.30 (s, 2H), 1.88-1.95 (m, 1H), 1.01-1.09 (m, 2H), 0.43 (d, J=4.04 Hz, 2H). MS (ESI+) m/z 421 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[O:11][CH2:12][CH:13]1[CH2:15][CH2:14]1.[Li]CCCC.C(O[B:25]1[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]1)(C)C>C(OC)CCC>[CH:13]1([CH2:12][O:11][C:3]2[CH:4]=[CH:5][C:6]([CH:8]([F:10])[F:9])=[CH:7][C:2]=2[B:25]2[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]2)[CH2:15][CH2:14]1
Reactant: FC(F)c1ccc(OCC2CC2)c(Br)c1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: CCCCOC
Agent: [Li]CCCC
Product: CC1(C)OB(c2cc(C(F)F)ccc2OCC2CC2)OC1(C)C
Yield: 98.6 %

Procedure:
2-Bromo-1-cyclopropylmethoxy-4-difluoromethyl-benzene (example B.b18; 24.35 g; 87.9 mmol) is dissolved in dry tert. BuOMe (440 mL). n-BuLi (1.6M in hexane; 60.0 mL; 96.0 mmol) is slowly syringed into the well stirred reaction mixture at −40° C. After one hour commercially available 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (17.86 g; 96.0 mmol) is added at −40° C. followed by stirring at 0° C. for one additional hour. The reaction mixture is quenched by addition of 2M aqueous citric acid (90.0 mL). The organic layer is separated, washed with brine, dried over Mg2SO4 and filtered through a pad of neutral alumina (act.2-3). The solvent is removed under reduced pressure to yield 28.1 g of the title compound as pale yellow oil.
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([C:8](OCC)=[O:9])[N:5]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:3]=1.[BH4-].[Na+].I.C([O-])(O)=O.[Na+]>CCO>[OH:9][CH2:8][C:6]1[N:5]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:3]=[C:2]([I:1])[CH:7]=1
Reactant: CCOC(=O)c1cc(I)cc(C(=O)OCC)n1
Agent: I
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CCO
Product: CCOC(=O)c1cc(I)cc(CO)n1
Reaction time: 0.67 h
Yield: 62.7 %

Procedure:
Compound 1 (5.24 g, 15.0 mmol) was dissolved in EtOH (270 ml) at 40° C. NaBH4 (0.57 g, 15 0 mmol) was carefully added and the mixture stirred for 40 min. The reaction was stopped by adjusting the pH to 3 with 28% (w/w) aqueous hydriodic acid. The mixture was neutralized with saturated NaHCO3 solution and evaporated to dryness. The residue was suspended in water (150 mL) and the product was extracted from the aqueous phase with 10% EtOH/CH2Cl2 solution (3×150 ml). The combined organic fractions were dried with Na2SO4 and evaporated to dryness. Purification on silica gel (petroleum ether, by 40-60° C./ethyl acetate 2:5) yielded 2.89 g (63%) of the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH:11]=[CH:10][C:9]=1[NH:20][C:21](=[O:37])[CH2:22][C:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[CH:25]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:32]1[CH:33]=[CH:34][CH:35]=[C:30]([C:26]2[CH:25]=[C:24]([C:23]3[CH2:22][C:21](=[O:37])[NH:20][C:9]4[CH:10]=[CH:11][C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:13][C:8]=4[N:7]=3)[CH:29]=[CH:28][CH:27]=2)[CH:31]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)ccc1NC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3cccnc3)c2)=Nc2cc(OCC(F)(F)F)ccc2N1

Procedure:
The title compound was prepared from [2-[3-oxo-3-(3-pyridin-3-yl-phenyl)-propionylamino]-5-(2,2,2-trifluoro-ethoxy)-phenyl]-carbamic acid tert-butyl ester (Example M53) (356 mg, 0.67 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (190 mg).
Reaction SMILES: Br[C:2]1[C:3]([O:37][CH3:38])=[CH:4][C:5]2[CH2:6][CH2:7][N:8]3[C:14]4[C:15](=[O:31])[N:16]([CH:28]([CH3:30])[CH3:29])[CH2:17][CH2:18][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][C:13]=4[C:12]([C:32]4[S:33][CH:34]=[CH:35][CH:36]=4)=[C:9]3[C:10]=2[CH:11]=1.[N:39]1[CH:44]=[CH:43][CH:42]=[C:41](B(O)O)[CH:40]=1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[CH:28]([N:16]1[C:15](=[O:31])[C:14]2[N:8]3[CH2:7][CH2:6][C:5]4[CH:4]=[C:3]([O:37][CH3:38])[C:2]([C:41]5[CH:40]=[N:39][CH:44]=[CH:43][CH:42]=5)=[CH:11][C:10]=4[C:9]3=[C:12]([C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)[C:13]=2[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18][CH2:17]1)([CH3:30])[CH3:29]
Reactant: OB(O)c1cccnc1
Reactant: COc1cc2c(cc1Br)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)C)CCN(C(=O)OC(C)(C)C)C3
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COc1cc2c(cc1-c1cccnc1)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)C)CCN(C(=O)OC(C)(C)C)C3
Yield: 93.6 %

Procedure:
A mixture of 60 mg of 10l, 22 mg of 3-pyridylboronic acid, 12 mg of Pd(PPh3)4 and 40 mg of K2CO3 in 3 ml of degassed 90% aq. DME was heated under N2 for 16 h. The reaction mixture was poured onto 1M K2CO3 solution and the product was extracted with ethyl acetate. The organic extract was washed once with sat. NaCl, dried and concentrated. The crude material thus obtained was chromatographed over silica gel, using heptane/acetone in a gradient. The isolated product was triturated with diethyl ether, to give 56 mg of 10m, Mp: 207-208° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][OH:10])=[C:6]([OH:8])[CH:7]=1.[OH-].[Na+].Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1.O>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][OH:10])=[C:6]([O:8][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:7]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: OCc1ccc(Cl)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OCc1ccc(Cl)cc1OCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.7 %

Procedure:
To a solution of 5-chloro-2-(hydroxymethyl)phenol (943 mg, 5.95 mmol) and NaOH (3.5 mL, 6.54 mmol, 2M in water) in ethanol (10 mL) was added 4-(bromomethyl)-1-fluorobenzene (1.13 g, 5.95 mmol) slowly, the mixture was then stirred at room temperature overnight. Water was added to the reaction mixture, and extracted with ethyl acetate. The organic phase was collected and washed with water, brine, and dried with anhydrous Na2SO4. The solvent was removed to give 900 mg of the title compound (57%). 1H NMR (400 MHz, CDCl3): δ 2.08 (1H, t, J=6.4 Hz), 4.67 (2H, d, J=6.4 Hz), 5.05 (2H, s), 6.93 (1H, d, J=1.2 Hz), 6.96 (1H, dd, J=1.6 Hz, 8.0 Hz), 7.07-7.11 (2H, m), 7.25 (1H, d, J=6.0 Hz), 7.37-7.40 (2H, m).
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:12][CH2:13][NH2:14]>ClCCl>[Br:1][C:6]1[C:5]([CH2:12][CH2:13][NH2:14])=[C:4]([CH3:3])[C:9]([O:10][CH3:11])=[CH:8][CH:7]=1
Reactant: BrBr
Reactant: COc1cccc(CCN)c1C
Solvent: ClCCl
Product: COc1ccc(Br)c(CCN)c1C
Yield: 114.6 %

Procedure:
Bromine (2.38 g; 14.9 mmol) in dichloromethane (10 ml) was added to a solution of {2-[2-methyl-3-(methyloxy)phenyl]ethyl}amine (Preparation 10; 2.73 g; 16.52 mmol) in dichloromethane (150 ml) over 3 min at 0° C. Removal of the solvent, trituration with diethyl ether, filtration and drying under vacuum gave the title compound (4.17 g) as a pale orange solid.