Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:13][CH:12]([C:14]([N:16]3[CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[O:15])[CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:23][C:24]([CH3:26])=O>CCO.[Pd]>[CH3:23][CH:24]([N:19]1[CH2:20][CH2:21][CH2:22][N:16]([C:14]([CH:12]2[CH2:13][N:10]([C:8]([C:5]3[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=3)=[O:9])[CH2:11]2)=[O:15])[CH2:17][CH2:18]1)[CH3:26]
Reactant: Cc1ccc(C(=O)N2CC(C(=O)N3CCCNCC3)C2)cn1
Reactant: CC(C)=O
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(C(=O)N2CC(C(=O)N3CCCN(C(C)C)CC3)C2)cn1
Yield: 27.5 %

Procedure:
To a stirred solution of 1-({1-[(6-methylpyridin-3-yl)carbonyl]azetidin-3-yl}carbonyl)-1,4-diazepane (60 mg, 0.194 mmol) in EtOH (3 mL) was added Pd/C (10% wt/wt, 6 mg) and acetone (143 μL, 1.95 mmol). The flask was purged with N2 (N2/vacuum cycle×3) and then H2 (H2/vacuum cycle×3). After 24 hours the reaction was filtered through Celite® and concentrated at reduced pressure. Purification by silica FCC (90:9:1 Et2O/MeOH/NH3) and capture and release (SCX-2, flush with MeOH, then release with 7M NH3 in MeOH) gave the title compound (18.4 mg, 27%).
Reaction SMILES: [CH2:1]([CH:3]([OH:14])[C:4]1[CH:13]=[CH:12][C:9]([O:10][CH3:11])=[C:6]([O:7][CH3:8])[CH:5]=1)[CH3:2].[H-].[Na+].[CH2:17](Br)[C:18]#[CH:19]>CN(C)C=O>[CH3:11][O:10][C:9]1[CH:12]=[CH:13][C:4]([CH:3]([O:14][CH2:19][C:18]#[CH:17])[CH2:1][CH3:2])=[CH:5][C:6]=1[O:7][CH3:8]
Reactant: C#CCBr
Reactant: CCC(O)c1ccc(OC)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCOC(CC)c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 20.8 g of α-ethylveratryl alcohol in 15 ml of dimethylformamide is added dropwise with stirring to a suspension of 12.5 g of sodium hydride in 75 ml of dimethylformamide. The mixture is stirred for 0.5 hour at room temperature (about 22°C.), and 11.8 g of propargyl bromide are then added dropwise, the temperature not being allowed to exceed 30°C. After stirring for 3 hours at room temperature, the mixture is cooled in a ice-bath to 5°C., decomposed with ice-cold water at a temperature of approximately 15°C. and extracted three times with 150 ml of diethyl ether. The extract is washed neutral with water, dried over sodium sulphate, filtered and the filtrate evaporated to dryness under reduced pressure. The oily residue is chromatographed on silica gel using benzene/ether (9:1 parts by volume) as the elution agent. There is obtained 1,2-dimethoxy-4-[1-(2-propynyloxy)propyl]-benzene; nD24 = 1.5248.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2([C:27]#N)[CH2:14][CH2:13][N:12]([CH:15]3[C:25]4=[C:26]5[C:21](=[CH:22][CH:23]=[CH:24]4)[CH:20]=[CH:19][CH:18]=[C:17]5[CH2:16]3)[CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33]>C(OCC)C>[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33].[CH:15]1([N:12]2[CH2:11][CH2:10][C:9]3([N:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=4)[C:32](=[O:33])[CH2:27]3)[CH2:14][CH2:13]2)[C:25]2=[C:26]3[C:21](=[CH:22][CH:23]=[CH:24]2)[CH:20]=[CH:19][CH:18]=[C:17]3[CH2:16]1
Reactant: N#CC1(Nc2cccc(F)c2)CCN(C2Cc3cccc4cccc2c34)CC1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCOCC
Product: O=C1CC2(CCN(C3Cc4cccc5cccc3c45)CC2)N1c1cccc(F)c1

Procedure:
Reaction of (RS)-4-(3-fluoro-phenylamino)-1-(acenaphthen-1-yl)-piperidine-4-carbonitrile in accordance with the general method of example 1 and treatment of the base with fumaric acid in diethyl ether yielded the title compound, white solid, m.p. 230° C. and MS: m/e=387.3 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1B(O)O>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:24]2[CH:25]=[C:20]([F:19])[CH:21]=[CH:22][C:23]=2[F:26])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cc(F)ccc1F
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cc(F)ccc2F)cc1[N+](=O)[O-]

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1) and 2,5-difluorobenzene boronic acid according to the general procedure B. Obtained as a yellow solid (2.85 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=[O:4].Br[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][O:22][CH2:23][CH3:24])=[CH:17][CH:16]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>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.O>[CH2:23]([O:22][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)=[CH:16][CH:17]=1)[CH3:24]
Reactant: CCOCc1ccc(Br)cc1
Reactant: COC(=O)c1ccc(B(O)O)cc1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOCc1ccc(-c2ccc(C(=O)OC)cc2)cc1
Temperature: 80 °C
Yield: 73.6 %

Procedure:
To a mixture of 4-methoxycarbonylphenylboronic acid (2.01 g) and 1-bromo-4-ethoxymethylbenzene (2.00 g) in a mixed solvent of ethylene glycol dimethyl ether (20 ml) and 2M aqueous sodium carbonate solution (6 ml) was added tetrakis(triphenylphosphine)palladium (0) (0.54 g). The mixture was heated at 80° C. for 5 hours. After cooling to room temperature, water (150 ml) was added to the reaction mixture and the resulting precipitate was collected by filtration, washed thoroughly with water and dried to give a crude solid. This solid was purified by column chromatography on silica gel (60 g) eluting successively with the following solvents: (1) n-hexane:ethyl acetate=50:1, (2) n-hexane:ethyl acetate=10:1. The fractions containing the object compound were concentrated and dried to give methyl 4-(4′-ethoxymethylphenyl)benzoate as a white solid (1.85 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]([O:23][CH2:24][C:25]2([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[CH2:30][CH2:29][N:28]([C:31](OC(C)(C)C)=O)[CH2:27][CH2:26]2)[CH3:22])[C:5]2[N:9]([CH3:10])[C:8](=[O:11])[N:7](COCC[Si](C)(C)C)[C:6]=2[CH:20]=1.C([BH3-])#N.[Na+].C(O)(=O)C.[F:53][C:54]([F:59])([F:58])[C:55]([OH:57])=[O:56]>>[F:53][C:54]([F:59])([F:58])[C:55]([OH:57])=[O:56].[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]([O:23][CH2:24][C:25]2([C:38]3[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=3)[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]2)[CH3:22])[C:5]2[N:9]([CH3:10])[C:8](=[O:11])[NH:7][C:6]=2[CH:20]=1
Reactant: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2c1n(C)c(=O)n2COCC[Si](C)(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(OCC1(c2ccc(F)cc2)CCN(C)CC1)c1cc(Cl)cc2[nH]c(=O)n(C)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 4-((1-(6-chloro-3-methyl-2-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazol-4-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (26 mg, 0.040 mmol) was dissolved in trifluoroacetic acid (40% in dichloromethane, 1 mL) and stirred at room temperature for 1 h. The reaction was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which were discarded. The crude piperidine was eluted with 2M ammonia in methanol and concentrated. The crude product was dissolved in acetonitrile (1 mL) and treated with formalin (50 μL) followed quickly by sodium cyanoborohydride (5.0 mg, 0.08 mmol). To this was added two small drops of acetic acid over 5 minutes. The reaction was concentrated and the residue taken up in ethyl acetate, washed with saturated sodium bicarbonate, then brine, dried over magnesium sulfate, and concentrated. The crude product was dissolved in ethanol (10 mL) and heated at reflux overnight. The reaction was concentrated and purified by preparative HPLC (28% B isocratic method, TFA/ACN) to give 10.3 mg (47%). 1H-NMR (CD3OD, 500 MHz) δ 7.44 (m, 1.5H), 7.35 (m, 0.5H), 7.14 (m, 1.5H), 7.06 (m, 0.5H), 6.90-7.20 (m, 1H), 6.78 (d, J=2.1 Hz, 0.6H), 6.68 (m, 0.3H), 4.99 (m, 1H), 3.35-3.52 (m, 5H), 3.30 (d, J=9.2 Hz, 1H), 2.55-3.00 (m, 6H), 2.05 (m, 2H), 1.30-1.50 (m, 3H). Mass spec.: 432.1 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[N:14]=[CH:15][C:16]([C:17]([OH:19])=O)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.O[NH:21][C:22](=[NH:33])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([S:29](=[O:32])(=[O:31])[NH2:30])[CH:24]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[N:14]=[CH:15][C:16]([C:17]4[O:19][N:33]=[C:22]([C:23]5[CH:24]=[C:25]([S:29]([NH2:30])(=[O:31])=[O:32])[CH:26]=[CH:27][CH:28]=5)[N:21]=4)=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: N=C(NO)c1cccc(S(N)(=O)=O)c1
Reactant: O=C(O)c1cnn2ccc(-c3ccc(Cl)cc3)nc12
Product: NS(=O)(=O)c1cccc(-c2noc(-c3cnn4ccc(-c5ccc(Cl)cc5)nc34)n2)c1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.22) (137 mg, 0.5 mmol) and N-hydroxy-3-sulfamoyl-benzamidine [CAS-No. 9000-88-7](161 mg, 0.75 mmol) according to general procedure II. Obtained after purification by flash chromatography (dichloromethane/MeOH) and crystallization (dichloromethane) as an off-white solid (86 mg, 38%). MS (ISN) 451.2 [(M−H)−]; mp 223° C.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][CH:8]1[CH2:19][C:18]2[C:10](=[CH:11][C:12]3[CH2:13][CH2:14][CH2:15][C:16]=3[CH:17]=2)[C:9]1=O.Cl>CCOCC>[CH3:7][C:8]1[CH2:19][C:18]2[CH:17]=[C:16]3[C:12](=[CH:11][C:10]=2[CH:9]=1)[CH2:13][CH2:14][CH2:15]3
Reactant: CC1Cc2cc3c(cc2C1=O)CCC3
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CC1=Cc2cc3c(cc2C1)CCC3
Temperature: 0 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
3.8 g (0.1 mol) of LiAlH4 was carefully added under cooling (0° C.) and stirring to the solution of 37.2 g (0.2 mol) of 2-methyl-3,5,6,7-tetrahydro-s-indacen-1(2H)-one in 300 ml of Et2O. The resulting mixture was allowed to warm to room temperature and then was stirred overnight. Next day the mixture obtained was cooled to 0° C. and 10% HCl was carefully added. The organic phase was separated, dried over MgSO4. The 0.5 g of TSA was then added and the reaction mixture was refluxed in 1 h. After that it was washed by water solution of NaHCO3 and saturated water solution of NaCl. The organic phase was dried over MgSO4, evaporated and then isolated by distillation to give 28.5 g of the product (83%). B.p. 140° C./5 torr.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([C:15](=[O:29])[CH2:16][N:17]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:18]([CH3:21])([CH3:20])[CH3:19])[CH:11]=[CH:10][C:9]=2[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=O)C.O1CCCC1.C(OCC)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O>[CH2:22]([N:17]([CH2:16][CH:15]([C:12]1[CH:11]=[CH:10][C:9]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:8]2[C:13]=1[CH:14]=[C:6]([CH2:4][OH:3])[NH:7]2)[OH:29])[C:18]([CH3:20])([CH3:19])[CH3:21])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1cc2c(C(=O)CN(Cc3ccccc3)C(C)(C)C)ccc(OCc3ccccc3)c2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)N(Cc1ccccc1)CC(O)c1ccc(OCc2ccccc2)c2[nH]c(CO)cc12
Yield: 92.4 %

Procedure:
4 g of 7-benzyloxy-4-(N-benzyl-N-tert-butylaminoacetyl)-2-indolecarboxylic acid ethyl ester is combined with 75 ml of absolute tetrahydrofuran and 150 ml of diethyl ether and stirred under ice cooling for 9 hours with 1.2 g of lithium aluminum hydride. Then a small amount of water is added to the reaction mixture, the precipitate is vacuum-filtered, washed with ethyl acetate/diethyl ether, the combined filtrates are concentrated, and the residue is recrystallized from diisopropyl ether, thus obtaining 3.4 g of 2-(N-benzyl-N-tert-butylamino) -1-(7-benzyloxy-2-hydroxymethylindol-4-yl)ethanol, mp 135.5°-136.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12](O)=[O:13])[CH:6]=[C:5]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[N:4]=1.[CH3:29][S:30]([NH2:33])(=[O:32])=[O:31].Cl.CN(C)CCCN=C=NCC.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C1C=CN=CC=1.C(Cl)Cl.O>[CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([NH:33][S:30]([CH3:29])(=[O:32])=[O:31])=[O:13])[CH:6]=[C:5]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[N:4]=1
Reactant: CS(N)(=O)=O
Reactant: COc1ccc(CCNc2cc(-c3cccc(C(=O)O)c3)nc(OC)n2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: COc1ccc(CCNc2cc(-c3cccc(C(=O)NS(C)(=O)=O)c3)nc(OC)n2)cc1
Reaction time: 8 h
Yield: 44.7 %

Procedure:
A solution of 3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzoic acid [100 mg, 0.26 mmol, Example 35(a)], methanesulfonamide (38 mg, 0.4 mmol), and dimethyl-pyridin-4-yl-amine (64 mg, 0.53 mmol) in DCM (5 mL) is treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (101 mg, 0.53 mmol). After 8 hours at 20° C., the mixture is diluted with water, acidified (pH2 with citric acid), and extracted with DCM. The extracts are dried over magnesium sulfate, filtered and concentrated. The residue is subjected to chromatography on silica gel eluting with 10% MeOH in DCM to afford N-(3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzoyl)-methanesulfonamide [53 mg, 45%, Example 25(a)]. LCMS: RT=2.35 minutes, MS: 457 (M+H). 1H NMR (300 MHz, CDCl3) □8.3 (1H, s), 8.08 (1H, brs), 7.9 (1H, d, J=4.8 Hz), 7.34 (1H, brs), 7.12 (2H, d, J=8.4 Hz), 6.82 (2H, d, J=8.4 Hz), 6.46 (1H, brs), 6 (1H, brs), 3.91 (3H, s), 3.76 (3H, s), 3.61 (2H, brs), 3.31 (3H, s), 2.86 (2H, t, J=6.9 Hz).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([OH:21])=[C:8]([CH2:18][CH:19]=[CH2:20])[CH:9]=[C:10]([C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[O:12])[C:5]=2[O:4][CH:3]=1.CC1C2C(OCC=C)=CC=C(C(C3SC=CC=3)=O)C=2OC=1.[H][H]>C(O)C.[Pd]>[CH3:1][C:2]1[C:6]2[C:7]([OH:21])=[C:8]([CH2:18][CH2:19][CH3:20])[CH:9]=[C:10]([C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[O:12])[C:5]=2[O:4][CH:3]=1
Reactant: C=CCc1cc(C(=O)c2cccs2)c2occ(C)c2c1O
Reactant: [H][H]
Agent: [Pd]
Agent: C=CCOc1ccc(C(=O)c2cccs2)c2occ(C)c12
Solvent: CCO
Product: CCCc1cc(C(=O)c2cccs2)c2occ(C)c2c1O

Procedure:
A mixture of 3-methyl-4-hydroxy-5-(2-propen-1-yl)-7-(2-thienoyl)benzofuran, compound 4 (0.228 g, 0.76 mmol) and 5% Pd/C (0.020 g) in absolute ethanol (5 mL) was hydrogenated at 3 atmospheres pressure. After 0.5 hours the requisite amount of hydrogen had been taken up. The catalyst was removed by filtration through celite and the filtrate concentrated to an oil that slowly solidified. Recrystallization of this material from ether/hexane afforded pure 3-methyl-4-hydroxy-5-propyl-7-(2-thienoyl)benzofuran, compound 5 as an off white solid. 1H NMR d 0.98 (3H, t, J=8 Hz), 1.67 (2H, m), 2.40 (3H, s), 2.64 (2H, t, J=6 Hz), 7.14 (1H, m), 7.30 (1H, s), 7.48 (1H, s), 7.63 (1H, d, J=4 Hz), 7.68 (1H, d, J= 4 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].C([O-])(=O)C.[K+].C(OC(=O)C)(=O)C.[N:23](OCCC(C)C)=O>C1C=CC=CC=1>[Cl:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:4]2[C:3]=1[CH:10]=[N:23][NH:5]2
Reactant: CC(C)CCON=O
Reactant: Cc1ccc(N)c(C)c1Cl
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: Cc1ccc2[nH]ncc2c1Cl
Reaction time: 18 h
Yield: 58.1 %

Procedure:
the known 3-chloro-2,4-dimethylaniline (14.9 g, 96 mmol) in 250 mL of anhydrous benzene was treated with potassium acetate (9.4 g, 96 mmol) and acetic anhydride (29.4 g, 288 mmol). This mixture was slowly heated to reflux while a precipitate formed. Subsequently, isoamyl nitrite (17 g, 144 mmol) was added rapidly to the refluxing suspension and heating was continued for 18 hours. The cooled suspension was filtered and the solid rinsed with benzene. The combined filtrates were evaporated and the solid residue was dissolved in 200 mL of ethanol containing 1 mL of conc. hydrochloric acid. This mixture was heated under reflux for 5 hours and the solvent was removed in vacuo. The solid residue was washed with 5% sodium bicarbonate and dissolved in ethyl acetate, dried over sodium sulfate and evaporated to give 9.3 g of intermediate solid.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]O)=[CH:7][CH:6]=1)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:33]>>[Cl:33][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][O:3][CH2:1][CH3:2])=[CH:6][CH:7]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: CCOCc1ccc(CO)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOCc1ccc(CCl)cc1

Procedure:
[4-(Ethoxymethyl)phenyl]methanol (1.52 g) synthesized in Reference Example 39 was dissolved in carbon tetrachloride (20 mL), triphenylphosphine (2.64 g) was added thereto, and the mixture was heated under reflux for 2.5 hr. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in hexane, the insoluble material was filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=20:1) to give the title compound (1.07 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]([F:32])([O:21][C:22]([F:31])([F:30])[C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])[C:3]([F:20])([F:19])[O:4][C:5]1[CH:14]=[C:13]([C:15]([O:17]C)=[O:16])[CH:12]=[CH:11][C:6]=1[C:7]([O:9]C)=[O:8].[OH-].[K+].Cl>O>[Cl:1][C:2]([F:32])([O:21][C:22]([F:30])([F:31])[C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])[C:3]([F:19])([F:20])[O:4][C:5]1[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[CH:12]=[CH:11][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1ccc(C(=O)OC)c(OC(F)(F)C(F)(Cl)OC(F)(F)C(F)(F)C(F)(F)F)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc(C(=O)O)c(OC(F)(F)C(F)(Cl)OC(F)(F)C(F)(F)C(F)(F)F)c1
Temperature: 25 °C

Procedure:
Dimethyl 2-(2-chloro-1,1,2-trifluoro-2-(perfluoropropoxy)ethoxy)terephthalate as prepared in Example 6 (50.00 g, 0.35 mol) was added to a solution of water (726 mL) and potassium hydroxide (KOH, 56.95 g) in a reaction flask. The resulting solution in the reaction flask was heated to reflux overnight, cooled to room temperature (about 25° C.) and then acidified to a pH of ˜1 by adding concentrated HCl until a precipitate formed. The resulting precipitate was filtered and dried under vacuum. Proton NMR of this material showed the desired material, 2-(2-chloro-1,1,2-trifluoro-2-(perfluoropropoxy)ethoxy)terephthalic acid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([NH:14][C:15](=[O:27])[C:16]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH3:18])[CH3:17])[C:11]([OH:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(C)C.[Rh]>[C:23]([O:22][C:20]([NH:19][C:16]([CH3:18])([CH3:17])[C:15]([NH:14][CH:10]([CH2:9][O:8][CH2:1][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)[C:11]([OH:13])=[O:12])=[O:27])=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](COCc1ccccc1)C(=O)O
Agent: [Rh]
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)NC(COCC1CCCCC1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5% rhodium on alumina (80 mg) and (R)-3-benzyloxy-2-(2-tert-butoxy carbonylamino-2-methyl-propionylamino)-propionic acid (500 mg, 1.31 mmol) (intermediate 3A) in isopropanol (12 ml) was stirred under a hydrogen atmosphere at room temperature overnight. To ensure completion, a further 120 mg of catalyst were added and the reaction was left to stir at room temperature under a hydrogen atmosphere for a further 5 h. The reaction mixture was filtered through Celite® (filter material) and concentrated in vacuo to give the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[N:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]([C:22]1[CH:23]=[C:24]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][NH2:35])=[CH:30][CH:29]=2)[CH:25]=[CH:26][CH:27]=1)=[O:21].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.O>[CH3:18][O:19][C:20]([C:22]1[CH:23]=[C:24]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][NH:35][C:9]([C:8]3[C:7]([O:6][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:17][CH:16]=4)=[N:15][CH:14]=[CH:13][CH:12]=3)=[O:11])=[CH:30][CH:29]=2)[CH:25]=[CH:26][CH:27]=1)=[O:21]
Reactant: O=C(O)c1cccnc1Oc1ccc(F)cc1
Reactant: COC(=O)c1cccc(-c2ccc(CN)cc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-c2ccc(CNC(=O)c3cccnc3Oc3ccc(F)cc3)cc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.8 %

Procedure:
To a stirred solution of 290 mg (1.24 mmol.) 2-[4-fluoro-phenoxy]-nicotinic acid, 300 mg (1.24 mmol.) 4′-aminomethyl-biphenyl-3-carboxylic acid methyl ester and 184 mg (1.36 mmol.) 1-hydroxybenzotriazole hydrate in 10 mL dimethylformamide at ambient temperature was added 285 mg (1.49 mmol.) 1-[3-[dimethylamino]propyl]-3-ethylcarbodiimide hydrochloride. The mixture was stirred at ambient temperature for 18 hours then poured into water and extracted with ethyl acetate. The ethyl acetate extracts were combined, washed successively with 1N NaOH, water, brine then dried (MgSO4) and concentrated in vacuo to give an oil. Chromatography on silica Gel eluting with ethyl acetate/hexanes (1:1) gave 310 mg 4′-[[[2-[4-Fluorophenoxy]-pyridine-3-carbonyl]-amino]-methyl]-biphenyl-3-carboxylic acid methyl ester as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][C:5]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:4][N:3]=1.[OH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH:21]([NH:23][C:24](=[O:26])[CH3:25])[CH3:22])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.CN(C)CC(O)=O>O1CCOCC1.[Cu](I)I>[CH:9]([O:8][C:5]1[N:6]=[CH:7][C:2]([O:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][CH:21]([NH:23][C:24](=[O:26])[CH3:25])[CH3:22])=[CH:17][CH:18]=2)=[N:3][CH:4]=1)([CH3:11])[CH3:10]
Reactant: CC(C)Oc1cnc(Br)cn1
Reactant: CC(=O)NC(C)CCc1ccc(O)cc1
Agent: I[Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)NC(C)CCc1ccc(Oc2cnc(OC(C)C)cn2)cc1

Procedure:
2-Bromo-5-isopropoxypyrazine (100 mg, 0.46 mmol), N-[3-(4-hydroxyphenyl)-1-methylpropyl]acetamide (143 mg, 0.69 mmol), cesium carbonate (300 mg, 0.92 mmol), copper iodide (8.77 mg, 0.046 mmol) and N,N-dimethylglycine hydrochloride (19.3 mg, 0.138 mmol) were stirred in 2 ml of dioxane at 100° C. under argon for 7 h. The batch was filtered, the filtrate was concentrated and admixed with ethyl acetate and water, and the organic phase was separated off, concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 88 mg (56%), M+H+: 344.16.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][CH:11]([C:15]2[N:16]=[CH:17][N:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:19]=2)[C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1.[CH2:26](O)[CH2:27][OH:28]>>[NH2:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][CH:11]([C:15]2[N:16]=[CH:17][N:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:19]=2)[C:12]([O:14][CH2:26][CH2:27][OH:28])=[O:13])=[CH:6][CH:5]=1
Reactant: OCCO
Reactant: Nc1ccc(CC(C(=O)O)c2cn(C3CCCCC3)cn2)cn1
Agent: Cl
Product: Nc1ccc(CC(C(=O)OCCO)c2cn(C3CCCCC3)cn2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.4 ml of an HCl-saturated ether solution was added to a solution of 50.0 mg (0.16 mmol) of the compound from example 1i in 1 ml of ethylene glycol and stirred at RT for 1 h. The solution was then concentrated to dryness, and the residue was taken up in sat. NaHCO3 solution and extracted with EA several times. The combined EA extracts were dried, filtered and concentrated. The resulting residue was dried under high vacuum, resulting in 33 mg of the title compound in the form of a pale yellow oil.