Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.B([O-])([O-])O[C:35]1[CH:40]=[C:39]([CH3:41])[C:38]([O:42][CH2:43][CH2:44][O:45][CH2:46][CH3:47])=[C:37]([CH3:48])[CH:36]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>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.C1(C)C=CC=CC=1>[CH2:46]([O:45][CH2:44][CH2:43][O:42][C:38]1[C:39]([CH3:41])=[CH:40][C:35]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[CH:21][CH:22]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)=[CH:36][C:37]=1[CH3:48])[CH3:47]
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: CCOCCOc1c(C)cc(OB([O-])[O-])cc1C
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: Cc1ccccc1
Solvent: CCO
Product: CCOCCOc1c(C)cc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
A mixture of 7-bromo-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (0.3 g), 4-(2-ethoxyethoxy)-3,5-dimethylphenyl borate (0.16 g), 1M potassium carbonate solution (1.3 ml), ethanol (1.3 ml) and toluene (25 ml) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (0.03 g), and the mixture was refluxed under argon atmosphere for 6 hours and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated to precipitate crude crystals, which were collected by filtration, washed with ethyl acetate/hexane, recrystallized from ethanol to give 7-[4-(2-ethoxyethoxy)-3,5-dimethylphenyl]-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 124) (0.32 g) as colorless crystal.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([Mg]Br)=[CH:12][CH:11]=1>C(OCC)C.C(OCC)(=O)C.[Cl-].[NH4+]>[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:5]2([OH:8])[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[CH:12][CH:11]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CN1CCC(=O)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CN1CCC(O)(c2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 32 %

Procedure:
A solution of N-methyl-piperidin-4-one (1.50 g, 13.3 mmol) in diethyl ether (10 mL) was degassed under a nitrogen stream. The solution was cooled to 0° C. in an salt ice bath. To the stirring solution was added 4-fluorophenylmagnesium bromide (1.74 g, 14.6 mmol) dropwise over 5 min. A solid formed partway through the addition, and additional diethyl ether was added (2 mL). The reaction was then stirred at 0° C. for 2 h. To the suspension was added aqueous ammonium chloride (15 mL). The biphasic solution was diluted with ethyl acetate (40 mL) and additional saturated aqueous ammonium chloride (20 mL). The layer was separated, and the organic extract washed with brine (50 mL), dried over sodium sulfate, filtered, and the solvent removed under vacuum to give I-293 (965 mg, 32% yield) as a brown powder. The product was taken on without further purification. 1H NMR (400 MHz, DMSO-d6): 7.51-7.48 (m, 2H), 7.13-7.09 (m, 2H), 4.80 (s, 1H), 2.52-2.53 (m, 3H), 2.36-2.30 (m, 2H), 2.19 (s, 3H), 1.94-1.87 (m, 2H), 1.57-1.54 (m, 2H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH3:14][C:15]1[CH:16]=[C:17]([OH:22])[C:18]([OH:21])=[CH:19][CH:20]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:20]2[CH:19]=[C:18]([OH:21])[C:17]([OH:22])=[CH:16][C:15]=2[CH3:14])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1cc(S(=O)O)ccc1Cl
Reactant: Cc1ccc(O)c(O)c1
Product: Cc1cc(O)c(O)cc1S(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
66 g (297.8 mmol) of 4-chloro-3-nitrobenzenesulphinic acid (produced by reduction of 4-chloro-3-nitrobenzenesulphonyl chloride with sodium sulphite) are condensed with 41.95 g (337.9 mmol) of 4-methyl-1,2-benzenediol in a manner analogous to that described in Example 4, yielding 4-(4-chloro-3-nitrophenylsulphonyl)-5-methyl-1,2-benzenediol in the form of crystals having a melting point of 196°-197° (from ethyl acetate/hexane).
Reaction SMILES: [CH:1]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.[C:34](Cl)(=[O:38])[CH:35]([CH3:37])[CH3:36].CS(C)=O>C1C=CC=CC=1>[C:34]([N:14]([CH:1]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:38])[CH:35]([CH3:37])[CH3:36]
Reactant: CC(C)C(=O)Cl
Reactant: CCOC(=O)CCCCCNC(c1ccccc1)c1ccccc1
Solvent: CS(C)=O
Solvent: c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCCCN(C(=O)C(C)C)C(c1ccccc1)c1ccccc1
Yield: 91.7 %

Procedure:
Analogously to Example 19, 7 g of ethyl 6-benzhydrylaminocaproate and 3.1 g of ethyl diisopropylamine are dissolved in 100 ml of benzene and reacted with 2.5 g of isobutyryl chloride. As reaction product one obtains 7.8 g of ethyl N-isobutyryl-6-benzhydrylaminocaproate as a viscous non-distillable oil. The saponification of this ester yields 6.1 g (77%) of N-isobutyryl-6-benzhydrylaminocaproic acid (M.P. 106° to 107°).
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[CH2:7]([O:9][C:10](=[O:19])[CH2:11][C:12]1[C:17](=[O:18])[CH2:16][CH2:15][CH2:14][CH:13]=1)[CH3:8].O>CS(C)=O>[CH2:7]([O:9][C:10](=[O:19])[CH2:11][C:12]12[CH2:2][CH:13]1[CH2:14][CH2:15][CH2:16][C:17]2=[O:18])[CH3:8]
Reactant: C[S+](C)(C)=O
Reactant: CCOC(=O)CC1=CCCCC1=O
Agent: [I-]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)CC12CC1CCCC2=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76.3 %

Procedure:
Sodium hydride (18.1 mmol, 543 mg of an 80% dispersion in mineral oil) was washed with 2×5 mL of petroleum ether under nitrogen, then it was dried and trimethylsulfoxonium iodide (3.99 g, 18.1 mmol) was added to the flask followed by 21.6 mL dimethylsulfoxide added dropwise. Next, a solution of 6-oxo-1-cyclohexeneacetic acid ethyl ester (2.90 g, 17.3 mmol) was added dropwise as a solution in 4.5 mL of dimethylsulfoxide as the reaction mixture was cooled with a water bath. After the addition, the reaction mixture was stirred at room temperature for 1.5 hours then poured into 80 mL of cold water and extracted with 4×60 mL of ether. The extracts were combined, washed with 80 mL of brine, dried over magnesium sulfate and concentrated affording 2.4 g (13.2 mmol, 73% yield) of the title compound as a yellow oil.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[C:12]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([NH2:26])=[N:24][CH:25]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:27][C:28]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:29]=1[CH:30]=O.C([BH3-])#N>C(O)C.C(O)(=O)C>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[C:12]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([NH:26][CH2:30][C:29]4[C:32]([F:36])=[CH:33][CH:34]=[CH:35][C:28]=4[Cl:27])=[N:24][CH:25]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccc(Cc2cn(S(=O)(=O)c3ccccc3)c3ncccc23)cn1
Reactant: O=Cc1c(F)cccc1Cl
Agent: [BH3-]C#N
Solvent: CCO
Solvent: CC(=O)O
Product: O=S(=O)(c1ccccc1)n1cc(Cc2ccc(NCc3c(F)cccc3Cl)nc2)c2cccnc21

Procedure:
5-(1-Benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine (600, 30 mg, 0.083 mmol, prepared as described in Example 68, Scheme 185) was combined with 2-chloro-6-fluoro-benzaldehyde (616, 26.2 mg, 0.165 mmol) in a 2 mL microwave reaction vial. The mixture was dissolved in ethanol:acetic acid (95:5, 0.6 mL). Silica supported cyanoborohydride (1.0 mmol/g, 83 mg, 0.083 mmol) was added and the mixture was irradiated with microwave on 300 watts for 5 minutes at 100° C. The silica was separated by centrifuging and the supernatant solution was decanted. The silica residue was rinsed with ethanol (0.500 mL) and centrifuged. The solvents were combined and removed under reduced pressure to give compound 617, which was used in the next step without further purification.
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Br)=[O:4].C(N(CC)CC)C.[CH2:14]([S:21][CH2:22][CH2:23][OH:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[Br:1][CH:2]([CH3:6])[C:3]([O:24][CH2:23][CH2:22][S:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:4]
Reactant: CC(Br)C(=O)Br
Reactant: OCCSCc1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(Br)C(=O)OCCSCc1ccccc1

Procedure:
A solution of 21.6 g of 2-bromopropionyl bromide in 30 ml of toluene was added dropwise to a solution of 10.1 g of triethylamine and 16.8 g of 2-benzylthioethanol in 150 ml of toluene at room temperature whilst stirring. After the addition was completed, the reaction mixture was stirred for a further 2 hours at room temperature. The mixture was then washed successively with 1% strength by weight aqueous solution of sodium hydroxide and water. After drying the organic phase over anhydrous sodium sulphate, the toluene was distilled off under reduced pressure, and the end product of 2-benzylthioethyl 2-bromopropionate was obtained in a yield of 28.8 g as a colorless product. nD20 =1.5570.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=1.[Li+].CC([N-]C(C)C)C.[CH2:29]([Si:31]([CH2:35][CH3:36])([CH2:33][CH3:34])Cl)[CH3:30]>C1COCC1>[Br:13][C:14]1[CH:19]=[C:18]([Si:31]([CH2:35][CH3:36])([CH2:33][CH3:34])[CH2:29][CH3:30])[C:17]([F:20])=[CH:16][N:15]=1
Reactant: Fc1ccc(Br)nc1
Reactant: CC[Si](Cl)(CC)CC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)c1cc(Br)ncc1F
Yield: 96 %

Procedure:
To a solution of diisopropylamine (25.3 g, 250 mmol) in THF (400 ml) was added n-BuLi (100 ml, 2.5 mol/L in hexanes) below −50° C. A solution of 2-bromo-5-fluoropyridine (41.9 g, 238 mmol) in THF (60 ml) was added to the LDA-solution at −78° C. in a dropwise manner below −63° C. After 60 minutes at −78° C. triethylchlorosilane (44 ml, 262 mmol) was added in a fast manner keeping the temperature below −50° C. The cooling bath was removed and the reaction mixture was allowed to reach −20° C. The reaction mixture was poured on a mixture of 1M aq. HCl (250 ml) and aq. NH4Cl (10%). Tert.-butyl methyl ether was added and the layers were separated. The organic phase was washed with brine, dried over magnesium sulfate, filtered and evaporated to give a yellow liquid. Distillation (bp. 99-101° C., 0.5 mmHg). afforded the title compound as a slightly yellow liquid: 66.26 g (96% yield).
Reaction SMILES: [C:1]1([C:7](=O)[C:8](=O)[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:12][CH:13]([C:17]([NH2:19])=[O:18])[C:14]([NH2:16])=[O:15]>>[CH3:9][C:8]1[NH:16][C:14](=[O:15])[C:13]([C:17]([NH2:19])=[O:18])=[N:12][C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)C(=O)c1ccccc1
Reactant: NC(=O)C(N)C(N)=O
Product: Cc1[nH]c(=O)c(C(N)=O)nc1-c1ccccc1

Procedure:
In analogy to the procedure described in example 12 1-phenyl-1,2-propanedione and 2-aminomalonamide were heated in an aqueous solution to give 5-methyl-3-oxo-6-phenyl-3,4 -dihydro-pyrazine-2-carboxylic acid amide. Then, the 5-methyl-3-oxo-6-phenyl-3,4-dihydro-pyrazine-2-carboxylic acid amide was treated with triethylamine and phosphorus pentachloride in phosphorus oxychloride at reflux to give the 3-chloro-5-methyl-6-phenyl-pyrazine-2-carbonitrile. The 3-chloro-5-methyl-6-phenyl-pyrazine-2-carbonitrile was finally treated with 2,3,4,5-tetrahydro-1H-benzo[d]azepine hydrochloride (J. Heterocycl. Chem. 1971, 8(5), 779-83) and N-ethyldiisopropylamine in N,N-dimethylformamide at room temperature to yield the 5-methyl-6-phenyl-3-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-pyrazine-2-carbonitrile as yellow amorphous solid; MS: 341 (M+H)+.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([C:12]1[NH:13][N:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15](=[O:17])[CH:16]=1)([OH:11])=[O:10].[S:24](=O)(=[O:27])([OH:26])[OH:25]>C(OCC)(=O)C>[CH2:1]([O:10][C:9]([C:12]1[NH:13][N:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15](=[O:17])[CH:16]=1)=[O:11])[CH3:2].[C:9]([C:12]1[NH:13][N:14]([CH2:1][C:2]2[CH:7]=[CH:6][C:5]([S:24]([OH:27])(=[O:26])=[O:25])=[CH:4][CH:3]=2)[C:15](=[O:17])[CH:16]=1)([OH:11])=[O:10]
Reactant: O=Cc1ccccc1
Reactant: O=S(=O)(O)O
Reactant: O=C(O)c1cc(=O)n(-c2ccccc2)[nH]1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(=O)n(-c2ccccc2)[nH]1
Product: O=C(O)c1cc(=O)n(Cc2ccc(S(=O)(=O)O)cc2)[nH]1
Temperature: 110 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
3-Ethoxycarbonyl-1-phenylpyrazoline-5-one (F-1) was prepared in the same manner as in Synthesis 1-(1), except benzaldehyde was used in place of sodium 2-formylbenzenesulfonate. Further, (F-1) was hydrolyzed by the same method as used in Synthesis 1-(5) to be converted to 3-carboxy-1-phenylpyrazoline-5-one (F-2). 7 g of (F-2) was added to 28 ml of concentrated sulfuric acid and heated at 110° C. for 2 hours. After cooling, 140 ml of ethyl acetate was added to the reaction mixture and allowed to stand overnight to yield 7.8 g (yield: 82%) of Intermediate F. Melting Point: 276° C. (decomposed).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:11][CH:12]([C:18]([CH3:20])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>CC(C)=O>[ClH:11].[N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[NH:6][C:2]=1[S:1][CH:12]([C:18]([CH3:20])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: CC(C)=O
Product: CCOC(=O)C(Sc1nc2ccccc2[nH]1)C(C)=O
Product: Cl
Temperature: 25 °C
Yield: 96.4 %

Procedure:
Acetone (1.5 L) solution of 2-mercaptobenzoimidazole (150 g) and ethyl 2-chloroacetoacetate (247 g) was heated under reflux for 5 hours. The reaction solution was cooled to room temperature, and then the resulting precipitate was collected by filtration to obtain ethyl 2-[(benzoimidazol-2-yl)thio]acetoacetate hydrochloride (303 g) as colorless crystals. The thus obtained crystals (45 g) were dissolved in DMF (200 ml), and the solution was mixed with Py (32 ml) and acetic acid formic acid anhydride (35 g) and stirred for 3 hours while heating at 100° C. After cooling, the reaction solution was poured into water, and the resulting precipitate was collected by filtration and washed with water. The thus obtained solid was dried under a reduced pressure, purified by a column chromatography (eluent; CHCl3) and then recrystallized from EtOAc/Hex to obtain the title compound (22 g).
Reaction SMILES: C[O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13]C)=[C:5]([CH3:15])[C:4]=1/[CH:16]=[C:17](\[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])/[C:18]([OH:20])=[O:19].C1(=O)C2C(=CC=CC=2)C(=O)C=C1/C=C(\C)/C(O)=O>CCOCC>[CH3:15][C:5]1[C:6](=[O:13])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3](=[O:2])[C:4]=1/[CH:16]=[C:17](\[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])/[C:18]([OH:20])=[O:19]
Reactant: CCCCCCCCC/C(=C\c1c(C)c(OC)c2ccccc2c1OC)C(=O)O
Agent: C/C(=C\C1=CC(=O)c2ccccc2C1=O)C(=O)O
Solvent: CCOCC
Product: CCCCCCCCC/C(=C\C1=C(C)C(=O)c2ccccc2C1=O)C(=O)O

Procedure:
Compound 35c was prepared from 99c (0.152 g, 0.381 mmol) as described above for 30a to give 0.050 g (0.14 mmol, 36%) of the product as a yellow solid following flash chromatography (2:3 Et2O:hexanes 0.5% AcOH) and recrystallization from Et2O/hexanes.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[H-].[Na+].[H][H].[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29](Br)([F:31])[F:30]>CN(C=O)C>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[Br:22])([F:31])[F:30])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([F:31])([F:30])[O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:16])([F:17])[F:1])=[CH:4][CH:5]=2)=[CH:10][CH:11]=1
Reactant: [H][H]
Reactant: FC(F)(Br)c1ccccc1Br
Reactant: Oc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(-c2ccc(OC(F)(F)c3ccccc3Br)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a cooled (0° C.) solution of 4′-(trifluoromethyl)[1,1′-biphenyl]-4-ol (178 mg, 0.75 mmol) in DMF was added sodium hydride (27.0 mg, 1.12 mmol). Once the hydrogen evolution subsided, the reaction mixture was allowed to warm to ambient temperature. The title compound from Example 303 Step A (373 mg, 1.30 mmol) was then added to the reaction flask, and the reaction mixture was stirred at 60° C. After 15 h, the reaction mixture was quenched by addition of 2 N aqueous HCl. The aqueous phase was extracted with hexanes/ethyl acetate (3:1 v/v). The organic phase was separated, dried over sodium sulfate and concentrated in vacuo. Purification was by flash chromatography on silica gel (0-20% dichloromethane in hexanes) provided the title compound: LCMS m/z 423.5 [M−F]+; 1H NMR (500 MHz, CD2Cl2) δ 7.85 (dd, J=7.8, 1.6 Hz, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.72 (s, 4H), 7.65 (dd, J=6.8, 1.9 Hz, 2H), 7.45 (d, J=8.7 Hz, 3H), 7.40 (td, J=7.7, 1.5 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[C:23]([CH3:33])=[CH:24][C:25]([O:31][CH3:32])=[C:26]([CH:30]=1)[C:27](O)=[O:28].Cl.[N:35]1[CH:40]=[CH:39][C:38]([C:41]2([NH2:44])[CH2:43][CH2:42]2)=[N:37][CH:36]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[F:1][C:2]1[C:7]2[C:8]([C:18]([NH:19][CH3:20])=[O:21])=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:30]=[C:26]([C:27](=[O:28])[NH:44][C:41]2([C:38]3[CH:39]=[CH:40][N:35]=[CH:36][N:37]=3)[CH2:43][CH2:42]2)[C:25]([O:31][CH3:32])=[CH:24][C:23]=1[CH3:33]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)c(F)c12
Reactant: NC1(c2ccncn2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ccncn5)CC4)c(OC)cc3C)c(F)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.080 g, 0.185 mmol, 1.0 eq), 1-(pyrimidin-4-yl)cyclopropanamine HCl (0.025 g, 0.185 mmol, 1.0 eq) in DMF and at 0° C. was added TEA (0.094 g, 0.930 mmol, 5.0 eq) and BOP reagent (0.120 g, 0.271 mmol, 1.5 eq). The reaction mixture was warmed to RT, and stirring was continued at RT overnight. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by prep HPLC. Yield: 0.058 g (58.0%). 1H NMR (400 MHz, CD3OD): δ 9.03 (s, 1H), 8.64 (d, J=1.4 Hz, 1H), 7.97-7.79 (m., 2H), 7.76 (s, 1H), 7.65 (d, J=5.6 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H), 7.31-7.25 (m, 3H), 7.19 (s, 1H), 4.09 (s, 3H), 2.95 (s, 3H), 2.30 (s, 3H), 1.88-1.85 (m, 2H), 1.55-1.52 (m, 2H). 19F NMR (376.57 MHz, CD3OD): δ −77.58 (TFA), −112.32, −122.76. LCMS: (ES+) m/z=569.2 (M+H)+
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.Cl.[F:7][C:8]1[CH:9]=[C:10]([CH:32]=[CH:33][CH:34]=1)[CH2:11][N:12]1[C:16]2=[C:17]([N:21]3[CH2:30][CH2:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22]3)[N:18]=[CH:19][CH:20]=[C:15]2[CH:14]=[C:13]1[CH3:31].[C:35](=O)(O)[O-:36].[Na+]>CN(C)C=O>[ClH:3].[CH2:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:29][CH2:30][N:21]1[C:17]1[N:18]=[CH:19][CH:20]=[C:15]2[C:14]([CH:35]=[O:36])=[C:13]([CH3:31])[N:12]([CH2:11][C:10]3[CH:32]=[CH:33][CH:34]=[C:8]([F:7])[CH:9]=3)[C:16]=12
Reactant: O=C([O-])O
Reactant: Cc1cc2ccnc(N3CCc4ccccc4C3)c2n1Cc1cccc(F)c1
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(C=O)c2ccnc(N3CCc4ccccc4C3)c2n1Cc1cccc(F)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Phosphorus oxychloride (44 μl, 0.47 mmol) was added to a solution of 2-[1-(3-fluorobenzyl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-7-yl]-1,2,3,4-tetrahydroisoquinoline hydrochloride (115 mg, 0.31 mmol) prepared in Example 613 in N,N-dimethylformamide (2 ml). The reaction mixture was stirred overnight at 100° C. under heating. The reaction mixture was cooled to room temperature, added to ice water, basified with a sodium bicarbonate solution, and then extracted with ethyl acetate. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/1, v/v). The resulting product was dissolved in ethyl acetate, saturated with hydrochloric acid gas, and then filtered to give 28 mg of the titled compound as a white solid.
Reaction SMILES: [CH2:1]([C:8]1([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(=O)CC>[CH2:1]([C:8]1([OH:14])[CH2:13][CH2:12][N:11]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:21][CH:20]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1(Cc2ccccc2)CCNCC1
Reactant: BrCCOc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: OC1(Cc2ccccc2)CCN(CCOc2ccc(OCc3ccccc3)cc2)CC1
Temperature: 25 °C
Yield: 98 %

Procedure:
A mixture of 4-benzyl-4-hydroxy-piperidine (0.62 g, 3.3 mmol), 1-(2-bromoethoxy)-4-(phenylmethoxy)-benzene (1.0 g, 3.3 mmol) and potassium carbonate (0.9 g, 6.5 mmol) in 2-butanone (15 ml) was refluxed overnight. It was cooled to room temperature, 30 ml of H2O were added and the organic phase was separated. The water phase was extracted two times with ethyl acetate. The organic phases were then pooled, dried with Na2SO4 and the solvent evaporated to give 4-benzyl-1-[2-(4-benzyloxy-phenoxy)-ethyl]-piperidin-4-ol as a yellowish solid (1.35 g, 99%). MS: m/e=418.4 (M+H+).
Reaction SMILES: [CH2:1]([C:3]1([CH3:23])[CH:8]([CH3:9])[CH:7]([OH:10])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[N:4]1[O:14][CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])[CH3:2].C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>C1(C)C=CC=CC=1>[CH2:1]([C:3]1([CH3:23])[CH:8]([CH3:9])[CH:7]([O:10][C:31](=[O:33])[CH3:32])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[N:4]1[O:14][CH:15]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH3:16])[CH3:2]
Reactant: CCC1(C)CC(O)C(C)C(C)(CC)N1OC(C)c1ccccc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCC1(C)CC(OC(C)=O)C(C)C(C)(CC)N1OC(C)c1ccccc1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a solution of 6.36 g (2 mmol) of 2,6-diethyl-2,3,6-trimethyl-1-(1-phenyl-ethoxy)-piperidin-4-ol (prepared as described in GB 2335190, example 7, compound 102) and 2.02 g (2 mmol) of triethylamine in 50 ml toluene are added 1.57 g (2 mmol) acetyl chloride at 0–5° C. and the reaction mixture is stirred for 2 hours at 20° C. The reaction mixture is then several times extracted with water. The organic phase is dried over Na2SO4 and after removing the solvent 6.9 g (96%) acetic acid 2,6-diethyl-2,3,6-trimethyl-1-(1-phenyl-ethoxy)-piperidin-4-yl ester are obtained as yellowish liquid.