Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([C:23]([CH3:25])=[CH2:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][C:34]=2[O:37][CH2:38][CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)[CH2:29]1)=[O:27])C1C=CC=CC=1.Cl.CCOC(C)=O>CC(C)=O>[OH:8][C:9]1[CH:14]=[C:13]([OH:15])[C:12]([CH:23]([CH3:25])[CH3:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][C:34]=2[O:37][CH2:38][CH2:39][CH2:40][N:41]2[CH2:42][CH2:43][O:44][CH2:45][CH2:46]2)[CH2:29]1)=[O:27]
Reactant: C=C(C)c1cc(C(=O)N2Cc3cccc(OCCCN4CCOCC4)c3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: Cl
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC(C)c1cc(C(=O)N2Cc3cccc(OCCCN4CCOCC4)c3C2)c(O)cc1O

Procedure:
Hydrogenation of (2,4-bis-benzyloxy-5-isopropenyl-phenyl)-[4-(3-morpholin-4-yl-propoxy)-1,3-dihydro-isoindol-2-yl]-methanone (as described in method A5) followed by treatment with saturated HCl/EtOAc and trituration with hot acetone afforded 890 mg of the title compound (hydrochloride salt) as a cream solid. 1H NMR (DMSO-d6) 10.78 (1H, br s), 10.05 (1H, br s), 9.55 (1H, br s), 7.30 (1H, t), 7.08 (1H, s) 6.98-6.90 (2H, m), 6.45 (1H, s), 4.80 (2H, s), 4.75 (2H, s), 4.15 (2H, t), 3.95 (2H, br m), 2.80 (2H, br m), 3.50-3.35 (2H, br m), 3.25 (2H, br m,), 3.18-3.02 (3H, br m), 2.20 (2H, br m), 1.15 (6H, d). MS: [M+H]+ 441.
Reaction SMILES: [SH2:1].[CH2:2]([O:4][C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][C:12]([C:19]#[N:20])=[C:13]([F:18])[CH:14]=2)[N:9]([CH2:21][CH3:22])[CH:8]=1)=[O:6])[CH3:3]>N1C=CC=CC=1.C(N(CC)CC)C>[CH2:2]([O:4][C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][C:12]([C:19](=[S:1])[NH2:20])=[C:13]([F:18])[CH:14]=2)[N:9]([CH2:21][CH3:22])[CH:8]=1)=[O:6])[CH3:3]
Reactant: CCOC(=O)c1cn(CC)c2cc(C#N)c(F)cc2c1=O
Reactant: S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCOC(=O)c1cn(CC)c2cc(C(N)=S)c(F)cc2c1=O
Reaction time: 8 h

Procedure:
Hydrogen sulfide was passed through a solution of 1.50 g (5.2 mmol) 7-cyano-1-ethyl-6-fluoro-4-oxo-3-quinolinecarboxylic acid ethyl ester in 25 ml pyridine and 1 ml triethylamine for five hours. After stirring overnight in a closed flask, the precipitated solid was filtered, washed with pyridine and ether, and dried to afford 1.28 g of yellowish solid of the title compound, mp 198°-199° C. (dec).
Reaction SMILES: [CH:1]1([CH:4]([C:6]2[CH:16]=[CH:15][C:9]3[O:10][C:11]([F:14])([F:13])[O:12][C:8]=3[CH:7]=2)O)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[F:24][C:25]1[CH:26]=[C:27]2[C:31](=[C:32]([CH2:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH:33]=1)[NH:30][CH:29]=[CH:28]2>ClCCl>[CH:1]1([CH:4]([C:6]2[CH:16]=[CH:15][C:9]3[O:10][C:11]([F:14])([F:13])[O:12][C:8]=3[CH:7]=2)[C:28]2[C:27]3[C:31](=[C:32]([CH2:34][S:35]([CH3:38])(=[O:36])=[O:37])[CH:33]=[C:25]([F:24])[CH:26]=3)[NH:30][CH:29]=2)[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Cc1cc(F)cc2cc[nH]c12
Reactant: OC(c1ccc2c(c1)OC(F)(F)O2)C1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)Cc1cc(F)cc2c(C(c3ccc4c(c3)OC(F)(F)O4)C3CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
100 mg (0.44 mmol) of the compound from Example 157A and 0.04 ml (0.53 mmol) of trifluoroacetic acid were added to 100 mg (0.44 mmol) of the compound from Example 87A in 5 ml of dichloromethane. The reaction mixture was stirred at RT for 45 min, the solvent was removed in vacuo, and the crude product was then purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 151 mg (78% of theory) of the title compound were obtained.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=1.[F:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=1[F:27]>>[F:20][C:21]1[CH:22]=[C:23]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[C:7]([CH3:17])[C:6]=3[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=2)[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCCNC2=O
Product: Cc1c2n(c3c(-c4ccc(F)c(F)c4)cc(C#N)cc13)CCCNC2=O

Procedure:
The title compound, white solid (54 mg, 62%), MS (ISP) m/z=352.5 [(M+H)+], mp 278° C., was prepared in accordance with the general method of example 1 from 7-bromo-11-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 17) (79.5 mg, 0.25 mmol) and commercially available 3,4-difluoro-phenylboronic acid (51.3 mg, 0.325 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1.C1(C)C=CC(S([O:37][CH:38]2[CH2:42][CH2:41][CH:40](O)[CH2:39]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][CH:40]2[CH2:41][CH2:42][CH:38]([OH:37])[CH2:39]2)=[CH:25][CH:26]=1
Reactant: OC[C@H]1O[C@](O)(c2ccc(Cl)c(Cc3ccc(O)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: Cc1ccc(S(=O)(=O)OC2CCC(O)C2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: OC[C@H]1O[C@](O)(c2ccc(Cl)c(Cc3ccc(OC4CCC(O)C4)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 70 °C
Reaction time: 16 h

Procedure:
A mixture of 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzene (0.25 g), 3-hydroxy-cyclopent-1-yl p-tolylsulfonate (0.19 g) and cesium carbonate (0.33 g) in dimethylformamide (1.5 mL) is stirred at 70° C. for 16 h. After cooling to ambient temperature, water is added and the resultant mixture is extracted with ethyl acetate. The combined organic phases are dried (Na2SO4), the solvent is removed and the residue is purified by chromatography on silica gel (dichloromethane/methanol 1:0→4:1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([OH:16])=O)=[C:12]([CH3:17])[NH:11][C:10](=[O:18])[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[CH3:29][N:26]1[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][CH2:20][NH:19][C:14]([C:13]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[NH:9][C:10](=[O:18])[NH:11][C:12]=2[CH3:17])=[O:16])[CH2:24][CH2:25]1
Reactant: CN1CCN(CCCN)CC1
Reactant: CC1=C(C(=O)O)C(c2cccc(Cl)c2)NC(=O)N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CC1=C(C(=O)NCCCN2CCN(C)CC2)C(c2cccc(Cl)c2)NC(=O)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
225 mg (0.844 mmol) of 4-(3-chlorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid and 159 mg (1.01 mmol) of 1-(aminopropyl)-4-methylpiperazine were dissolved in 10 ml of DMF. 243 mg (1.27 mmol) of WSC hydrochloride was added to the obtained solution under cooling with ice, and they were stirred at room temperature overnight. After the concentration under reduced pressure, the reaction mixture was diluted with ethyl acetate and then washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (dichloromethane/methanol=50/1 to 10/1) to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[CH:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[NH:34]1[CH2:39][CH2:38][S:37][CH2:36][CH2:35]1>C1COCC1.CCOC(C)=O>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:34]4[CH2:39][CH2:38][S:37][CH2:36][CH2:35]4)(=[O:22])=[O:21])[CH:15]=3)[CH:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(S(=O)(=O)Cl)c3)c2)n1
Reactant: C1CSCCN1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(S(=O)(=O)N4CCSCC4)c3)c2)n1
Temperature: 25 °C
Yield: 66 %

Procedure:
The title compound was prepared from the solution of 3-[6-methyl-4-(4-trifluoromethylphenyl)-[2,4′]bipyridinyl-2′-yl]-benzenesulfonyl chloride (example 346 step 2) (ca. 0.2 g, 0.41 mmol) by treatment with excess thiomorpholine in THF (5 mL) at 50° C. for 16 h. Cooled to rt, diluted with EtOAc, washed with 1 N HCl, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with n-heptane/EtOAc followed by trituration with n-heptane/diethyl ether to give the title compound (0.150 g, 66%) as a white solid. MS (ISP) 555.8 [(M+H)+]; mp 156° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[S:5][C:6]=1[CH:7]=[O:8].[O:19]1[CH2:24][CH2:23][CH2:22][O:21][CH:20]1[CH2:25][CH2:26][Mg]Br.[NH4+].[Cl-]>O1CCCC1>[O:19]1[CH2:24][CH2:23][CH2:22][O:21][CH:20]1[CH2:25][CH2:26][CH:7]([C:6]1[S:5][C:4]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:13][CH:14]=2)=[N:3][C:2]=1[CH3:1])[OH:8]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C=O
Reactant: Br[Mg]CCC1OCCCO1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(O)CCC1OCCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution of 4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbaldehyde (200 mg, 0.74 mmol) in tetrahydrofuran (2 ml) was added slowly a 0.5 M solution of (1,3-dioxan-2-ylethyl)magnesiumbromide in tetrahydrofuran (2.06 ml, 1.03 mmol) at ambient temperature under an argon atmosphere. The reaction mixture was stirred 1 h at ambient temperature, saturated aqueous NH4Cl solution was added (15 ml) and the mixture was extracted two times with ethyl acetate. The combined organic layers were washed two times with brine/ice water 1/1 and dried over sodium sulfate. The solvent was removed under reduced pressure to give 280 mg (0.72 mmol, 98%) of the title compound as colorless oil which was used in the next step without further purification.
Reaction SMILES: [C:1]([O-:10])(=[S:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Na+].Cl[CH2:13][CH2:14][CH2:15][Si:16]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19]>[Cl-].C[N+](CCCCCCCC)(CCCCCCCC)CCCCCCCC>[C:1]([S:9][CH2:13][CH2:14][CH2:15][Si:16]([O:17][CH2:18][CH3:19])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCO[Si](CCCCl)(OCC)OCC
Reactant: CCCCCCCC([O-])=S
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Product: CCCCCCCC(=O)SCCC[Si](OCC)(OCC)OCC
Temperature: 50 °C

Procedure:
The aqueous solution of sodium thiooctanoate was heated to 50° C. and stirred with a mechanical stirrer throughout this procedure. To this solution was added 3-chloro-1-propyltriethoxysilane (444 grams, 1.84 moles) all at once. Immediately thereafter was added 0.15 grams of a concentrated aqueous solution of methyltrioctylammonium chloride. A temperature of 50° C. was maintained for 9 hours, with continued stirring, whereupon the temperature was raised to and subsequently maintained at 74° C. for an additional 15 hours, with continuous stirring. At this point, the solution was allowed to cool to ambient temperature, the stirring was stopped, and the organic phase separated from the aqueous phase by decantation in a separatory funnel. Gas chromatography and mass spectrometry (GC and GCMS) revealed a product containing 80% 3-octanoylthio-1-propyltriethoxysilane and 15.5% residual 3-chloro-1-propyltriethoxysilane (reported purities are based on area percent GC responses). The product was vacuum stripped at 110° C. at 0.1 torr to remove volatiles, primarily 3-chloro-1-propyltriethoxysilane, to yield a product of 94% purity. Product identity using this process confirmed by nuclear magnetic resonance spectroscopy (NMR).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:11]([C:26](OCC)=[O:27])=[CH:12][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:14][CH:15]=1.[C:31]([Li])([CH3:34])([CH3:33])[CH3:32].[Cl-].[NH4+]>C1COCC1.CCCCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)=[CH:12][C:11]=1[C:26](=[O:27])[C:31]([CH3:34])([CH3:33])[CH3:32]
Reactant: [Li]C(C)(C)C
Reactant: CCOC(=O)c1cc(OCc2ccc(OC)cc2)ccc1-c1cc(OC)ccc1F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCC
Solvent: C1CCOC1
Product: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(C(=O)C(C)(C)C)c2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere, to a solution of ethyl 2′-fluoro-5′-methoxy-4-((4-methoxybenzyl)oxy)biphenyl-2-carboxylate (524 mg) in THF (10 mL) was added a solution (1.6 M, 1.6 mL) of tert-butyllithium in pentane at −78° C., and the mixture was stirred at −78° C. for 30 min. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (268 mg) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:12][CH3:13])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl[C:15]([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:16]>ClCCl>[CH3:13][O:12][C:3]1[C:2]([NH:1][C:15](=[O:16])[O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1nc2ccccc2cc1N
Solvent: ClCCl
Product: COc1nc2ccccc2cc1NC(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
3-Amino-2-methoxyquinoline(4 g, 23 mmol) and phenyl chloroformate(4.04 g, 25 mmol) were dissolved in dichloromethane and stirred at room temperature for 2 hours. The above mixture was concentrated under the reduced pressure to remove dichloromethane and purified by column chromatography(hexane:ether=8:1) to obtain the titled compound.
Reaction SMILES: [CH3:1][C:2]([S@@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[I-].C([Zn+])C(C)(C)C.[Br:15][C:16]1[CH:17]=[CH:18][C:19]([O:29][CH2:30][O:31][CH3:32])=[C:20]([C:22](=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:21]=1>>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([O:29][CH2:30][O:31][CH3:32])=[C:20]([C:22](=[N:7][S@:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:21]=1
Reactant: CC(C)(C)[S@@](N)=O
Reactant: CCOC(=O)C(=O)c1cc(Br)ccc1OCOC
Agent: CC(C)(C)C[Zn+]
Agent: [I-]
Product: CCOC(=O)C(=N[S@@](=O)C(C)(C)C)c1cc(Br)ccc1OCOC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51 %

Procedure:
A flask was charged with 2,4-dibromophenol (50.4 g, 200 mmol), potassium carbonate (69.1 g, 500 mmol) and acetone (500 mL). The suspension was stirred at RT for 30 minutes and then treated dropwise with chloromethyl ethyl ether (19 mL, 213 mmol). After 3 h at RT the mixture was filtered and the filtrate was partitioned between EtOAc and water. The organic phase was separated, washed with water, aqueous saturated NaHCO3 and brine. The organic phase was dried over MgSO4 and the solvent was removed under reduced pressure to afford 54.2 g 2,4-dibromo-1-(methoxymethoxy)benzene, which was used in the next step without further purification. Step 2: A solution of 2,4-dibromo-1-(methoxymethoxy)benzene (40.5 g, 137 mmol) in Et2O (140 mL) was cooled to −78° C. and treated with n-BuLi (2.5M in hexanes; 60.2 mL, 151 mmol) under nitrogen atmosphere. After 30 minutes a solution of diethyl oxalate (27.9 mL, 205 mmol) in Et2O (20 mL) was added dropwise. The reaction mixture was stirred for 45 minutes at that temperature then quenched cold with saturated ammonium chloride solution. The mixture was partitioned between Et2O and water. The organic phase was separated, washed with water, brine, then dried over MgSO4. The solvent was removed under reduced pressure to afford 49 g of ethyl 2-(5-bromo-2-(methoxymethoxy)phenyl)-2-oxoacetate, which was used in the next step without further purification. Step 3: A flask was charged with (S)-2-methylpropane-2-sulfinamide (0.764 g, 6.31 mmol) and neopentylzinc(II) iodide (0.5 M in THF, 10.0 mL, 5.00 mmol) was added under nitrogen atmosphere. The mixture was stirred at RT for 15 minutes and ethyl 2-(5-bromo-2-(methoxymethoxy)phenyl)-2-oxoacetate (1.00 g, 3.15 mmol) was added in one portion. The reaction mixture was quenched with saturated aqueous ammonium chloride after 8 h. The reaction was partitioned between EtOAc and water. The organic phase was separated, washed with NH4Cl, water and brine. The organic phase was dried over MgSO4 and the solvent was removed under reduced pressure. The crude material was purified by silica gel chromatography (10-30% EtOAc/hexane) to provide 0.675 g (S)-ethyl 2-(5-bromo-2-(methoxymethoxy)phenyl)-2-(tert-butylsulfinylimino)acetate.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])[CH2:12]2)=[N:8][C:9]=1[NH2:10].C(N(CC)CC)C.[C:31]1([CH:37]([CH3:40])[CH:38]=O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(O)C>[C:31]1([CH:37]([C:40]2[NH:10][C:9]3=[N:8][C:7]([N:11]4[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]5[CH2:23][CH2:22][CH2:21][CH2:20]5)=[O:18])[CH2:12]4)=[CH:6][CH:5]=[C:4]3[N:3]=2)[CH3:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C=O)c1ccccc1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(c1ccccc1)c1nc2ccc(N3CCC[C@@H](C(=O)N4CCCC4)C3)nc2[nH]1
Yield: 9.5 %

Procedure:
To a solution of (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone dihydrochloride (Intermediate 1) (0.5 g, 1.7 mmol) in ethanol (20 mL) was added triethylamine (1 mL) and 2-phenylpropanal (0.25 g, 1.9 mmol). The reaction mixture was heated at reflux for 12 h. The mixture was then concentrated under reduced pressure, diluted with ice cold water and extracted with ethyl acetate. The organic layers were dried, filtered and concentrated, and the resulting residue was purified by preparative TLC to afford the title compound (65 mg, 9%). MS (ES+APCI) (M+H) 404.2; LCMS retention time 2.206 min (Method Y).
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.Cl.[NH2:25][OH:26].C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[ClH:1].[ClH:1].[NH2:23]/[C:22](=[N:25]\[OH:26])/[C:20]1[CH:19]=[CH:18][C:16]2[CH:17]=[C:13]([C:11]([NH:10][C@@H:4]3[CH:5]4[CH2:6][CH2:7][N:2]([CH2:9][CH2:8]4)[CH2:3]3)=[O:12])[S:14][C:15]=2[CH:21]=1
Reactant: NO
Reactant: N#Cc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N/C(=N\O)c1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1

Procedure:
800 mg (2.0 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-cyano-1-benzothiophene-2-carboxamide hydrochloride (Example 26A), 278.1 mg (4.0 mmol) of hydroxylamine hydrochloride and 829.5 mg (6.0 mmol) of potassium carbonate are heated in 8 ml of an 8:1 mixture of water and ethanol at 80° C. for 3 h. The mixture is purified by column chromatography on silica gel (mobile phase: dichloromethane/methanol/25% ammonia solution 100:20:4). The product fractions are combined, concentrated, mixed with methanol and 4 M hydrogen chloride in dioxane, then again concentrated and dried under high vacuum. 447.3 mg (53.6% of theory) of the title compound are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][NH:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:29][C:30]2[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=2)=[O:28])=[C:22]([C:39]([F:42])([F:41])[F:40])[CH:21]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.CC(=O)OCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH2:8][C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[C:34](=[O:35])[C:33]2[CH:37]=[CH:38][C:30]([NH:29][C:27](=[O:28])[CH2:26][C:23]3[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][C:22]=3[C:39]([F:42])([F:40])[F:41])=[CH:31][CH:32]=2)=[CH:16][CH:17]=1
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)O)cc2)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)CNCc1ccc(Br)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(Br)cc3)cc2)c(C(F)(F)F)c1
Yield: 91 %

Procedure:
Prepared from INT-60 and INT-18. To a stirring solution of tert-butyl 2-((4-bromobenzyl)amino)acetate INT-60 (2.7 g, 8.99 mmol), 4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzoic acid INT-18 (3.18 g, 8.99 mmol) and TEA (2.507 mL, 17.99 mmol) in DMF was added PyBOP (4.91 g, 9.44 mmol) at room temperature. After 2 h the reaction mixture was diluted with EA (200 mL) and washed with 1 M HCl (100 mL), NaHCO3 (200 mL) and brine (200 mL). The organics were dried over MgSO4, pre-absorbed onto silica gel and purified by chromatography (EA/hexanes) to afford 5.2 g (91%) of tert-butyl 2-(N-(4-bromobenzyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)acetate INT-81 as a white foamy solid. LCMS-ESI (m/z) calculated for C30H30BrF3N2O5: 635; found 579/581 [M-tBu+H]+, tR=2.83 min (Method 10).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[H-].[Na+].[N+]([C:15]1[CH:16]=[C:17]([CH3:22])[N+:18]([O-:21])=[CH:19][CH:20]=1)([O-])=O>CN1CCCC1=O.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:15]2[CH:20]=[CH:19][N+:18]([O-:21])=[C:17]([CH3:22])[CH:16]=2)=[CH:4][C:3]=1[F:9]
Reactant: Oc1ccc(Br)c(F)c1
Reactant: Cc1cc([N+](=O)[O-])cc[n+]1[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1cc(Oc2ccc(Br)c(F)c2)cc[n+]1[O-]
Temperature: 180 °C
Yield: 38.6 %

Procedure:
To a room temperature solution of 4-bromo-3-fluorophenol (6 g, 31.41 mmol) in N-methylpyrrolidone (20 ml) was added sodium hydride (1.34 g, 56 mmol, 60% in mineral oil) portionwise. After stirring for 10 minutes 4-nitro-2-picoline N-oxide (5.6 g, 36.12 mmol) was added. The reaction mixture was heated at 180° C. for 60 minutes under microwave irradiation. After cooling to room temperature the mixture was diluted with EtOAc (250 ml) and washed with water (250 ml). The solution was then extracted with additional EtOAc (2×150 ml) The combined organic extracts were dried (Na2SO4) and the solvent evaporated in vacuo. The crude product was purified by column chromatography (silica gel; DCM to DCM/MeOH(NH3) up to 2% as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate 13 (3.61 g, 39%).