Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[S:14](Cl)(=[O:16])=[O:15].Cl.[CH3:19][O:20][C:21](=[O:34])[C@@H:22]([NH2:33])[CH2:23][NH:24][C:25]([C:27]1[S:28][C:29]([Cl:32])=[CH:30][CH:31]=1)=[O:26]>C(Cl)Cl>[CH3:19][O:20][C:21](=[O:34])[C@@H:22]([NH:33][S:14]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:2]=1[CH3:1])(=[O:16])=[O:15])[CH2:23][NH:24][C:25]([C:27]1[S:28][C:29]([Cl:32])=[CH:30][CH:31]=1)=[O:26]
Reactant: Cc1c(-c2cccnc2)cccc1S(=O)(=O)Cl
Reactant: COC(=O)[C@@H](N)CNC(=O)c1ccc(Cl)s1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)[C@H](CNC(=O)c1ccc(Cl)s1)NS(=O)(=O)c1cccc(-c2cccnc2)c1C
Reaction time: 16 h

Procedure:
Intermediate 75 (0.85 g, 3.17 mmol) was dissolved in 10 ml DCM and TEA (1.55 ml, 11.11 mmol). Intermediate 76 (876 mg, 3.33 mmol) in 10 ml DCM was slowly added at 0° C. and the reaction was stirred for 16 h. After that the solution was evaporated to dryness and purified by silica gel chromatography (cyclohexane/AcOEt from 0% to 100% AcOEt). Yield: 589 mg, 38%
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([NH:9][C:10](=[O:14])[O:11][CH2:12][CH3:13])=[C:4](F)[C:3]=1[N+:16]([O-:18])=[O:17].[CH3:19][OH:20]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([NH:9][C:10](=[O:14])[O:11][CH2:12][CH3:13])=[C:4]([O:20][CH3:19])[C:3]=1[N+:16]([O-:18])=[O:17]
Reactant: CO
Reactant: CCOC(=O)Nc1c(F)cc(Cl)c([N+](=O)[O-])c1F
Solvent: C1COCCO1
Product: CCOC(=O)Nc1c(F)cc(Cl)c([N+](=O)[O-])c1OC
Temperature: 65 °C
Reaction time: 3 h
Yield: 66.8 %

Procedure:
Under a nitrogen atmosphere, a solution of 30.6 grams (0.109 mole) of ethyl N-(4-chloro-2,6-difluoro-3-nitrophenyl)carbamate and 18 mL (0.449 mole) of methanol in 175 mL of dioxane was stirred and 218 mL (0.218 mole) of 1M sodium trimethylsilanoate (in tetrahydrofuran) was added dropwise during a 45 minute period. Upon completion of addition, the reaction mixture was heated to 65° C. where it stirred for three hours. At the conclusion of this period, the reaction mixture was allowed to cool to ambient temperature where it stirred for about 18 hours. The reaction mixture was concentrated under reduced pressure to a residue. The residue was taken up in cold 3N hydrochloric acid. The resulting solid was collected by filtration, washed with petroleum ether, and heat dried under vacuum, yielding 21.3 grams of title compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:35][C:36](=[O:45])[O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:35][C:36](=[O:45])[O:37][CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[O:11])=[CH:13][CH:14]=1
Reactant: NCCCN1CCC(c2cccc(NC(=O)OCc3ccccc3)c2)CC1
Reactant: O=C(O)C(c1ccc(F)cc1)c1ccc(F)cc1
Product: O=C(Nc1cccc(C2CCN(CCCNC(=O)C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c1)OCc1ccccc1

Procedure:
Example 141 was prepared from bis(4-fluorophenyl)acetic acid and benzyl 3-[1-(3-aminopropyl)-4-piperidinyl]phenylcarbamate according to the procedures described in Scheme 9: ESMS m/e: 598.5 (M+H)+.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[C:2]#[CH:3].[C:8]([O:25][CH:26]1[CH2:31][C:30]([CH3:33])([CH3:32])[NH:29][C:28]([CH3:35])([CH3:34])[CH2:27]1)(=[O:24])/[CH:9]=[CH:10]/[C:11]([O:13][CH:14]1[CH2:19][C:18]([CH3:21])([CH3:20])[NH:17][C:16]([CH3:23])([CH3:22])[CH2:15]1)=[O:12]>C(O)C>[C:8]([O:25][CH:26]1[CH2:31][C:30]([CH3:33])([CH3:32])[N:29]([C:2]([C:1]([O:5][CH2:6][CH3:7])=[O:4])=[CH2:3])[C:28]([CH3:35])([CH3:34])[CH2:27]1)(=[O:24])/[CH:9]=[CH:10]/[C:11]([O:13][CH:14]1[CH2:15][C:16]([CH3:23])([CH3:22])[N:17]([C:2]([C:1]([O:5][CH2:6][CH3:7])=[O:4])=[CH2:3])[C:18]([CH3:21])([CH3:20])[CH2:19]1)=[O:12]
Reactant: C#CC(=O)OCC
Reactant: CC1(C)CC(OC(=O)/C=C/C(=O)OC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Solvent: CCO
Product: C=C(C(=O)OCC)N1C(C)(C)CC(OC(=O)/C=C/C(=O)OC2CC(C)(C)N(C(=C)C(=O)OCC)C(C)(C)C2)CC1(C)C
Temperature: 25 °C

Procedure:
44 g of ethanol propiolate were added dropwise to a solution of 78.4 g of bis(2,2,6,6-tetramethyl-4-piperidinyl) fumarate in 300 ml of ethanol at 40° to 60° C. The mixture was then refluxed for 3 hours. The precipitate which resulted on cooling to room temperature was filtered off, washed with petroleum ether and dried. 107 g of the compound of the formula shown below were obtained in the form of a colorless solid of melting point 185°-186° C. ##STR24##
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=2[F:28])[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:32]O.Cl>CO>[F:28][C:19]1[CH:20]=[C:21]([C:24]([F:27])([F:26])[F:25])[CH:22]=[CH:23][C:18]=1[C@H:10]1[CH2:9][C@@H:8]([C:6]2[O:7][NH:32][C:4](=[O:3])[CH:5]=2)[CH2:13][CH2:12][N:11]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](c2ccc(C(F)(F)F)cc2F)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(C(F)(F)F)cc1F
Temperature: -45 °C
Reaction time: 0.33 h
Yield: 76.4 %

Procedure:
Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-fluoro-4-(trifluoromethyl)phenyl)piperidine-1-carboxylate (3 g, 7.15 mmol) was dissolved in MeOH (25 mL) and cooled to −45° C. under nitrogen. Sodium hydroxide (2.104 mL, 7.15 mmol) was added during 10 min and the yellow solution continued to stir at −45° C. for 20 min. Hydroxylamine (50% by weight in water, 0.438 mL, 7.15 mmol) was added during 8 min. The resulting solution was stirred at −45° C. for 3 h. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (36.8 mL, 221.05 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a slightly yellow solid. The compound was purified by preparative HPLC on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 10-60% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Cis-methyl 2-(2-fluoro-4-(trifluoromethyl)phenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (2.12 g, 76%) was isolated as a colourless oil. MS m/z 389 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Br:9])[CH:8]=1)[NH2:5].[C:10]([N:18]=[C:19]=[S:20])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CC(C)=O>[C:10]([NH:18][C:19]([NH:5][C:4]1[CH:3]=[C:2]([Br:1])[CH:8]=[C:7]([Br:9])[CH:6]=1)=[S:20])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Nc1cc(Br)cc(Br)c1
Solvent: CC(C)=O
Product: O=C(NC(=S)Nc1cc(Br)cc(Br)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
To the solution of 3,5-dibromoaniline (65.0 g, 0.26 mol) in anhydrous acetone (1.6 L) was added benzoylisothiocyanate (46.4 g, 0.28 mol) and the reaction mixture was stirred at room temperature for 30 min. Acetone was distilled off and the crude residue was washed with hexane to obtain desired compound as yellow solid (96.5 g, 90%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]1([CH3:17])[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.O>[C:8]1([CH3:17])[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccccc1B(O)O
Reactant: Brc1ccccn1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccccc1-c1ccccn1
Yield: 68.9 %

Procedure:
A mixture of 8.1 g (51.5 mmol) of 2-bromopyridine, 7 g (51.5 mmol) o-tolylboronic acid, 0.47 g (0.51 mmol) of Pd2(dba)3, 0.84 g (2.06 mmol) of 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl and 32 g (154.5 mmol) of potassium phosphate tribasic, 100 mL of toluene and 30 mL of water was purged with nitrogen. The solution was heated to reflux for 12 hours. Upon cooling, the organic layer was separated, and dried with MgSO4. The product was separated by column chromatography using hexanes/ethyl acetate (5% ethyl acetate) as the eluent. The solvent was removed by rotary evaporation, and the product was dried under vacuum resulting in 6 g (35.5 mmol) of 2-(o-tolyl)pyridine.
Reaction SMILES: [O:1]1[CH2:20][CH:2]1[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:14]3[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=3[O:12][N:11]=2)[CH2:6][CH2:5]1.Cl.[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][C:33]=1[O:34][CH3:35])[CH2:30][NH:29][CH2:28][CH2:27]2>C(O)(C)C>[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][C:33]=1[O:34][CH3:35])[CH2:30][N:29]([CH2:20][CH:2]([OH:1])[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]3[C:14]4[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=4[O:12][N:11]=3)[CH2:6][CH2:5]1)[CH2:28][CH2:27]2
Reactant: Fc1ccc2c(C3CCN(CC4CO4)CC3)noc2c1
Reactant: COc1cc2c(cc1OC)CNCC2
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2c(cc1OC)CN(CC(O)CN1CCC(c3noc4cc(F)ccc34)CC1)CC2
Reaction time: 8 h
Yield: 11 %

Procedure:
A stirred mixture of 1-(2,3-epoxypropyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (3.2 g, 11.6 mmol), K2CO (2 gm, 1.25 eq) and 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (3.3 g, 1.25 eq) in isopropyl alcohol (200 ml) was heated at reflux for 6 hours. The mixture was cooled and filtered. The solvent was removed to about 50 ml and the solution was allowed to stand overnight. Crystals (0.6 g) formed and were collected. The mother liquor was concentrated to a white solid. Recrystallization twice from ethanol yielded the product (1.95 g, m.p. 153°-154° C.
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:25]2[O:29][C:28]([CH3:30])=[N:27][C:26]=2[C:31](O)=[O:32])[CH:22]=[CH:23][CH:24]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH:16][C:31]([C:26]3[N:27]=[C:28]([CH3:30])[O:29][C:25]=3[C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([O:18][CH3:17])[CH:20]=3)=[O:32])=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: COc1cccc(-c2oc(C)nc2C(=O)O)c1
Reactant: CC(F)(F)c1ccc(Cn2ccc(N)n2)o1
Product: COc1cccc(-c2oc(C)nc2C(=O)Nc2ccn(Cc3ccc(C(C)(F)F)o3)n2)c1

Procedure:
Following general procedure B, starting from 1-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(3-methoxy-phenyl)-2-methyl-oxazole-4-carboxylic acid. LC-MS-conditions 05b: tR=1.18 min; [M+H]+=443.0.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O>>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1
Reactant: Brc1cncc(N2CC3CC4CC2CN(C4)C3)c1
Reactant: COc1ccccc1B(O)O
Product: COc1ccccc1-c1cncc(N2CC3CC4CC2CN(C4)C3)c1

Procedure:
The title compound was prepared from the product of Example 65A and 2-methoxyphenylboronic acid according to General Method B: LC-MS Method D (ESI+) m/z 336.0 (M+H)+, retention time 1.30 minutes.
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.C(N(CC)CC)C.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.O>C1C=CC=CC=1>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([O:1][N:2]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[N:4]=[N:3]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: On1nnc2ccccc21
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=S(=O)(On1nnc2ccccc21)c1ccc(Cl)cc1
Yield: 87.3 %

Procedure:
In benzene (40 ml) are dissolved 1-hydroxy-1,2,3-benzotriazole (10.6 g) and triethylamine (11.1 ml). To the solution is added dropwise a solution of p-chlorobenzenesulfonyl chloride (16.6 g) in benzene (8 ml) with stirring under ice-cooling during about 20 minutes, and the mixture is stirred at 15° C. for 4 hours. To the reaction mixture is added water and the benzene layer is separated. The aqueous layer is extracted twice with ethyl acetate (100 ml). The extract is combined with the above benzene layer, washed with a small amount of an aqueous sodium hydrogen carbonate and water in order and dried over anhydrous sodium sulfate. After drying, the solvent is distilled off under a reduced pressure. The resulting crystals are cracked in petroleum ether and separated by filtration and dried to give faint yellow crystals of 1-(p-chlorobenzensulfonyloxy)-1,2,3-benzotriazole (21.2 g), melting point: 94°-95° C. Ultraviolet spectrum (methanol): λmax 224 mμ, E=365.
Reaction SMILES: [N:1]1([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH:15]3[CH2:20][CH2:19][CH2:18][N:17]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)[CH:16]3[CH2:27][CH2:28][NH:29][C:30]([CH:32]3[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]3)=[O:31])[N:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(OCC)(=O)C.[ClH:51]>C(OCC)(=O)C>[ClH:51].[ClH:51].[ClH:51].[N:1]1([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH:15]3[CH2:20][CH2:19][CH2:18][N:17]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)[CH:16]3[CH2:27][CH2:28][NH:29][C:30]([CH:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[O:31])[N:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NCCC2C(Nc3nccc(N4CCCCCC4)n3)CCCN2C2CCCCC2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(NCCC1C(Nc2nccc(N3CCCCCC3)n2)CCCN1C1CCCCC1)C1CCNCC1

Procedure:
The compound 23 (74 mg), ethyl acetate (0.6 mL) and 4N hydrogen chloride-ethyl acetate solution (0.6 mL) were stirred at room temperature for 2 hours. The reaction solution was concentrated and obtained the title compound (80 mg) having the following physical properties.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[F:15][C:16]1[CH:17]=[C:18]([CH:28]([NH:30][C:31]([C:33]2[N:34]=[C:35](Cl)[O:36][CH:37]=2)=[O:32])[CH3:29])[CH:19]=[C:20]([F:27])[C:21]=1[NH:22][S:23]([CH3:26])(=[O:25])=[O:24].C([O-])([O-])=O.[Cs+].[Cs+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:27][C:20]1[CH:19]=[C:18]([CH:28]([NH:30][C:31]([C:33]2[N:34]=[C:35]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:11]([F:14])([F:13])[F:12])[CH:4]=3)[O:36][CH:37]=2)=[O:32])[CH3:29])[CH:17]=[C:16]([F:15])[C:21]=1[NH:22][S:23]([CH3:26])(=[O:25])=[O:24]
Reactant: OB(O)c1ccc(F)c(C(F)(F)F)c1
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(NC(=O)c1coc(-c2ccc(F)c(C(F)(F)F)c2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 7.6 %

Procedure:
4-Fluoro-3-trifluoromethylphenylboronic acid (54.1 mg, 0.26 mmol) and 2-chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylaminophenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted using Pd(PPh3)2Cl2 (7 mg, 0.01 mmol), Cs2CO3 (127 mg, 0.39 mmol) as described above to give the title compound (5 mg, 8%) after purification by flash chromatography on silica gel (hexane: EtOAc=1:1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](/[CH:16]=[CH:17]/[C:18]([O:20][CH3:21])=[O:19])[CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13].[C:22]1([CH2:28][CH2:29][CH:30]=O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>C(#N)C.C(OCC)(=O)C>[CH2:14]([N:11]([CH2:12][CH3:13])[CH2:10][CH2:9][S:8][C:7]1[CH:6]=[CH:5][C:4](/[CH:16]=[CH:17]/[C:18]([O:20][CH3:21])=[O:19])=[CH:3][C:2]=1[NH:1][CH2:30][CH2:29][CH2:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:15]
Reactant: O=CCCc1ccccc1
Reactant: CCN(CC)CCSc1ccc(/C=C/C(=O)OC)cc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CCN(CC)CCSc1ccc(/C=C/C(=O)OC)cc1NCCCc1ccccc1
Yield: 86.6 %

Procedure:
250 mg (0.62 mmol) of (E)-methyl 3-(3-amino-4-(2-(diethylamino)ethylthio)-phenyl)acrylate was suspended in acetonitrile (5 mL) and to this solution, 3-phenylpropionaldehyde (108 mg, 0.8 mmol) was added under stirring. Then, sodium triacetoxyborohydride (636 mg, 3 mmol) was added and the resulted mixture was stirred at room temperature for 3-60 hours. Water and ethyl acetate was added after removing the solvent—acetonitrile. Collecting organic layers and drying it, 229 mg of (E)-methyl 3-(4-(2-(diethylamino)ethylthio)-3-(3-phenylpropylamino)phenyl)acrylate was obtained in a form of an oily product after being purified by chromatography. Yield: 86.6%. TLC: Rf=0.6 (DCM:MeOH=9:1). HPLC: 91%; tR=9.90 min (LC/PDA: Diamonsil C18.5μ 150×4.6 mm, flow rate 1.0 mL/min, grade: 10-100% B, 18 minutes; mobile phase A: H2O; mobile phase B: acetonitrile; UV254). MS (m/z): 427 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:19]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[C:20]([C:22]2([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23]2)=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16](I)[S:17][C:10]=12.[CH2:35]([N:37]([CH2:41][CH3:42])[CH2:38][C:39]#[CH:40])[CH3:36]>>[CH2:35]([N:37]([CH2:41][CH3:42])[CH2:38][C:39]#[C:40][C:16]1[S:17][C:10]2[C:11](=[N:12][CH:13]=[CH:14][C:9]=2[O:8][C:7]2[CH:6]=[CH:5][C:4]([N:19]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[C:20]([C:22]3([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23]3)=[O:21])=[CH:3][C:2]=2[F:1])[CH:15]=1)[CH3:36]
Reactant: NC(=O)C1(C(=O)N(c2ccc(F)cc2)c2ccc(Oc3ccnc4cc(I)sc34)c(F)c2)CC1
Reactant: C#CCN(CC)CC
Product: CCN(CC)CC#Cc1cc2nccc(Oc3ccc(N(C(=O)C4(C(N)=O)CC4)c4ccc(F)cc4)cc3F)c2s1
Temperature: 50 °C

Procedure:
Prepared from N-(3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)phenyl) -N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (500 mg, 0.845 mmol) and N, N-diethylprop-2-yn-1-amine (118 mg, 1.06 mmol) according to the procedure described for Example 6, Step B, except the reaction was heated at 50° C. for 1 hour. The crude was purified by two successive Biotage 40M silica gel columns eluting with 5% MeOH in EtOAc, and then on a second column with 5% MeOH (containing 7N NH3) in CHCl3. Yield: 115 mg (24%). 1H NMR (400 MHz, CDCl3) δ 10.15 (s, 1H), 8.47 (m, 2H), 7.77 (m, 1H), 7.55 (s, 1H), 7.45 (m, 2H), 7.20 (m, 2H), 7.05 (m, 2H), 6.50 (d, J=5 Hz, 1H), 3.71 (s, 2H), 2.65 (m, 4H), 1.78 (m, 2H), 1.62 (m, 2H), 1.13 (m, 6H). LRMS (APCI pos) m/e 575 (M+1). HPLC: 99% purity (220 nm).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16]([CH3:19])([OH:18])[CH2:15]1)([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.[CH3:20]I.[H-].[Na+]>CN(C=O)C>[CH:1]([N:14]1[CH2:17][C:16]([O:18][CH3:20])([CH3:19])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(O)CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1(C)CN(C(c2ccccc2)c2ccccc2)C1
Reaction time: 1 h
Yield: 29.2 %

Procedure:
To a DMF (2 mL) solution of 1-benzhydryl-3-methylazetidin-3-ol (123 mg, 0.486 mmol), methyl iodide (33.2 μl, 0.534 mmol) and 60% sodium hydride (29 mg, 0.729 mmol) were added at 0° C. under a nitrogen stream, and the mixture was stirred for one hour at the same temperature. The reaction liquor was poured onto ice water, and the mixture was extracted with ethyl acetate. The extract was washed with ice water and saturated brine in this order, and then dried over anhydrous sodium sulfate. Sodium sulfate was removed, and then the solvent was concentrated under reduced pressure. The obtained residue was purified by thin layer chromatography (ethyl acetate/n-hexane=10/1, v/v), to obtain the title compound (38 mg, 29%) as an oily matter.
Reaction SMILES: [C:1]1([CH3:32])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:19][CH:18]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[C:21]=3[CH2:30]O)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1>S(=O)(=O)(O)O>[CH3:29][O:28][C:22]1[C:23]([O:26][CH3:27])=[CH:24][CH:25]=[C:20]2[C:21]=1[CH2:30][C:16]1[C:17]3[CH:18]2[CH2:19][N:10]([S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:32])=[CH:2][CH:3]=2)(=[O:8])=[O:9])[CH2:11][C:12]=3[CH:13]=[CH:14][CH:15]=1
Reactant: COc1ccc(C2CN(S(=O)(=O)c3ccc(C)cc3)Cc3ccccc32)c(CO)c1OC
Agent: O=S(=O)(O)O
Product: COc1ccc2c(c1OC)Cc1cccc3c1C2CN(S(=O)(=O)c1ccc(C)cc1)C3
Temperature: -5 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
Powdered compound 13 (427 mg, 0.98 mmol) was added in several portions to 50 mL of cold concentrated sulfuric acid (50 mL) at −40° C. under nitrogen with vigorous mechanical stirring. After the addition, the reaction mixture was warmed to −5° C. over 2 h and then poured onto crushed ice (450 g) and left stirring for 1 h. The product was extracted with dichloromethane (2×150 mL), washed with water (2×150 mL ), dried (MgSO4), filtered and evaporated to afford an oil that on trituration with ether at 0° C. yielded compound 14 (353 mg, 82%) as a white solid that was used for the next step without further purification. An analytical sample was prepared by centrifugal rotary chromatography using 50% ethyl acetate-hexane as the eluent followed by recrystallization from EtOAc/Hexane: mp 204-206° C.; 1H NMR (CDCl3) δ 2.40 (s, 3 H, CH3), 2.80 (m, 1 H, H-1a), 3.50 (dd, 1 H, J=4.5, 17.5 Hz, H-1b), 3.70 (dd, 1 H, J=7, 14 Hz, H-3a), 3.828 (s, 3 H, OCH3), 3.832 (s, 3H, OCH3), 3.9 (m, 1H, H-11b), 4.31 (d, 1H, J=17.6 Hz, H-7a), 4.74 (ddd, 1 H, J=1.7, 6.0, 11.2 Hz, H-7b), 4.76 (d, 1 H, J=14.8 Hz, H-3b), 6.77 (d, 1 H, J=8.3 Hz, ArH), 6.87 (d, 1 H, J=8.4 Hz, ArH), 6.94 (d, 1 H, J=7.6 Hz, ArH), 7.13 (t, 1 H, J=7.5 Hz, Ar-H-5), 7.18 (d, 1 H, J=7.2 Hz, ArH), 7.33 (d, 2 H, J=8.1 Hz, ArH), 7.78 (d, 2 H, J=8.2 Hz, ArH); MS (CI) m/z 436 (55), 198 (86), 157 (100); HRCIMS Calculated for C25H25NO4S: 436.1583; Found 436.1570; Anal. (C25H25NO4S) C, H, N.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(N(C(C)C)CC)(C)C.Cl[C:37]([O:39][CH:40]([CH3:42])[CH3:41])=[O:38]>ClCCl>[F:2][C:3]1[CH:4]=[C:5]([C:17]2[CH:18]=[CH:19][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:21][CH:22]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:37]([O:39][CH:40]([CH3:42])[CH3:41])=[O:38])[CH2:13][CH2:12]1
Reactant: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCNCC3)c(F)c2)cc1
Reactant: CC(C)OC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2F)CC1
Yield: 92.3 %

Procedure:
The title compound (83 mg, 92%) was prepared as a white solid from 4-({[3-fluoro-4′-(methylsulfonyl)-4-biphenylyl]oxy}methyl)piperidine hydrochloride (80 mg, 0.20 mmol), diisopropylethylamine (0.11 mL, 0.60 mmol), isopropyl chloroformate (1.0M in toluene, 0.22 mL, 0.22 mmol) and dichloromethane (6 mL) in a manner similar to Example 66, Step 2. 1H NMR (400 MHz, CDCl3): δ 7.98 (d, 2H, J=8.3 Hz), 7.70 (d, 2H, J=8.3 Hz), 7.40-7.25 (m, 2H), 7.10-7.00 (m, 1H), 4.92 (septet, 1H, J=6.2 Hz), 4.22 (bs, 2H), 3.92 (d, 2H, J=6.4 Hz), 3.08 (s, 3H), 2.85-2.70 (m, 2H), 2.15-2.00 (m, 1H), 1.95-1.80 (m, 2H), 1.35-1.20 (m, 8H); LRMS (ESI), m/z 450 (M+H).