Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].Cl.[CH2:6]([O:8][C:9]([C:11]1[N:12]([CH2:27][CH2:28][CH2:29][C:30](=O)[CH3:31])[C:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:14]2[C:19]=1[CH:18]=[CH:17][C:16]([Cl:20])=[CH:15]2)=[O:10])[CH3:7].C([BH3-])#N.[Na+]>CO>[ClH:20].[CH2:6]([O:8][C:9]([C:11]1[N:12]([CH2:27][CH2:28][CH2:29][CH:30]([NH:4][CH:1]([CH3:3])[CH3:2])[CH3:31])[C:13]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[C:14]2[C:19]=1[CH:18]=[CH:17][C:16]([Cl:20])=[CH:15]2)=[O:10])[CH3:7]
Reactant: CCOC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1CCCC(C)=O
Reactant: CC(C)N
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1CCCC(C)NC(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 5.2 ml. of isopropylamine in 25 ml. of methanol is treated with 4 ml. of 5-N methanolic hydrochloric acid. To this there are added successively under an atmosphere of argon at 20°-25° C. 3.85 g. of 5-chloro-2-(4-oxopentyl)-3-phenylisoindole-1-carboxylic acid ethyl ester and 0.4 g. of sodium cyanoborohydride and the mixture is then stirred for 48 hours at room temperature. While cooling, the mixture is made acidic with concentrated hydrochloric acid, stirred for an additional 1 hour at room temperature and subsequently evaporated to dryness under reduced pressure. The residue is made alkaline with 1-N sodium hydroxide with addition of ice and is extracted with ether. The extract is dried over sodium sulfate, concentrated, and the oily residue chromatographed on 200 g. of silica gel with a mixture of ethyl acetate/tetrahydrofuran/triethylamine (40:10:1). The homogeneous fractions are combined, concentrated, dissolved in ether and treated with an excess of ethereal hydrochloric acid. The precipitated hydrochloride is removed by filtration and washed with ether. After recrystallization from acetone, there is obtained 5-chloro-2-[4-(isopropylamino)pentyl]-3-phenylisoindole-1-carboxylic acid ethyl ester hydrochloride having a melting point of 183°-185° C. (decomposition).
Reaction SMILES: C[Si](C)(C)[C:3]([F:6])([F:5])[F:4].[CH3:9][C:10](=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].Cl>O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[F:4][C:3]([F:6])([F:5])[C:10]([CH3:9])([OH:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CCCCCC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCC(C)(O)C(F)(F)F
Temperature: 48 °C
Reaction time: 2 h
Yield: 102.3 %

Procedure:
24.9 g of trimethyl(trifluoromethyl)silane, 16.0 g of 2-heptanone, 38 g of tetrahydrofuran and 350 mg of tetrabutylammonium fluoride trihydrate were charged into a four-necked flask equipped with a nitrogen feeding tube, a reflux condenser, a dropping funnel and a thermometer, and a reaction was effected by a conventional method. Then, 17.5 g of hydrochloric acid was dropwise added to the reaction mixture at a temperature of 25 to 48° C. over 30 minutes, followed by stirring at about 48° C. for 2 hours. The reaction mixture was treated by a conventional method, and the resulting organic phase was washed with a saline solution, followed by drying with anhydrous magnesium sulfate. Thereafter, the resultant was concentrated under reduced pressure, thereby obtaining 26.4 g of 1,1,1-trifluoro-2-methyl-2-heptanol in the form of a pale brown oily matter.
Reaction SMILES: [NH2:1][S:2]([C:5]1[C:10]([NH:11][C:12]([C:14]2[C:15](=[O:29])[N:16]([CH2:25][CH2:26][CH2:27][CH3:28])[C:17]3[C:22]([C:23]=2[OH:24])=[CH:21][CH:20]=[CH:19][CH:18]=3)=O)=[CH:9][CH:8]=[CH:7][N:6]=1)(=[O:4])=[O:3].NS(C1C=C(Br)C=CC=1NC(C1C(=O)N(CC2C=CC=CC=2)C2C(C=1O)=CC=CN=2)=O)(=O)=O>>[CH2:25]([N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:23]([OH:24])=[C:14]([C:12]2[NH:11][C:10]3[CH:9]=[CH:8][CH:7]=[N:6][C:5]=3[S:2](=[O:4])(=[O:3])[N:1]=2)[C:15]1=[O:29])[CH2:26][CH2:27][CH3:28]
Reactant: CCCCn1c(=O)c(C(=O)Nc2cccnc2S(N)(=O)=O)c(O)c2ccccc21
Agent: NS(=O)(=O)c1cc(Br)ccc1NC(=O)c1c(O)c2cccnc2n(Cc2ccccc2)c1=O
Product: CCCCn1c(=O)c(C2=NS(=O)(=O)c3ncccc3N2)c(O)c2ccccc21

Procedure:
The title compound was prepared according to the procedure of Example 84D substituting the product of Example 98C for the product of Example 84C .as a white solid (0.065 g, 22%). MS (ESI−) m/z 397 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 0.96 (t, J=7.35 Hz, 3H), 1.46 (m, 2H), 1.66 (m, 2H), 4.34 (m, 2H), 7.46 (t, J=7.54 Hz, 1H), 7.82 (m, 3H), 8.23 (d, J=6.99 Hz, 1H), 8.26 (d, J=7.72 Hz, 1H), 8.70 (d, J=3.68 Hz, 1H), 14.38 (s, 1H), 15.12 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][C:9](=O)[CH2:8][CH2:7]2.[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([N:25]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1)[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][NH2:34])=[CH:29][CH:28]=1)(=[O:24])=[O:23])([O-:15])=[O:14].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.C(O)(=O)C>[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([N:25]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1)[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][NH:34][CH:9]2[CH2:8][CH2:7][C:6]3[C:11](=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=3)[CH2:10]2)=[CH:29][CH:28]=1)(=[O:23])=[O:24])([O-:15])=[O:14]
Reactant: O=C1CCc2cccc(F)c2C1
Reactant: NCc1ccc(CN(Cc2ccccn2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)N(Cc1ccc(CNC2CCc3cccc(F)c3C2)cc1)Cc1ccccn1
Yield: 91.9 %

Procedure:
Following General Procedure B: Reaction of 8-fluoro-2-tetralone (159 mg, 0.97 mmol), N-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-1,4-benzenedimethanamine (400 mg, 0.97 mmol) and NaBH(OAc)3 (411 mg, 1.9 mmol) in a mixture of CH2Cl2 (10 mL) and acetic acid (0.2 mL) for 18 hours followed by purification of the crude material by column chromatography on silica gel (CHCl3/MeOH/NH4OH 20:2:1) afforded the title compound (500 mg, 92%) as a yellow foam.
Reaction SMILES: Br[C:2]1[C:3]([F:22])=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH2:16][CH2:15]1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:20]=[S:17]1(=[O:21])[CH2:18][CH2:19][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:3]=3[F:22])[NH:7][CH:6]=2)[CH2:15][CH2:16]1
Reactant: NC(=O)c1cc(Br)c(F)c2c(C3CCS(=O)(=O)CC3)c[nH]c12
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: NC(=O)c1cc(-c2ccccc2)c(F)c2c(C3CCS(=O)(=O)CC3)c[nH]c12
Temperature: 130 °C
Reaction time: 0.3 h
Yield: 69 %

Procedure:
A mixture of 5-bromo-3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-4-fluoro-1H-indole-7-carboxamide (15 mg, 0.039 mmol), phenylboronic acid (9.40 mg, 0.077 mmol), and K2CO3 (15.98 mg, 0.116 mmol) was taken up in 1,4-dioxane (0.2 mL) and water (0.100 mL). The mixture was degassed with argon for 10 min, and PdCl2(dppf) (2.82 mg, 3.85 μmol) was added. The vial was sealed, and the reaction was heated in a Biotage microwave for 30 min at 130° C. on high absorption. The aqueous layer was removed via pipette, and the reaction mixture was filtered through a Stratosphere PL-Thio MP SPE cartridge (0.5 g), eluting with 1:1 DCM/MeOH (10 mL). The eluent was concentrated under a stream of nitrogen at 50° C., and the crude product was dissolved in DMSO (1.2 mL) and purified on a Gilson HPLC (XBridge C18 5 mm OBD 19×100 mm preparatory column), eluting at 15 mL/min with a linear gradient running from 20% CH3CN/H2O (0.1% NH4OH) to 70% CH3CN/H2O (0.1% NH4OH) over 18 min. The desired fractions were concentrated under a stream of nitrogen at 50° C. and dried under high vacuum, giving 10.4 mg (70%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:14][C:13]3([CH2:18][CH2:17][N:16]([C:19]([N:21]4[CH2:26][CH2:25]N(C)[CH2:23][CH2:22]4)=[O:20])[CH2:15]3)[O:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1.CN1CCN(C(Cl)=O)CC1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:14][C:13]3([O:12][N:11]=2)[CH2:18][CH2:17][N:16]([C:19]([N:21]2[CH2:26][CH2:25][CH2:23][CH2:22]2)=[O:20])[CH2:15]3)[CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCN(C(=O)N2CCC3(CC(C#Cc4cccc(Cl)c4)=NO3)C2)CC1
Agent: CN1CCN(C(=O)Cl)CC1
Product: O=C(N1CCCC1)N1CCC2(CC(C#Cc3cccc(Cl)c3)=NO2)C1
Yield: 72.8 %

Procedure:
The title compound was synthesized using the method described for the compound of Example 104, replacing 1-pyrrolidincarbonyl chloride for 4-methyl-1-piperazinecarbonyl chloride. After the usual work-up procedure, the crude was purified by means of automated flash chromatography (SP01®TM-Biotage; CHCl3-1.4N methanolic ammonia 100:0.5) to afford an ivory solid. Yield: 72.8%.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:22])[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:35].[Na+].O1CCCC1>CO.C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:35])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:22])[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)c2cccnc2)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Solvent: C1CCOC1
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)c2cccnc2)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-{5-chloro-8-[4-(pyridin-3-ylcarbonyl)piperazin-1-yl]quinolin-7-yl}ethanone (0.039 g, 0.099 mmol) and ammonium acetate (0.0761 g, 0.988 mmol) in methanol (0.4 mL) and acetonitrile (0.4 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.25 mL, 0.25 mmol). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution, extracted with dichloromethane, dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C21H23ClN5O (M+H)+: m/z=396.2; Found: 396.2.
Reaction SMILES: [NH2:1][CH:2]([C:6]([OH:8])=[O:7])[CH2:3][CH2:4][CH3:5].S(=O)(=O)(O)O.[CH2:14](O)[CH3:15]>>[CH2:14]([O:7][C:6](=[O:8])[CH:2]([NH2:1])[CH2:3][CH2:4][CH3:5])[CH3:15]
Reactant: CCO
Reactant: CCCC(N)C(=O)O
Agent: O=S(=O)(O)O
Product: CCCC(N)C(=O)OCC
Yield: 82 %

Procedure:
A suspension of 11.72 g of DL-norvaline in 90 ml of ethanol was combined with 3.6 ml of concentrated sulphuric acid and the mixture refluxed for eight days. A clear solution was formed, from which, after cooling, ethanol was removed by distillation. The residue was redissolved in 200 ml of distilled water and the pH adjusted to a value of between 10 and 12 by adding potassium carbonate. Extraction was then performed three times with 50 ml portions of ethyl acetate, the mixture washed once with 50 ml of a saturated sodium chloride solution and dried over sodium sulphate. Once the solvent had been removed by distillation, 11.93 g of 2-aminopentanoic acid ethyl ester (82% of th.) were obtained in the form of a yellowish oil.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:5]=1[NH:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]([N+]([O-])=O)[CH:8]=1)([O-:3])=[O:2].[CH2:27]([P:29]([O:32]C)[O:30][CH3:31])[CH3:28]>>[CH2:27]([P:29]([C:9]1[CH:8]=[C:7]([NH:6][C:5]2[CH:19]=[CH:20][C:21]([C:23]([F:24])([F:25])[F:26])=[CH:22][C:4]=2[N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][C:10]=1[N+:13]([O-:15])=[O:14])(=[O:32])[O:30][CH3:31])[CH3:28]
Reactant: CCP(OC)OC
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Product: CCP(=O)(OC)c1cc(Nc2ccc(C(F)(F)F)cc2[N+](=O)[O-])ccc1[N+](=O)[O-]

Procedure:
Following the procedure of Example 11, 4-(2-nitro-4-trifluoromethylanilino)-1,2-dinitrobenzene and dimethyl ethylphosphonite are reacted together to give methyl P-ethyl-2-nitro-5-(2-nitro-4-trifluoromethylanilino)-phenylphosphinate.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12](O)=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.ON1C2C=CC=CC=2N=N1.[C:31]1([C@@H:37]([NH2:40])[CH2:38][CH3:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.O.C1COCC1.CC#N>[CH2:38]([C@H:37]([NH:40][C:12]([C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:2]=1[OH:1])=[O:13])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:39]
Reactant: CC[C@H](N)c1ccccc1
Reactant: O=C(O)c1c(O)c(-c2ccccc2)nc2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: CC[C@H](NC(=O)c1c(O)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.7 %

Procedure:
2.49 g (9.4 mmols) of 3-hydroxy-2-phenyl-4-quinoline carboxylic acid (CAS [485-89-2]) were suspended in 150 ml of a mixture of THF/MeCN 7:3, respectively; 1.40 g (10.3 mmols) of 1-hydroxybenzotriazole (HOBT) were added to the suspension and then 1.27 g (9.4 mmols) of (S)-(−)-1-phenylpropylamine, dissolved in 20 ml of methylene chloride were added dropwise over 10 minutes period. The reaction mixture was stirred at room temperature for 30 minutes and then 2.13 g (10.3 mmols) of dicyclohexylcarbodiimide (DCC), dissolved in 20 ml of methylene chloride, were added dropwise and the reaction stirred overnight. 20 ml of H2O were added and the reaction stirred 30 minutes, then the solvent was evaporated in vacuo to dryness. The residue was taken up in EtOAc, the precipitated dicyclohexylurea (DCU) was filtered off and the filtrate washed with water, 20% citric acid, 5% NaHCO3, brine and the organic layer dried over Na2SO4 and the solvent evaporated in vacuo. The residue was purified by silica-gel (60-240 mesh) flash column chromatography, eluting with a mixture of hexane/EtOAc 9:1, containing increasing amounts of EtOAc, until the ratio 7:3. The purified product was crystallized from i-PrOH to yield 1.75 g of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:16]C1CCCCO1)[CH2:2][CH2:3][CH2:4][C:5]#[C:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[CH:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH2:1]([OH:16])[CH2:2][CH2:3][CH2:4][C:5]#[C:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[CH:15]
Reactant: C#CCCCCCCCC#CCCCCOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: C#CCCCCCCCC#CCCCCO
Yield: 94.7 %

Procedure:
A solution of the 2-(pentadeca-5,14-divnyloxy)tetrahydropyran (4.05 g, 13.27 mmol) and p-toluenesulphonic acid (42 mg) in MeOH (100 mL) was stirred at room temperature for 4 h. All volatiles were then removed in vacuo and the residue was purified by SiO2 column chromatography using 15% EtOAc/hexanes as eluent to give pentadeca-5,14-diyn-1-ol (2.77 g, 95%) as a colorless oil. TLC: 30% EtOAc/hexanes, Rf≈0.40; 1H NMR (300 MHz, CDCl3) δ 3.85 (t, 2H, J=7.0 Hz), 2.03-2.30 (m, 6H), 1.93 (t, 1H, J=2.6 Hz), 1.26-1.83 (m, 14H).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]([F:40])([F:39])[C:10]1[CH:11]=[C:12]([CH2:20][O:21][C@@H:22]2[CH2:28][CH2:27][C@@H:26]3[NH:29][C@@:23]2([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:24][C@H:25]3[C:30]([OH:32])=O)[CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1.[CH2:41]([N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>>[CH2:41]([N:48]1[CH2:53][CH2:52][N:51]([C:30]([C@@H:25]2[CH2:24][C@:23]3([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[NH:29][C@H:26]2[CH2:27][CH2:28][C@H:22]3[O:21][CH2:20][C:12]2[CH:11]=[C:10]([C:9]([F:39])([F:8])[F:40])[CH:15]=[C:14]([C:16]([F:18])([F:19])[F:17])[CH:13]=2)=[O:32])[CH2:50][CH2:49]1)[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: O=C(O)[C@@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@H]2OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: O=C([C@@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@H]2OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 85 %

Procedure:
A mixture of (1R*,2R*,5S*,6R*)-2-[3,5-bis(trifluoromethyl)phenyl]methoxy)-1-phenyl-8-azabicyclo[3.2.1]octan-6-carboxylic acid trifluoroacetate (Example 122; 100 mg, 0.19 mmol), N-benzylpiperazine (0.1 ml), triethylamine (0.1 ml, 0.7 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (44 mg, 0.23 mmol) and 4-N,N-dimethylaminopyridine (12 mg, 0.1 mmol)was prepared. The mixture was stirred at room temperature for 20 hours and purified by chromatography on silica gel (dichloromethane:methanol) to give the title compound (102 mg, 85%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=1.[CH2:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][C:20]1([CH2:26][O:27][CH3:28])[CH3:25])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:12]([N:19]1[CH2:24][CH2:23][N:22]([C:9]([C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=2)=[O:11])[CH2:21][C:20]1([CH2:26][O:27][CH3:28])[CH3:25])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COCC1(C)CNCCN1Cc1ccccc1
Reactant: COc1cccc(C(=O)O)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCC1(C)CN(C(=O)c2cccc(OC)n2)CCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 77.6 mg (507 μmol) 6-methoxy-2-pyridinecarboxylic acid, 125 mg (507 μmol) 1-benzyl-2-methoxymethyl-2-methyl-piperazine, 177 mg (551 μmol) TBTU and 100 μL (581 μmol) DIPEA in 1.5 mL DMF was stirred at RT for 2 h. The reaction mixture was poured into ice water and extracted with EtOAc. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo.
Reaction SMILES: C1C=CC=CC=1.[CH2:7]([N:14]1[C:23]2[C:18](=[CH:19][C:20]([CH:24]([CH3:28])[C:25]([OH:27])=[O:26])=[CH:21][CH:22]=2)[CH2:17][CH2:16][C:15]1([CH3:30])[CH3:29])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:42][C:43]1[CH:50]=[CH:49][C:46]([CH2:47]O)=[CH:45][CH:44]=1>O>[CH2:7]([N:14]1[C:23]2[C:18](=[CH:19][C:20]([CH:24]([CH3:28])[C:25]([O:27][CH2:47][C:46]3[CH:49]=[CH:50][C:43]([Cl:42])=[CH:44][CH:45]=3)=[O:26])=[CH:21][CH:22]=2)[CH2:17][CH2:16][C:15]1([CH3:29])[CH3:30])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OCc1ccc(Cl)cc1
Reactant: CC(C(=O)O)c1ccc2c(c1)CCC(C)(C)N2Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC(C(=O)OCc1ccc(Cl)cc1)c1ccc2c(c1)CCC(C)(C)N2Cc1ccccc1
Yield: 83.5 %

Procedure:
To 30 ml of benzene were added 3.2 g of 2-(1-benzyl-1,2,3,4-tetrahydro-2,2-dimethylquinolin-6-yl)propionic acid (Compound 54), 4,4 g of p-toluenesulfonic acid and 14.3 g of 4-chlorobenzyl alcohol. The solution was heated and refluxed with removing water. The reaction mixture was concentrated, followed by washed petroleum ether and addition of ethyl acetate. Then the mixture was washed with sodium hydrogencarbonate, water and saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by column chromatography on silica gel (Hexan acetate) to give 3.7 g of 4-chlorobenzyl 2-(1-benzyl-1,2,3,4-tetrahydro-2,2-dimethylquinolin-6-yl)propionate (Compound 59).
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][C:5]([O:10][CH2:11][CH2:12][CH2:13][C:14](=[O:16])[CH3:15])=[C:6]([CH:9]=1)[C:7]#[N:8].[B:18]1([OH:28])[C:22]2[CH:23]=[CH:24][C:25]([OH:27])=[CH:26][C:21]=2[CH2:20][O:19]1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[Cl:1][C:2]1[C:3]([O:27][C:25]2[CH:24]=[CH:23][C:22]3[B:18]([OH:28])[O:19][CH2:20][C:21]=3[CH:26]=2)=[N:4][C:5]([O:10][CH2:11][CH2:12][CH2:13][C:14](=[O:16])[CH3:15])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: OB1OCc2cc(O)ccc21
Reactant: CC(=O)CCCOc1nc(Cl)c(Cl)cc1C#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC(=O)CCCOc1nc(Oc2ccc3c(c2)COB3O)c(Cl)cc1C#N
Temperature: 40 °C
Reaction time: 2 h

Procedure:
Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen were placed a solution of 5,6-dichloro-2-(4-oxopentyloxy)nicotinonitrile (1.12 g, 4.12 mmol, 1.00 equiv) in DMSO (50 mL), benzo[c][1,2]oxaborole-1,5(3H)-diol (650 mg, 4.33 mmol, 1.05 equiv) and Cs2CO3 (1.60 g, 4.92 mmol, 1.20 equiv). The resulting solution was stirred for 2 h at 40° C., then quenched by the addition of 100 mL of ice water. The resulting solution was extracted with 3×50 mL of ethyl acetate. The organic layers were combined, washed with 2×50 mL of water and 1×50 mL of brine, then dried over Na2SO4 and concentrated under vacuum. This resulted in 1.3 g (80%) of 5-chloro-6-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)-2-(4-oxopentyloxy)nicotinonitrile as a white solid. LC-MS (ES, m/z): 387 [M+H]+. 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 9.28 (1H, s), 8.60 (1H, s), 7.81 (1H, d, J=7.8 Hz), 7.33 (1H, s), 7.25 (1H, d, J=7.8 Hz), 5.02 (2H, s), 4.00 (2H, t), 2.35 (2H, t), 2.05 (3H, s), 1.8-1.6 (2H, m).
Reaction SMILES: ON=C(N)CC1C=CC=CC=1.C(OC(N1CCC(C(O)=O)CC1)=O)(C)(C)C.[ClH:28].CS[C:31]1[CH:48]=[CH:47][C:34]([CH2:35][C:36]2[N:40]=[C:39]([CH:41]3[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)[O:38][N:37]=2)=[CH:33][CH:32]=1>>[ClH:28].[CH2:35]([C:36]1[N:40]=[C:39]([CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[O:38][N:37]=1)[C:34]1[CH:33]=[CH:32][CH:31]=[CH:48][CH:47]=1
Reactant: CSc1ccc(Cc2noc(C3CCNCC3)n2)cc1
Agent: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: Cl
Agent: NC(Cc1ccccc1)=NO
Product: c1ccc(Cc2noc(C3CCNCC3)n2)cc1

Procedure:
This was prepared from N′-hydroxy-2-phenylethanimidamide and 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid using a similar method to that used to prepare 4-{3-[4-(methylthio)benzyl]-1,2,4-oxadiazol-5-yl}piperidine hydrochloride (Method E, Steps 1, 2); NMR: 1.96 (2H, m), 2.15(2H, dd), 3.01(2H, t), 3.24 (2H, dd), 3.40 (1H, m), 4.09 (2H, s), 7.25 (5H, m), 9.31(2H, br s); MS: 244 (MH+).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.[CH3:19][O:20][C:21]1[C:22]([NH2:36])=[N:23][CH:24]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:26]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[CH3:19][O:20][C:21]1[C:22]([NH2:36])=[N:23][CH:24]=[C:25]([C:2]2[S:6][C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:4][C:3]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH:26]=1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cnc1N
Reactant: Brc1sc(-c2ccccc2)nc1-c1ccncc1
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: C1COCCO1
Product: COc1cc(-c2sc(-c3ccccc3)nc2-c2ccncc2)cnc1N
Temperature: 25 °C

Procedure:
A mixture of 5-bromo-2-phenyl-4-(pyridin-4-yl)thiazole (20 mg, 0.062 mmol), 3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (39 mg, 0.157 mmol), and aqueous 2.0 M K2CO3 solution (0.5 ml, 1 mmol) in dioxane (0.5 mL) was sparged with Ar. Pd(PPh3)4 (181 mg, 0.157 mmol) was added, the reaction was sealed and irradiated at 120° C. for 15 min. While allowing to cool to rt, the reaction partitioned and the resulting layers were separated. The aqueous phase was extracted with EtOAc (3×) and the combined organic phases were washed with brine, dried (Na2SO4), and concentrated. The resulting residue was purified by reverse phase HPLC to give, after freeze drying, 3-methoxy-5-(2-phenyl-4-(pyridin-4-yl)thiazol-5-yl)pyridin-2-amine as the TFA salt: LCMS (m/z): 361.0 (MH+), tR=0.58 min.