Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](Br)[CH:6]=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11].[CH2:13]([OH:16])[C:14]#[CH:15].C1N2CCN(CC2)C1>C(#N)C.C(OCC)C.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:15]#[C:14][CH2:13][OH:16])[CH:6]=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11]
Reactant: C#CCO
Reactant: COc1cc(Br)ccc1[N+](=O)[O-]
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: C1CN2CCN1CC2
Solvent: CC#N
Solvent: CCOCC
Product: COc1cc(C#CCO)ccc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 47.6 %

Procedure:
To 5-bromo-2-nitrophenyl methyl ether (4.0 g, 17.24 mmol) in 80 mL of acetonitrile was added, Bis(tri-t-butylphosphine)palladium(0) (0.253 g, 0.5 mmol), 2-propyn-1-ol (3.33 g, 59.4 mmol), and DABCO (4.44 g, 39.6 mmol). The mixture was heated to 60° C. for 1 h. The mixture was rotovaped down and then taken up in diethyl ether. The organic layer was washed with H2O, dried (Na2SO4), filtered, and rotovaped. The crude product was purified by flash chromatography to give the title compound of step A (1.7 g, 8.2 mmol, 41%). 1H NMR (400 MHz, CDCl3) δ ppm 7.80 (d, J=8.24 Hz, 1H), 7.12 (d, J=1.65 Hz, 1H), 7.06 (dd, J=8.33, 1.56 Hz, 1H), 4.52 (s, 2H), 3.94 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[C:16]1(/[CH:22]=[CH:23]/B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2](/[CH:23]=[CH:22]/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]=1[CH3:12]
Reactant: OB(O)/C=C/c1ccccc1
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c(/C=C/c2ccccc2)nc2cc(F)cc(F)c2c1Cl

Procedure:
Prepared according to procedure F by stirring 2,4-dichloro-5,7-difluoro-3-methylquinoline (700 mg, 2.82 mmol), trans-2-phenylvinylboronic acid (501 mg, 3.39 mmol), Pd(PPh3)4 (245 mg, 0.212 mmol), sodium carbonate (0.590 mL, 14.11 mmol), toluene (23 mL), and water (6 mL) at 95° C. for 18 h. Purification by column chromatography (silica gel, 0-10% EtOAc in hexanes as eluent) gave (E)-4-chloro-5,7-difluoro-3-methyl-2-styrylquinoline. Mass Spectrum (ESI) m/e=316.0 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:10]2[CH2:11][N:12](C(OC(C)(C)C)=O)[CH2:13][C:9]=2[C:8]([NH:21][C:22](=[O:35])[CH:23]([C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)[CH3:24])=[N:7]1)=[O:5])[CH3:2].C(O)(C(F)(F)F)=O.C(Cl)Cl>C(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[C:10]2[CH2:11][NH:12][CH2:13][C:9]=2[C:8]([NH:21][C:22](=[O:35])[CH:23]([C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)[CH3:24])=[N:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)n1nc(NC(=O)C(C)c2ccc3ccccc3c2)c2c1CN(C(=O)OC(C)(C)C)C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)n1nc(NC(=O)C(C)c2ccc3ccccc3c2)c2c1CNC2
Reaction time: 0.5 h
Yield: 101.6 %

Procedure:
2.5 g (5.2 mmol) of 3-(2-naphthalen-2-yl-propionylamino)-4,6-dihydro-pyrrolo[3,4-c]pyrazole-1,5-dicarboxylic acid 5-tert-butyl ester 1-ethyl ester in 15 ml DCM was treated with 16 ml of (1:1) TFA/DCM. The reaction mixture was stirred for 30 min. and evaporated to dryness. The resulting residue was dissolved in DCM and the solution was washed with brine and then treated with NaHCO3 aq. The obtained precipitate was filtered, washed with water and DCM, and then dried under vacuum to give 2.0 g (quantitative yield) of the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH3:9])=[N:5][O:6][C:7]=1[CH3:8].[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:9][C:4]1[C:3]([CH2:2][N:20]2[CH2:19][CH2:18][N:17]([C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:16])[CH2:22][CH2:21]2)=[C:7]([CH3:8])[O:6][N:5]=1
Reactant: Cc1noc(C)c1CCl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1noc(C)c1CN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 35 °C
Reaction time: 8 h
Yield: 54.5 %

Procedure:
A solution of 4-chloromethyl-3,5-dimethylisoxazole (100 mg, 0.69 mmol) in CH2Cl2 (4 mL) was treated with tert-butyl-1-piperazine carboxylate (2.5 eq, 1.71 mmol, 320 mg) and iPr2NEt (3.0 eq, 2.06 mmol, 0.36 mL) and stirred at 35° C. for 8 h. Concentration in vacuo and preparative tlc purification (EtOAc) gave the desired product (111 mg, 55%) as a colourless solid; δH (500 MHz, DMSO-d6) 1.39 (s, 9H, C(CH3)3), 2.17 (s, 3H, CH3), 2.28 (t, J=4.5 Hz, 4H, piperazine N(CH2)2), 2.31 (s, 3H, CH3), 3.23 (s, 2H, NCH2), 3.30 (hidden by DMSO peak, 4H, piperazine N(CH2)2);
Reaction SMILES: [F:1][CH:2]([F:26])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([CH3:25])[CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[CH:29]=[C:30]([S:34]([NH:37][CH:38]2[CH2:40][CH2:39]2)(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>>[CH:38]1([NH:37][S:34]([C:30]2[CH:29]=[C:28]([NH:27][C:12]([C:11]3[CH:10]=[N:9][N:8]4[C:3]([CH:2]([F:1])[F:26])=[CH:4][C:5]([C:15]5[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[C:17]([CH3:25])[CH:16]=5)=[N:6][C:7]=34)=[O:13])[CH:33]=[CH:32][CH:31]=2)(=[O:36])=[O:35])[CH2:40][CH2:39]1
Reactant: Cc1cc(-c2cc(C(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Reactant: Nc1cccc(S(=O)(=O)NC2CC2)c1
Product: Cc1cc(-c2cc(C(F)F)n3ncc(C(=O)Nc4cccc(S(=O)(=O)NC5CC5)c4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(3-methyl-4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.5) and 3-amino-N-cyclopropyl-benzenesulfonamide [CAS 459434-39-0] according to general procedure II. Light yellow solid. MS (ISP) 564.2 [(M−H)−]; mp 199° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[C:37]([F:38])=[CH:36][C:31]([C:32]([O:34]C)=[O:33])=[CH:30][C:29]=2[F:39])[CH2:24][CH:23]1[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[OH-].[Na+].Cl>CO>[C:1]([O:5][C:6]([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[C:29]([F:39])=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:36][C:37]=2[F:38])[CH2:24][CH:23]1[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1cc(F)c(N2CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C(c3ccccc3)C2)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](c1cccc2ccccc12)N(CC1CCN(c2c(F)cc(C(=O)O)cc2F)CC1c1ccccc1)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
To a mixture of 247 mg of the crude methyl 4-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]-3,5-difluorobenzoate, 4.0 mL of THF, and 2.0 mL of methanol was added dropwise a 1 M aqueous sodium hydroxide solution at room temperature, followed by stirring overnight. The reaction mixture was neutralized by addition of 1 M hydrochloric acid, and then extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol-chloroform) to obtain 233 mg of 4-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]-3,5-difluorobenzoic acid as a white solid. FAB+: 601
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[C:27]1[S:35](Cl)(=[O:37])=[O:36]>ClCCl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][S:35]([C:27]3[N:26]([CH3:25])[C:34]4[C:29]([CH:28]=3)=[CH:30][CH:31]=[CH:32][CH:33]=4)(=[O:36])=[O:37])=[C:16]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1c(S(=O)(=O)Cl)cc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)c(S(C)(=O)=O)c2)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cn1c(S(=O)(=O)Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2S(C)(=O)=O)cc2ccccc21
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of 4-(4-amino-3-methanesulfonyl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (cf. Example 20e, 0.050 g) in dichloromethane (2.0 ml) was added 1-methyl-1H-indole-2-sulfonyl chloride (0.036 g; cf. Chan, Ming Fai; Wu, Chengde; Raju, Bore Gowda; Kogan, Timothy; Kois, Adam; Verner, Erik Joel; Castillo, Rosario Silvestre; Yalamorri, Venkatachalapathi; Balaji, Vitukudi Narayanaiyengar, U.S. Pat. No. 5,962,490) and DMAP (0.021 g). The reaction mixture was stirred at 80° C. for 18 h, cooled and directly chromatographed on silica gel using heptane/ethyl acetate as eluent to obtain the title compound (0.048 g) as a yellowish foam. MS (ISN): 546.5 (M−H)−
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:2].[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][N:18]=1.C(=O)(O)[O-].[K+]>O.C(OCC)C>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][N:7]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:19]1[C:20]([N+:24]([O-:26])=[O:25])=[CH:21][N:22]=[C:17]([Cl:16])[N:18]=1)[CH3:2]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CCOC(=O)CCNCc1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)CCN(Cc1ccccc1)c1nc(Cl)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.2 %

Procedure:
A solution of 1.04 g (0.005 mole) of 3-benzylamino-propanoic acid ethyl ester in 20 mL of water was added dropwise to a solution of 0.97 g (0.005 mole) of 2,4-dichloro-5-nitro-pyrimidine in 20 mL of ethyl ether. At 0 degrees, 1.0 g (0.010 mole) of potassium bicarbonate was added. The mixture was stirred at ambient temperature for 3 hours. The layers were then separated, and the aqueous layer extracted twice with 30 mL of ether. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with hexanes-ethyl acetate (100:0-90:10) gave 1.70 g of 3-[benzyl-(2-chloro-5-nitro-pyrimidin-4-yl)-amino]-propanoic acid ethyl ester (IV-22).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=O.C[Mg]Br.Cl.[Br:14][C:15]1[N:16]=[CH:17][N:18]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=2[CH3:30])[C:19]=1C(Cl)=O>C1COCC1>[Br:14][C:15]1[N:16]=[CH:17][N:18]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=2[CH3:30])[C:19]=1[C:3](=[O:5])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: Cc1ccc(-n2cnc(Br)c2C(=O)Cl)c(C)c1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1c(Br)ncn1-c1ccc(C)cc1C
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
To 1.6 mL (14 mmol) of mono-ethyl malonate in 35 mL of THF at 0° C. was added 9.3 mL (28 mmol) of 3.0 M methyl magnesium bromide (ether solution). The dianion solution was stirred for 30 min before adding 1.2 g (3.5 mmol) of 4-bromo-1-(2,4-dimethylphenyl)-1H-imidazole-5-carbonyl chloride hydrochloride in 50 mL of THF dropwise. The cooling bath was then removed and the mixture was allowed to stir at room temperature for 3 h. The reaction was quenched by pouring onto ice and was extracted with ethyl acetate after neutralizing to pH 7 with saturated ammonium chloride. The combined extracts were washed with brine, dried over sodium sulfate, filtered and the resulting filtrate was concentrated to an oil. The oil was purified by flash chromatography eluting with a 25% ethyl acetate/hexanes mixture to give 1.2 g (94%) of the title compound as a viscous golden oil.
Reaction SMILES: [C:1]1([N:7]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[C:8]([C:10]2[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:12][O:13][C:14]=2[CH3:15])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCCCCC>[Pd].CN(C)C=O>[NH2:12][C:11]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[C:10]([C:14](=[O:13])[CH3:15])[C:8]([N:7]([CH2:22][CH2:23][N:24]([CH3:25])[CH3:26])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:9]
Reactant: Cc1onc(-c2ccccc2)c1C(=O)N(CCN(C)C)c1ccccc1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(=O)C(C(=O)N(CCN(C)C)c1ccccc1)=C(N)c1ccccc1

Procedure:
A mixture of 35 grams (0.1 mole) of N-phenyl-N-(2-dimethylaminoethyl)-5-methyl-3-phenyl-4-isoxazole carboxamide and 3.8 grams of 10% palladium on carbon in 200 milliliters of dimethylformamide is hydrogenated at 50 psi and 50°-60° C. overnight. The mixture is cooled, filtered, and the filtrate evaporated in vacuo. The residue obtained is then treated with hexane and the resulting crystals triturated with ether to give 2-(aminophenylmethylene)-N-(2-dimethylaminoethyl)-N-phenyl-3-oxobutanamide; M.P. 81°-83° C.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[CH2:27]([O:29][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]2[C:39]=1[CH:38]=[C:37]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)[CH:36]=[CH:35]2)[CH3:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:43]2[CH2:42][CH2:41][N:40]([C:37]3[CH:36]=[CH:35][C:34]4[C:39](=[C:30]([O:29][CH2:27][CH3:28])[CH:31]=[CH:32][CH:33]=4)[CH:38]=3)[CH2:45][CH2:44]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: CCOc1cccc2ccc(N3CCNCC3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cccc2ccc(N3CCN(CCCCC4(C(=O)NCC(F)(F)F)c5ccccc5-c5ccccc54)CC3)cc12
Temperature: 90 °C
Reaction time: 14 h

Procedure:
A suspension of 0.5 g (1.17 mmol) of 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide, 0.3 g (1.17 mmol) of 1-(8-ethoxy-naphthalen-2-yl)-piperazine and 1 g (7 mmol) of potassium carbonate in 50 ml of dimethylformamide is stirred for 14 hours at 90° C. The reaction mixture is poured onto water and the precipitate is filtered off. The product is purified by column chromatography on silica gel (eluant: cyclohexane/ethyl acetate=3:2).
Reaction SMILES: [CH:1]([O:3][CH2:4][CH3:5])=[CH2:2].S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH+]1C=CC=CC=1.[OH:23][CH:24]([CH:32]1[CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]1)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl>[CH2:1]([O:3][CH:4]([O:23][CH:24]([CH:32]1[CH2:33][CH2:34][C:35](=[O:38])[CH2:36][CH2:37]1)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:5])[CH3:2]
Reactant: O=C1CCC(C(O)Cc2ccccc2)CC1
Reactant: C=COCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(C)OC(Cc1ccccc1)C1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl vinyl ether (998 mg, 1.32 ml, 13.8 mmol) and pyridinium tosylate (44 mg, 0.17 mmol) were added to a solution of 4-(1-hydroxy-2-phenylethyl)cyclohexanone (2.52 g, 11.5 mmol) in anhydrous methylene chloride (50 ml) and the mixture was stirred at room temperature overnight. Methylene chloride (20 ml) was added to the mixture and the mixture was washed with water, 5% sodium bicarbonate solution and sodium chloride solution (50 ml of each). The combined organic phases were dried with sodium sulfate and concentrated i. vac.
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.C(=O)([O-])[O-].[K+].[K+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C=O)C>[CH2:27]([O:20][C:9]1[CH:8]=[CH:7][C:6]2[C@@H:5]3[C@H:14]([C@H:15]4[C@@:2]([CH2:3][CH2:4]3)([CH3:1])[C:18](=[O:19])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1ccccc1
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@@H]1CCC2=O
Reaction time: 26 h
Yield: 80.7 %

Procedure:
To a solution of estrone (11, 2.70 g, 10 mmol) in DMF (40 mL) were added potassium carbonate (2.76 g, 20 mmol) and benzyl bromide (1.8 mL, 15 mmol) at room temperature. The reaction mixture was stirred for 26 h, then quenched with H2O, and extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl, and then dried (Na2SO4). The desiccant was filtered and the solvent was evaporated at reduced pressure. The residue was washed with Et2O to afford 2.91 g of 40 (81% yield) mp: 126-127° C.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=2)[CH2:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[NH2:1][CH2:4][C@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=2)[CH2:6]1
Reactant: [N-]=[N+]=NC[C@@H]1CN(c2ccc(Cl)cn2)C(=O)O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NC[C@@H]1CN(c2ccc(Cl)cn2)C(=O)O1
Temperature: 25 °C
Yield: 82 %

Procedure:
A mixture of (5S)-5-(azidomethyl)-3-(5-chloropyridin-2-yl)-1,3-oxazolidin-2-one (2.31 g, INTERMEDIATE 8) and triphenylphosphine (3.58 g) was heated to 65° C. for 6 h in 444 ml of tetrahydrofuran and 56 ml of water. The sample was then cooled to room temperature, and concentrated in vacuo. The residue was purified via column chromatography on a Biotage Horizon 40M column eluting with 100% ethyl acetate (5 column volumes) to remove excess triphenylphosphine and triphenylphosphine oxide, followed by 100% methanol (5 column volumes), to provide the title compound (1.70 g, 82%). Mass spectrum (ESI) 228.1 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][CH2:17][CH2:18][CH3:19])=[CH:11][CH:10]=1)#[N:2].[Cl-].CO[C:23](=[O:33])[C:24]1[CH:32]=[CH:31][CH:30]=[C:26]([C:27]([OH:29])=[O:28])[CH:25]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[CH:11][C:12]([CH2:15][N:16]([CH2:17][CH2:18][CH3:19])[C:23](=[O:33])[C:24]2[CH:32]=[CH:31][CH:30]=[C:26]([C:27]([OH:29])=[O:28])[CH:25]=2)=[CH:13][CH:14]=1)#[N:2]
Reactant: CCCNCc1ccc(-c2ccccc2C#N)cc1
Reactant: COC(=O)c1cccc(C(=O)O)c1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCN(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)c1cccc(C(=O)O)c1

Procedure:
A solution of 2.50 g of N-(2'-cyanobiphenyl-4-ylmethyl)-N-propyl-amine, 2.98 g of isophthalic acid monomethyl ester monochloride and 2.10 ml of triethylamine in 100 ml of CH2Cl2 is stirred at room temperature for 1 hour. Extraction twice with 50 ml of water each time and customary treatment of the organic phase yields a crude product that, after chromatography on silica gel 60 (40-63 μm) using CH2Cl2 as eluant, yields N-(2'-cyanobiphenyl-4-ylmethyl)-N-propyl-isophthalic acid monoamide that has an Rf value of 0.61 [CH2Cl2 /CH3OH (4:1)].
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][CH:7]2[CH2:12][CH:11]([C:13]([OH:15])=O)[CH2:10][CH2:9][N:8]2[C:16]([O:18][CH3:19])=[O:17])=[CH:4][CH:3]=1.[CH3:22][C:23]1([CH3:31])[O:28][C:27](=[O:29])[CH2:26][C:25](=[O:30])[O:24]1.CCN(C(C)C)C(C)C.Cl.C(N=C=NCCCN(C)C)C>CN(C1C=CN=CC=1)C.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:12][CH:11]([C:13](=[C:26]3[C:27](=[O:29])[O:28][C:23]([CH3:31])([CH3:22])[O:24][C:25]3=[O:30])[OH:15])[CH2:10][CH2:9][N:8]2[C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=1
Reactant: COC(=O)N1CCC(C(=O)O)CC1Cc1ccc(Cl)cc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N1CCC(C(O)=C2C(=O)OC(C)(C)OC2=O)CC1Cc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 116.7 %

Procedure:
Dichloromethane (200 mL) was added to 2-(4-chlorobenzyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (4.27 g, 13.7 mmol) (reference compound 51). The mixture was cooled with an ice bath. DMAP (2.008 g, 16.44 mmol), 2,2-dimethyl-1,3-dioxane-4,6-dione (2.96 g, 20.54 mmol) and DIPEA (5.25 mL, 30.13 mmol) were added and then N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (5.25 g, 27.39 mmol) was added. The mixture was stirred at 0° C. for 15 min, then the mixture was warmed to room temperature and stirred overnight. The organic phase was washed with 1 M HCl and once with water. The organic layer was filtered through a phase separator and evaporated to yield crude methyl 2-(4-chlorobenzyl)-4-((2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)(hydroxy)methyl)-piperidine-1-carboxylate (7.00 g, 117%). MS m/z 438, 440 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([O:9][CH2:10][C@H:11]([OH:14])[CH2:12][OH:13])=[O:8])=[CH:5][CH:4]=1.O([Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])S(C(F)(F)F)(=O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([O:9][CH2:10][C@H:11]([O:14][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:12][O:13][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])=[O:8])=[CH:15][CH:16]=1
Reactant: COc1ccc(C(=O)OC[C@H](O)CO)cc1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C(=O)OC[C@@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a 1.0 L RB flask containing (R)-2,3-dihydroxypropyl 4-methoxybenzoate (4.800 g, 21.2 mmol; according to the procedure described in Corey, E. J.; Guzman-Perez, A.; and Noe, M. C. J. Am. Chem. Soc. 1995, 117, 10805-10816) was added DCM (100 mL) and the mixture was allowed to stir at 0° C. for 5 minutes. At this time, TEA (8.87 ml, 63.7 mmol) was added and the reaction was allowed to stir for 5 min before the dropwise addition of tert-butyldimethylsilyl triflate (10.2 ml, 44.6 mmol) via syringe. The reaction was allowed to stir for 1 h and then quenched by pouring into HCl (0.1 N, 100 mL). The aqueous layer was extracted with DCM (2×75 mL). The combined organics were washed with HCl (0.1 N, 2×150 mL), sodium bicarbonate (1×150 mL, sat), brine, dried sodium sulfate. The concentrated solution was passed through a plug of silica gel to and concentrated to give the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([NH:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:12]=[N:13][CH:14]=2)=[CH:5][CH:4]=1>C(O)(=O)C>[F:24][C:2]([F:1])([F:25])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([NH:15][C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:23])[CH2:10]2)=[CH:7][CH:8]=1
Reactant: O=C(Nc1cncc(-c2ccc(C(F)(F)F)cc2)c1)c1ccccc1
Solvent: CC(=O)O
Product: O=C(NC1CNCC(c2ccc(C(F)(F)F)cc2)C1)c1ccccc1

Procedure:
A solution of 1.0 g (2.9 mmol) of N-{5-[4-(trifluoromethyl)phenyl]pyridin-3-yl]benzamide in 120 ml of glacial acetic acid was reacted according to General Method 6A. The solution was concentrated under reduced pressure. The product was purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 657 mg (50% pure).