Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[C:7]2=[O:14].[CH3:23][S:24](Cl)(=[O:26])=[O:25]>N1C=CC=CC=1>[F:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][N:6]2[CH2:5][CH2:4][C:3]3[C:2]([NH:1][S:24]([CH3:23])(=[O:26])=[O:25])=[N:11][CH:10]=[C:9]([O:12][CH3:13])[C:8]=3[C:7]2=[O:14])=[CH:21][CH:20]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cnc(N)c2c1C(=O)N(Cc1ccc(F)cc1)CC2
Solvent: c1ccncc1
Product: COc1cnc(NS(C)(=O)=O)c2c1C(=O)N(Cc1ccc(F)cc1)CC2
Temperature: 25 °C

Procedure:
To a solution of 5-amino-2-(4-fluorobenzyl)-8-methoxy-3,4-dihydro-2,6-naphthyridin-1(2H)-one (0.889 g, 2.95 mmol) in pyridine (5 mL) was added dropwise methanesulfonyl chloride (0.575 g, 5.016 mmol). After stirring for an hour at room temperature, the product mixture was quenched with pH 7 buffer, then concentrated under vacuum. The residue was dissolved in CHCl3 and pH 7 buffer, the pH of the aqueous layer was adjusted to pH 5 with 1N NaOH and the layers separated. Several more extractions with CHCl3 were performed. The organic extracts were dried with Na2SO4, filtered, and concentrated under vacuum, then dissolved in toluene and CHCl3 and evaporated to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[O:17](C(OC(C)(C)C)=O)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=O>C(Cl)Cl.C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:18](=[O:17])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: C[C@H](N)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(Br)cc1
Reaction time: 1 h

Procedure:
To 150 g (735 mmol) (S)-1-(4-bromophenyl)ethylamine in 2 L DCM are added 459 mL (918 mmol) of an aq. Na2CO3 solution (c=2 mol/L). To this mixture a solution of 164 g (749 mmol) BOC2O in 350 mL THF is added dropwise at r.t. and stirring is continued for 1 h. After that the mixture is poured onto water and stirred for additional 20 min. The layers are separated, the org. layer is washed with water (2×), dried over Na2SO4 and the solvent is removed in vacuo.
Reaction SMILES: [F:1][C:2]([F:19])([CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]([OH:5])=O.Br.[NH2:21][CH2:22][CH2:23][C:24]1[C:32]2[S:31][C:30](=[O:33])[NH:29][C:28]=2[C:27]([OH:34])=[CH:26][CH:25]=1>>[F:19][C:2]([F:1])([CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]([NH:21][CH2:22][CH2:23][C:24]1[C:32]2[S:31][C:30](=[O:33])[NH:29][C:28]=2[C:27]([OH:34])=[CH:26][CH:25]=1)=[O:5]
Reactant: NCCc1ccc(O)c2[nH]c(=O)sc12
Reactant: O=C(O)C(F)(F)CCCCOCCc1ccccc1
Agent: Br
Product: O=C(NCCc1ccc(O)c2[nH]c(=O)sc12)C(F)(F)CCCCOCCc1ccccc1

Procedure:
The subtitled compound was prepared by the method outlined in Example 15a) using the material from step c) and 7-[2-aminoethyl]-4-hydroxy-1,3-benzothiazol-2(3H)-one hydrobromide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([C:19]#[N:20])([CH3:18])[CH3:17])[CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[CH:22](O)=[O:23].C(OC(=O)C)(=O)C.C(=O)([O-])O.[Na+]>O1CCCC1>[C:19]([C:16]([C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[C:9]([NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][CH:22]=[O:23])[CH:3]=1)=[O:21])([CH3:18])[CH3:17])#[N:20]
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(N)c2)c1
Reactant: O=CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(NC=O)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To a solution of the above-mentioned crude product of N-(3-aminophenyl)-3-(1-cyano-1-methylethyl)benzamide in tetrahydrofuran (15 mL) was added a mixture of formic acid (1 mL) and acetic anhydride (2 mL), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (15 mL), and the mixture was extracted with ethyl acetate (20 mL, 5 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=40/60→20/80), and the fractions containing the object product were concentrated under reduced pressure to give the title compound (407 mg, 83%) as a colorless amorphous solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([OH:18])[CH2:16][Br:17])=[CH:11][C:10]=1[N+:19]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1>O=[Pt]=O.C1(C)C=CC=CC=1>[NH2:19][C:10]1[CH:11]=[C:12]([C@@H:15]([OH:18])[CH2:16][Br:17])[CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cc([C@@H](O)CBr)ccc1OCc1ccccc1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Nc1cc([C@@H](O)CBr)ccc1OCc1ccccc1

Procedure:
(R)-1-[4-(benzyloxy)-3-nitrophenyl]-2-bromoethanol (0.200 g, 0.569 mmol) in 1:1 THF:toluene (5 mL) was reacted with 1% (w/w) PtO2 on a Parr shaker at 45 psi at rt overnight. The next morning the PtO2 was removed by filtration over celite. The product was concentrated to give the title compound. ES/MS calcd. for C15H17BrNO2+ 322.0. found m/z=322 (M+H)+.
Reaction SMILES: F[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]2[C:10]3([CH2:27][O:28][C:4]=2[CH:3]=1)[C:18]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[N:12]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[C:11]3=[O:26].C([NH:32][OH:33])(=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[NH2:9][C:8]1[C:7]2[CH:6]=[C:5]3[C:10]4([C:18]5[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=5)[N:12]([CH2:19][C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=5)[C:11]4=[O:26])[CH2:27][O:28][C:4]3=[CH:3][C:2]=2[O:33][N:32]=1
Reactant: CC(=O)NO
Reactant: N#Cc1cc2c(cc1F)OCC21C(=O)N(Cc2ccccn2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1noc2cc3c(cc12)C1(CO3)C(=O)N(Cc2ccccn2)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 1.6 %

Procedure:
To a stirred solution of 6-fluoro-2′-oxo-1′-(pyridin-2-ylmethyl)-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile (0.40 g, 2.7 mol) and acetohydroxamic acid (0.60 g, 8.0 mmol) in N,N-dimethylformamide (20 mL) was added cesium carbonate (2.60 g, 8.0 mmol). The reaction mixture was stirred at ambient temperature for 18 h and water was added. The aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography and eluted with (ethyl acetate/hexanes (2/3)+0.1% v/v 7 N methanolic ammonia) to afford 3-amino-1′-(pyridin-2-ylmethyl)spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one (0.05 g, 5%): mp 190-192° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 8.54-8.52 (m, 1H), 7.79-7.73 (m, 1H), 7.35-7.20 (m, 5H), 7.08-6.96 (m, 3H), 6.15 (s, 2H), 5.09-4.85 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ 177.2, 164.2, 163.3, 158.7, 155.6, 149.9, 143.5, 137.6, 131.7, 129.4, 126.4, 124.5, 123.6, 123.1, 121.9, 116.8, 111.5, 109.9, 91.4, 81.0, 56.8, 45.3; MS (ES+) m/z 384.9 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[CH2:15]([NH:22][C:23]([C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][N:26]=1)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([NH:22][C:23]([C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=3)[CH:4]=2)=[O:30])=[CH:27][N:26]=1)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)c1ccc(C(=O)NCc2ccccc2)nc1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(C(=O)NCc2ccccc2)nc1

Procedure:
250 mg of 5-(methoxycarbonyl)picolinic acid was coupled to benzylamine via Procedure G. Crude methyl 6-(benzylcarbamoyl)nicotinate was hydrolyzed via Procedure M to yield 300 mg of 6-(benzylcarbamoyl)nicotinic acid. 60 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 6-(benzylcarbamoyl)nicotinic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield N2-benzyl-N5-(4-chloro-3-(pyridin-2-yl)phenyl)pyridine-2,5-dicarboxamide.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH:9]([C:16]([O:18][CH2:19][CH:20]=[CH2:21])=[O:17])[C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])#[N:4].Br[CH2:23][CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1.O>CN(C=O)C>[C:3]([CH2:5][CH2:6][CH2:7][CH2:8][C:9]([CH2:23][CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)([C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])[C:16]([O:18][CH2:19][CH:20]=[CH2:21])=[O:17])#[N:4]
Reactant: C=CCOC(=O)C(CCCCC#N)C(=O)OCC=C
Reactant: COC(=O)c1ccc(CCBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOC(=O)C(CCCCC#N)(CCc1ccc(C(=O)OC)cc1)C(=O)OCC=C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 33.9 %

Procedure:
5.62 g (140 mmol; 60% content) of sodium hydride are added in portions to a solution of 48.64 g (127.73 mmol) of diallyl 2-(4-cyanobutyl)malonate from Example 90A in 160 ml of dry DMF at 0° C. The reaction solution is then allowed to reach room temperature and is stirred for 90 min. The reaction solution is then cooled to 0° C. again and, after addition of 45.72 g (153.3 mmol) of methyl 4-(2-bromoethyl)benzoate in 80 ml of dry DMF, stirred at this temperature for 45 min. The mixture is then stirred at room temperature overnight. The reaction mixture is mixed with water and extracted with ethyl acetate. After phase separation, the aqueous phase is extracted three times with 200 ml of ethyl acetate each time. The combined organic phases is washed with saturated sodium chloride solution and dried over sodium sulfate, and then the solvent is stripped off in vacuo. The resulting crude product is purified by silica gel chromatography (mobile phase: cyclohexane/ethyl acetate 10:1→100% ethyl acetate). 18.53 g (43.3 mmol, 34% yield) of a colorless liquid are obtained.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][N:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:64][N:65]([CH3:69])[CH2:66][CH2:67][NH2:68]>CN(C=O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:68][CH2:67][CH2:66][N:65]([CH3:69])[CH3:64])=[O:19])=[CH:16][N:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cn3)cc2[C@H](Nc2ccccn2)C[C@@H]1C
Reactant: CN(C)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)NCCN(C)C)cn3)cc2[C@H](Nc2ccccn2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a flask charged with 6-((2S,4R)-1-acetyl-2-methyl-4-(pyridin-2-ylamino)-1,2,3,4-tetrahydroquinolin-6-yl)nicotinic acid (for a preparation see Intermediate 28)(50 mg, 0.124 mmol) and HATU (56.7 mg, 0.149 mmol) was added DMF (2 mL) and the resulting mixture was treated with DIPEA (0.065 mL, 0.373 mmol) then after 5 min with N1,N1-dimethylethane-1,2-diamine (21.90 mg, 0.248 mmol. The resulting solution was stirred at room temperature for 30 min then partitioned between EtOAc and saturated NaHCO3. The organic phase was separated and aqueous layer extracted with EtOAc (×2). The combined organic layers were washed with saturated NaHCO3, dried over MgSO4 and concentrated in vacuo. The residue divided into 2 portions and each was purified by MDAP (HpH). The appropriate fractions were collected and concentrated in vacuo. The residue was dissolved in MeOH and concentrated again, then co-evaporated with toluene. The residue were then dissolved in 1,4-dioxane (2 mL) and treated with hydrogen chloride in 1,4-dioxane (4N, 0.5 mL). After 2 min the solvent was evaporated in vacuo and the precipitate formed triturated with Et2O then dried under house vacuum to give 6-((2S,4R)-1-acetyl-2-methyl-4-(pyridin-2-ylamino)-1,2,3,4-tetrahydroquinolin-6-yl)-N-(2-(dimethylamino)ethyl)nicotinamide, as the d-hydrochloride salt (37 mg, 0.068 mmol, 54.6% yield) as a yellow solid. LCMS (HpH, 2 min), Rt=0.81 min, MH+=473.
Reaction SMILES: [C:1]1([O-:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].[Cl:9][C:10](Cl)=[CH:11][C:12]([CH3:16])([CH3:15])[CH:13]=[CH2:14]>CN1CCCC1=O>[Cl:9][CH:10]=[C:11]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:12]([CH3:16])([CH3:15])[CH:13]=[CH2:14]
Reactant: C=CC(C)(C)C=C(Cl)Cl
Reactant: [O-]c1ccccc1
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: C=CC(C)(C)C(=CCl)Oc1ccccc1
Yield: 92 %

Procedure:
23.2 g (0.2 mol) of sodium phenolate and 16.5 g (0.1 mol) of 1,1-dichloro-3,3-dimethyl-1,4-pentadiene are heated to 180° C. in 100 ml of N-methylpyrrolidone, during the course of 10 hours. The working-up corresponding to Example A1(a) yields 20.5 g (92% of theory) of 1-chloro-3,3-dimethyl-2-phenoxy-1,4-pentadiene.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:22]=[C:21]4[C:15]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20]4)=[N:14]3)=[CH:9][CH:8]=2)[O:4][N:3]=1.[CH3:23][C:24]([CH3:26])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C.CO>[CH3:23][CH:24]([N:18]1[CH2:19][CH2:20][C:21]2=[CH:22][N:13]([C:10]3[CH:11]=[CH:12][C:7]([C:5]4[O:4][N:3]=[C:2]([CH3:1])[N:6]=4)=[CH:8][CH:9]=3)[N:14]=[C:15]2[CH2:16][CH2:17]1)[CH3:26]
Reactant: Cc1noc(-c2ccc(-n3cc4c(n3)CCNCC4)cc2)n1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1noc(-c2ccc(-n3cc4c(n3)CCN(C(C)C)CC4)cc2)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-[4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]-2,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepine (may be prepared as described in Description 35) (31 mg, 0.10 mmol) in dichloromethane (4 ml) was added acetone (24 mg, 0.42 mmol) and acetic acid (3 drops). The resulting mixture was stirred at room temperature, under argon, for 20 minutes. Sodium triacetoxyborohydride (89 mg, 0.42 mmol) was added and stirring continued overnight. The resulting crude mixture was diluted with methanol and then purified by SCX, eluting with methanol and then with 2M ammonia/methanol. The basic fractions were combined and solvent evaporated in vacuo. Crude product was purified further by column chromatography on silica gel, eluting with a mixture of 2M ammonia in methanol/dichloromethane (0-1%). Resulting crude product was purified further by column chromatography on silica gel, eluting with a mixture of 2M ammonia in methanol/dichloromethane (0-1%) to afford the title compound (E15). MS (ES+) m/e 338 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)C2C=CC=CC=2)=[C:4]([C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=O)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.O.C[N:41](C)C=O>>[C:19]1([C:17]2[C:4]3[C:5](=[CH:6][CH:7]=[C:2]([O:1][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:3]=3)[NH:8][N:41]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CN(C)C=O
Reactant: O=C(Nc1ccc(O)cc1C(=O)c1ccccc1)c1ccccc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: c1ccc(COc2ccc3[nH]nc(-c4ccccc4)c3c2)cc1
Reaction time: 8 h
Yield: 63 %

Procedure:
To a solution of N-[4-hydroxy-2-(phenylcarbonyl)phenyl]benzamide (4.0 g, 12.6 mmol) in dimethyl formamide (DMF) (15 mL) was added potassium carbonate (K2CO3) (large excess) then benzyl bromide (660 μL, 5.5 mmol). The reaction was stirred overnight. It was added to water (100 mL) then extracted with ethyl acetate (3×40 mL). The combined organic layers were dried (Na2SO4) then concentrated under vacuo to give a solid which was recrystallized with ethyl acetate/hexane to give the title compound (3.24 g, 63% yield, analytical).
Reaction SMILES: [OH:1][CH:2]([CH2:8][OH:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5].C(Cl)Cl.N1C=CC=CC=1.[C:19](Cl)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[C:20]1([C:19]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[O:9][CH2:8][CH:2]([OH:1])[CH2:3][C:4]([O:6][CH3:7])=[O:5])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)CC(O)CO
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)CC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 26.8 %

Procedure:
To 25 g of methyl 3,4-dihydroxybutanoate was added 250 mL of DCM and stirred to dissolve. 19.8 g of pyridine was added and cooled to 0° C. 41.4 g of trityl chloride was dissolved in 50 mL of DMC and was added at 0-5° C. for 15 minutes. The temperature was allowed to rise to room temperature and was stirred at room temperature for 17 hours. Water was added and the layers were separated. The organic layer was washed with brine, dried and concentrated. The residue was triturated with 25 mL of cyclohexane and the product was purified to give 15 g of the pure product. 1H NMR (CDCl3): 4.25 (m, 1H), 3.6 (s, 3H), 3.15 (d, 2H), 2.5 (m, 2H), 7.2-7.4 (m, 15H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[NH2:19][C:20](=[N:34]O)[CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1.[C:36]1([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:41]=[CH:40][C:39](C(Cl)=O)=[CH:38][CH:37]=1>>[C:36]1([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:41]=[CH:40][C:39]([C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]2[O:18][N:34]=[C:20]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]3)[N:19]=2)=[O:7])=[CH:38][CH:37]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=NO)CC1
Product: CON=C1C[C@@H](c2nc(C3CCN(C(=O)OC(C)(C)C)CC3)no2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Yield: 60 %

Procedure:
Following the general methods as outlined in Example 1 (Method A), starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidine-carboxylic acid (intermediate 2), tert-butyl 4-[amino(hydroxyimino)methyl]-1-piperidinecarboxylate (Intermediate 7) and [1,1′-biphenyl]-4-carbonyl chloride, the desired compound, tert-butyl 4-{5-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-3-yl}-1-piperidinecarboxylate, was isolated, after flash-chromatography (cyclohexane/ethylacetate 6/4), as a mixture of E-/Z-isomers in 60% yield (97.9% purity by HPLC).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][C:17]([NH2:22])([CH2:20][OH:21])[CH2:18][OH:19])=[CH:13][CH:14]=1.[ClH:23].[C:24]([OH:27])(=[O:26])[CH3:25]>C(OCC)(=O)C>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([NH2:22])([CH2:18][OH:19])[CH2:20][OH:21])=[CH:11][CH:10]=1.[ClH:23].[C:24]([O-:27])(=[O:26])[CH3:25]
Reactant: CC(=O)O
Agent: CCCCCCCCc1ccc(CCC(N)(CO)CO)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(=O)[O-]
Temperature: 25 °C

Procedure:
In an alternative procedure, FTY720 free base (2.27 mmol) was dissolved in ethyl acetate (16 ml) at 88-90° C. Then a solution of acetic acid (2.5 eq) in ethyl acetate (3 ml) was added at 75° C., whereupon the product started to crystallize out immediately after addition. The resulting suspension was cooled to room temperature. The product was collected by filtration and was washed with ethyl acetate (2 ml). After drying at 50° C. the product was obtained as white crystals in 99.4% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].[NH2:11][C:12]1[C:17]([CH:18]=O)=[CH:16][N:15]=[C:14]([CH3:20])[N:13]=1.[Na]>C(OCCO)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([NH2:10])=[N:11][C:12]2[N:13]=[C:14]([CH3:20])[N:15]=[CH:16][C:17]=2[CH:18]=1
Reactant: Cc1ncc(C=O)c(N)n1
Reactant: N#CCc1ccccc1Cl
Agent: [Na]
Solvent: CCOCCO
Product: Cc1ncc2cc(-c3ccccc3Cl)c(N)nc2n1

Procedure:
2-Chlorophenylacetonitrile 4.0 g and 4-amino-2-methylpyrimidine-5-carboxaldehyde 3.6 g are added to a solution prepared by dissolving 0.2 g of sodium metal in 40 ml of 2-ethoxy-ethanol. The mixture is heated at reflux for 2 hours, and then cooled. The crude product precipitates as a solid and is collected by filtration. After recrystallization from aqueous dimethylformamide, 3.4 g of 6-(2-chlorophenyl)-2-methylpyrido[2,3-d]pyrimidin-7-amine, mp 259°-260° C. is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)([NH:14][S:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:31]I.O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)([N:14]([CH3:31])[S:15]([C:17]([CH3:20])([CH3:18])[CH3:19])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccc(Cl)cc2)(NS(=O)C(C)(C)C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(S(=O)C(C)(C)C)C1(Cc2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 77 %

Procedure:
To a solution of 4-(4-chlorobenzyl)-4-(2-methylpropane-2-sulfinylamino)-piperidine-1-carboxylic acid tert-butyl ester (205 mg, 0.478 mmol) in DMF (4.8 mL) at 0° C. was added sodium hydride (25 mg of a 60% dispersion in mineral oil, 0.621 mmol). After 15 min methyl iodide (33 □l, 0.526 mmol) was added, and the solution warmed to rt. After 12 h, sodium hydride (120 mg, 60% dispersion in mineral oil, 3.00 mmol) and methyl iodide (165 □l, 2.65 mmol) were added. After 30 min water (20 mL) was added and the solution extracted with ethyl acetate (3×20 mL). Organic extracts were combined, dried over magnesium sulphate and the resulting crude product was purified by silica column chromatography, eluting with 66% ethyl acetate—hexanes, to give the title product as an oil (163 mg, 77%). LC-MS (LCT2) m/z 465 [M+Na+], Rt 8.41 min.