Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH:27]([F:31])[CH:26]([CH3:32])[CH2:25][CH:24]([O:33][CH3:34])[CH:23]2[O:35][C:19]([OH:39])([CH:20]([CH3:38])[CH2:21][CH:22]2[O:36][CH3:37])[C:18](=[O:40])[C:17](=[O:41])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:42])[O:9][CH:8]([C:43]([CH3:53])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([OH:52])[CH2:46]2)[CH:7]([CH3:54])[CH2:6][CH2:5][C:4]1=[O:55])[CH3:2].C(N(C(C)C)CC)(C)C.[N+:65]([C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][C:69]=1[S:74](Cl)(=[O:76])=[O:75])([O-:67])=[O:66]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH:27]([F:31])[CH:26]([CH3:32])[CH2:25][CH:24]([O:33][CH3:34])[CH:23]2[O:35][C:19]([OH:39])([CH:20]([CH3:38])[CH2:21][CH:22]2[O:36][CH3:37])[C:18](=[O:40])[C:17](=[O:41])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:42])[O:9][CH:8]([C:43]([CH3:53])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([O:52][S:74]([C:69]3[CH:70]=[CH:71][CH:72]=[CH:73][C:68]=3[N+:65]([O-:67])=[O:66])(=[O:75])=[O:76])[CH2:46]2)[CH:7]([CH3:54])[CH2:6][CH2:5][C:4]1=[O:55])[CH3:2]
Reactant: CCC1C=C(C)C(F)C(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)CCC1=O)C(C)CC2OC
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC1C=C(C)C(F)C(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OS(=O)(=O)c4ccccc4[N+](=O)[O-])C3)C(C)CCC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 17-ethyl-20-fluoro-1-hydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (200 mg) in dry methylene chloride (20 ml) is added diisopropylethylamine (150 μl) followed by 2-nitrobenzenesulonyl chloride (60 mg), then 4-dimethylaminopyridine (27 mg). The solution is stirred at room temperature under nitrogen atmosphere for 4 h, then quenched with sat'd aqueous sodium bicarbonate solution. The organic layer is washed (water, sat'd NaHCO3, sat'd NaCl), dried (anhydrous Na2SO4) and the solvent is removed in vacuo. Chromatography on silica gel gives the title compounds.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[CH:16]=[CH:15][C:9]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:8]([S:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])[CH:7]=1)(=[O:5])[CH3:4].C(O)(=O)C>CO>[F:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[S:17][C:8]1[CH:7]=[C:6]([CH:3]([OH:5])[CH3:4])[CH:16]=[CH:15][C:9]=1[NH:10][S:11]([CH3:14])(=[O:13])=[O:12]
Reactant: CC(=O)c1ccc(NS(C)(=O)=O)c(Sc2ccc(F)cc2F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(O)c1ccc(NS(C)(=O)=O)c(Sc2ccc(F)cc2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.1 %

Procedure:
Sodium borohydride (0.2 g) was added portionwise to a solution of 4'-acetyl-2'-(2,4-difluorophenylthio)methanesulfonanilide (1.55 g) in methanol (30 ml) at 15° C. The mixture was stirred overnight at room temperature, treated with acetic acid, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with an aqueous solution of sodium bicarbonate, dried, and concentrated. The residual oil (1.6 g) was purified by column chromatography on silica gel (50 g) eluting with a mixture of toluene and ethyl acetate (4:1). The purified product was recrystallized from a mixture of ethanol and water (2:1) to give crystals of 2'-(2,4-difluorophenylthio)-4'-(1-hydroxyethyl)methanesulfonanilide (1.03 g).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:7]=[CH:6][NH:5][N:4]=1.[Cl:10][C:11]1[CH:18]=[C:17](F)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:10][C:11]1[CH:18]=[C:17]([C:7]2[C:3]([C:2]([F:9])([F:8])[F:1])=[N:4][NH:5][CH:6]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: FC(F)(F)c1cc[nH]n1
Reactant: N#Cc1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(-c2c[nH]nc2C(F)(F)F)cc1Cl
Temperature: 25 °C
Yield: 92 %

Procedure:
2.5 g (18.4 mmol) of 3-trifluoromethylpyrazole, 2.9 g (18.4 mmol) of 2-chloro-4-fluorobenzonitrile and 2.8 g (20.2 mmol) of potassium carbonate in 20 ml of N,N-dimethylformamide were stirred at 60° C. for 2 hours. After cooling to room temperature, the reaction mixture was poured into 100 ml of water, and the organic matters were extracted with 50 ml of ethyl acetate twice. The ethyl acetate layers were combined, washed with 50 ml of water twice and dried over anhydrous magnesium sulfate, and the ethyl acetate was distilled off under reduced pressure. After washed with n-hexane, the residue afforded 4.6 g of 2-chloro-4-(3-trifluoromethylpyrazolyl)benzonitrile (yield 92.0%) as a white powder, which was used in Reference Example 3 as the starting material.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][O:8][CH2:9][CH:10]=[CH:11][CH2:12][O:13][C:14](=[O:18])[CH:15]=[N+]=[N-])=[CH:5][CH:4]=1>ClCCl>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][O:8][CH2:9][C@@H:10]2[C@@H:15]3[C@H:11]2[CH2:12][O:13][C:14]3=[O:18])=[CH:5][CH:4]=1
Reactant: COc1ccc(COCC=CCOC(=O)C=[N+]=[N-])cc1
Solvent: ClCCl
Product: COc1ccc(COC[C@H]2[C@@H]3COC(=O)[C@H]23)cc1
Yield: 95.1 %

Procedure:
To a solution of 1 g (3.6 mmol) of diazo-acetic acid 4-(4-methoxy-benzyloxy)-but-2-enyl ester in 50 ml dichloromethane under reflux were added within 8 hrs of 25 mg (0.03 mmol) of Rh2 (5S-MEPY)4 (Doyle dirhodium catalyst from Acros, CAS: 132435-65-5) dissolved in 100 ml of dichloromethane. Refluxing for another 20 hrs, evaporation of the solvent and chromatography on silica gel with heptane/AcOEt gave 850 mg (96%, >92% ee) of (1R,5S, 6S) 6-(4-methoxy-benzyloxymethyl)-3-oxa-bicyclo[3.1.0]hexan-2-one. Colorless oil. MS: 247 (M−H)−.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].C([CH:10]1[CH2:15][CH:14]2[O:16]C1C=C2)(OC)=O.Cl.C(Cl)Cl>O>[CH2:1]([N:3]([CH2:4][CH3:5])[C:14](=[O:16])[CH:15]=[CH2:10])[CH3:2]
Reactant: CCNCC
Reactant: COC(=O)C1CC2C=CC1O2
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: C=CC(=O)N(CC)CC
Temperature: 140 °C
Reaction time: 15 h

Procedure:
7.2 parts 30% methanolic Na-methylate solution are added to 36.5 parts diethylamine. 77 parts 2-carbomethoxy-7-oxabicyclo(2,2,1)hept-5-ene are added drop-wise at 40° C. The reaction medium is then stirred for 15 hours at this temperature and neutralised with 4 parts concentrated hydrochloric acid. 100 parts methylene chloride and 50 parts water are added, the organic phase separated off, and the aqueous phase extracted 3 times with 25 parts methylene chloride in each instance. The combined organic phases are reduced in a rotary evaporator at a bath temperature of 90° C. and under a vacuum of 20 Torr. The residue is heated under a vacuum of 20 Torr to 110° to 120° C. (bath temperature 140° C.). On conclusion of the furane separation, the sedimentation temperature increases and the product distills over at the now lowered pressure. 21 parts N,N-diethylacrylamide with a boiling point of 55° C. at 1 Torr are obtained.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[C:8]([C:19]([O:21][CH3:22])=[O:20])=[CH:9][N:10]([CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[C:5]2=[N:4][CH:3]=1.[Cl:23][C:24]1[CH:32]=[C:31]2[C:27]([C:28]([Sn](CCCC)(CCCC)CCCC)=[N:29][NH:30]2)=[CH:26][CH:25]=1>CN(C=O)C.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.[Cu]I>[Cl:23][C:24]1[CH:32]=[C:31]2[C:27]([C:28]([C:2]3[N:7]=[C:6]4[C:8]([C:19]([O:21][CH3:22])=[O:20])=[CH:9][N:10]([CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[C:5]4=[N:4][CH:3]=3)=[N:29][NH:30]2)=[CH:26][CH:25]=1
Reactant: COC(=O)c1cn(COC(=O)C(C)(C)C)c2ncc(Br)nc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1n[nH]c2cc(Cl)ccc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COC(=O)c1cn(COC(=O)C(C)(C)C)c2ncc(-c3n[nH]c4cc(Cl)ccc34)nc12
Temperature: 90 °C
Yield: 85.7 %

Procedure:
A mixture of methyl 2-bromo-5-(pivaloyloxymethyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylate (0.26 g, 0.7 mmol), 6-chloro-3-(tributylstannyl)-1H-indazole (0.31 g, 0.7 mmol), Pd(PPh3)4 (81 mg, 0.07 mmol) and CuI (27 mg, 0.14 mmol) in dry DMF (3 mL) was heated to 90° C. for 3 hours. Product was extracted with ethyl acetate (60 mL), and organic phase washed with water (3×10 mL) and brine (2×10 mL), dried over Na2SO4, filtered and concentrated to afford methyl 2-(6-chloro-1H-indazol-3-yl)-5-(pivaloyloxymethyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylate (265 mg, crude) as a brown oil. LCMS: (M+H)+=442.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[C:22](F)=[CH:21][C:20]([F:24])=[CH:19][N:18]=2)=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:26][NH2:27].C([O-])(O)=O.[Na+]>CC(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:17]3=[N:18][CH:19]=[C:20]([F:24])[CH:21]=[C:22]3[NH:27][N:26]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(c1ccc(OCc2ccccc2)cc1)c1ncc(F)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: Fc1cnc2c(-c3ccc(OCc4ccccc4)cc3)n[nH]c2c1
Temperature: 90 °C
Reaction time: 12 h
Yield: 79.5 %

Procedure:
A mixture of [4-(benzyloxy)phenyl](3,5-difluoropyridin-2-yl)methanone (41 mg), hydrazine hydrate (31.5 mg) and 2-propanol (10 mL) was stirred at 90° C. for 12 h, treated with saturated NaHCO3 aqueous solution, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (32.0 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][NH:11][CH3:12])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl.[O:14]=[C:15]1[NH:24][C:23]2[N:22]=[CH:21][C:20](/[CH:25]=[CH:26]/[C:27]([OH:29])=O)=[CH:19][C:18]=2[CH2:17][CH2:16]1>>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][N:11]([CH3:12])[C:27](=[O:29])/[CH:26]=[CH:25]/[C:20]3[CH:21]=[N:22][C:23]4[NH:24][C:15](=[O:14])[CH2:16][CH2:17][C:18]=4[CH:19]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CNCc1ccc2[nH]ccc2c1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: Cl
Product: CN(Cc1ccc2[nH]ccc2c1)C(=O)/C=C/c1cnc2c(c1)CCC(=O)N2
Yield: 38.8 %

Procedure:
According to the procedure of Example 35g (1H-indol-5-yl-methyl)-methyl-amine (257 mg, 1.62 mmol) and (E)-3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3yl)acrylic acid hydrochloride (312 mg, 1.23 mmol), were coupled to give crude product. Purification by column chromatography (silica gel, 5% MeOH/CH2Cl2) gave the title compound (172 mg, 39%) as a white solid and a mixture of amide rotomers: 1H NMR (300 MHz, DMSO-d6) δ 11.06-11.05 (m, 1H), 10.63-10.61 (m, 1H), 8.36-8.34 (m, 1H), 8.06 (s, 1H), 7.56-7.19 (m, 5H), 7.02-6.96 (m, 1H), 6.38 (s, 1H), 4.84-4.65 (m, 2H), 3.06-2.85 (m, 5H), 2.55-2.52 (m, 2H); ESI MS m/e 361 [C21H20N4O2+H]+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([NH:17][CH:18]([CH3:20])[CH3:19])([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1)C1C=CC=CC=1.C(O)=O>[Pd].CO>[C:14]([C:11]1([NH:17][CH:18]([CH3:20])[CH3:19])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)(=[O:15])[NH2:16]
Reactant: CC(C)NC1(C(N)=O)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Product: CC(C)NC1(C(N)=O)CCNCC1
Yield: 113.3 %

Procedure:
A mixture of the 1-benzyl-4-isopropylamino-4-piperidinecarboxamide (250 mg, 0.91 mmol) (commercially available from Aldrich Chemical, Milwaukee, Wis.), 10% palladium on charcoal (30% by weight, 81 mg) and formic acid (5 mmol) in methanol (4 ml) was stirred vigorously overnight at room temperature. The reaction mixture was filtered through a celite pad and concentrated in vacuo to provide the product 4-carbamoyl-4-(isopropylamino)piperidine (191 mg, 90%) as a formic acid salt. A mixture of the chloride I-1f (100 mg, 0.28 mmol), 4-carbamoyl-4-(isopropylamino)-piperidine (85 mg, 0.306 mmol) and triethylamine (0.13 ml, 0.92 mmol) in dry ethanol (2 ml) was refluxed for 3 hrs. The reaction mixture was cooled to room temperature and water was added to precipitate out solids. The filtrate was acidified and washed with ethyl acetate to remove impurities. The aqueous layer was basified with 1 N NaOH and extracted with dichloromethane, dried and concentrated to give crude solid. This was combined with the filtered solids and purified using short plug silica gel with 10% MeOH:EtOAc as eluant to provide the desired product 1A-1 (46 mg, 30%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 8.78 (s, 1H), 7.68–7.41 (m, 6H), 7.19–7.14 (t, 2H), 4.42 (br d, 2H), 4.16–4.13 (br t, 2H), 2.95–2.92 (m, 1H), 2.17–2.12 (m, 2H), 1.83–1.80 (br d, 2H), 1.10 (d, 6H); MS (m/z): 524.5 (M+H); Ret time (RT): 1.7 min.
Reaction SMILES: Cl.Cl.C[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6](C)[C:5]=1N.C[C:14]1[C:15](=[N:22]Cl)[C:16](C)=[CH:17][C:18](=[O:20])[CH:19]=1>C(O)(C)C>[CH:16]1[C:15](=[N:22][C:4]2[CH:5]=[CH:6][C:7]([NH2:10])=[CH:8][CH:9]=2)[CH:14]=[CH:19][C:18](=[O:20])[CH:17]=1
Reactant: Cc1ccc(N)c(C)c1N
Reactant: CC1=CC(=O)C=C(C)C1=NCl
Agent: Cl
Solvent: CC(C)O
Product: Nc1ccc(N=C2C=CC(=O)C=C2)cc1
Reaction time: 1 h
Yield: 100.9 %

Procedure:
0.003 mole (0.627 g) of 1,3-dimethyl 2,4-diamino benzene dihydrochloride is dissolved in 11 cc of 0.82 N soda solution. To this solution, cooled to 0°, there is added 0.002 mole (0.339 g) of 2,6-dimethyl N-chlorobenzoquinone monoimine in solution in 6 cc of isopropanol. The reaction mixture rapidly turns blue. It is allowed to stand for one hour at 0.20. Then 0.400 g of the above indoaniline is isolated in the form of beautiful green flakes with golden glints by filtering. After washing with water and extended vacuum drying, the product melts at 196° (no drop of melting point is observed when used in mixture with the product prepared according to Example 22).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][C:6]=2[CH:17]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[N+:47]([C:50]1[CH:55]=[CH:54][C:53]([NH:56][CH:57]2[CH2:62][CH2:61][CH:60]([O:63][CH2:64][C:65](O)=[O:66])[CH2:59][CH2:58]2)=[CH:52][C:51]=1[C:68]([F:71])([F:70])[F:69])([O-:49])=[O:48]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][N:11]3[CH2:16][CH2:15][N:14]([C:65](=[O:66])[CH2:64][O:63][CH:60]4[CH2:61][CH2:62][CH:57]([NH:56][C:53]5[CH:54]=[CH:55][C:50]([N+:47]([O-:49])=[O:48])=[C:51]([C:68]([F:70])([F:69])[F:71])[CH:52]=5)[CH2:58][CH2:59]4)[CH2:13][CH2:12]3)=[N:7][C:6]=2[CH:17]=1
Reactant: Fc1ccc2sc(CN3CCNCC3)nc2c1
Reactant: O=C(O)COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)N1CCN(Cc2nc3cc(F)ccc3s2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.3 %

Procedure:
A mixture of 5-fluoro-2-(piperazin-1-ylmethyl)-1,3-benzothiazole (130 mg, 0.52 mmol), EDAC.HCl (149 mg, 0.78 mmol), HOBt (105 mg, 0.78 mmol) and triethylamine (157 mg, 1.55 mmol) in dichloromethane (30 ml) was stirred for 1 hour at room temperature before the addition of 2-(-4-(4-nitro-3-(trifluoromethyl)phenylamino)cyclohexyloxy)acetic acid (187 mg, 0.52 mmol). After stirring overnight at room temperature, the solution was diluted with dichloromethane (100 ml) and washed with water (50 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue, which was purified by HPLC to afford 1-(4-((5-fluorobenzo[d]thiazol-2-yl)methyl)piperazin-1-yl)-2-(-4-(4-nitro-3-(trifluoromethyl)phenylamino)cyclohexyloxy)ethanone as a yellow solid (162.0 mg, 53%). (ES, m/z): [M+H]+ 596.00; 1H NMR (300 MHz, CDCl3): δ 8.01 (d, J=9.0 Hz, 1H), 7.87 (dd, J=8.7, 4.8 Hz, 1H), 7.72 (dd, J=9.0, 2.4 Hz, 1H), 7.29-7.23 (m, 1H), 6.84 (d, J=2.1 Hz, 1H), 6.62 (dd, J=9.0, 2.1 Hz, 1H), 5.52 (br s, 1H), 4.47 (s, 2H), 4.20 (s, 2H), 3.93-3.90 (m, 4H), 3.43-3.33 (m, 2H), 3.22-3.19 (m, 4H), 2.11-2.01 (m, 4H), 1.48-1.37 (m, 2H), 1.32-1.21 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].I[CH:20]([CH3:22])[CH3:21]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:20]([CH3:22])[CH3:21])[C:5]([O:7][CH3:8])=[O:6]
Reactant: CC(C)I
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC(C)C)c(Cl)c1
Reaction time: 18 h
Yield: 104.6 %

Procedure:
Methyl 3-chloro-4-hydroxybenzoate (50 g, 0.27 mole; available from Alfa Aesar), potassium carbonate (74 g, 0.54 mole) and 2-iodopropane (29.5 ml, 0.23 mole) were stirred at room temperature in DMF (100 ml). After 18 hours, the solvent was removed by evaporation under vacuum and the residue was chromatographed over a column of silica 60 eluting with ethyl acetate/hexane (1:1) to give the title compound as an oil (55 g). MS: m/z (API-ES) 229 [MH+]; 1H NMR (400 MHz, CDCl3) δ (inter alia) 8.05 (1H, d), 7.89 (1H, dd), 6.94 (1H, d), 4.60-4.72 (1H, m), 3.89 (3H, s), 1.41 (6H, d).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.[CH2:6]([O:8][C:9]([C:11]1([CH2:24][CH2:25]CO)[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)=[O:10])[CH3:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH2:6]([O:8][C:9]([C:11]1([CH2:24][CH2:25][CH2:1][Br:5])[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)=[O:10])[CH3:7]
Reactant: BrC(Br)(Br)Br
Reactant: CCOC(=O)C1(CCCO)CCN(C(=O)OC(C)(C)C)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)C1(CCCBr)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Carbon tetrabromide (1.6 gm, 0.0048 mol) is added to a stirred solution of 4-(3-hydroxypropyl) piperidine-1,4-dicarboxylic acid-1-tert-butyl ester-4-ethyl ester (1.27 gm, 0.0040 mol) and triphenyl phosphine (1.6 gm, 0.0060 mol) in dichloromethane (15 mL) at 0-5° C. temperature. Reaction mixture is allowed to stir at room temperature for 30 minutes. Removal of solvent gives a crude residue which is purified by column chromatography (silica gel 230-400 mesh, ethyl acetate:n-hexane 3:7) to get 4-(3-bromopropyl)piperidine-1,4-dicarboxylic acid-1-tert-butyl ester-4-ethyl ester.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:13]([NH:15][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:17][OH:18])=[O:14].ClC(Cl)(Cl)C(=N)O[CH2:34][CH:35]=[CH2:36].FC(F)(F)S(O)(=O)=O>C(Cl)Cl.C1CCCCC1.C(Cl)Cl>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:13]([NH:15][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:17][O:18][CH2:36][CH:35]=[CH2:34])=[O:14]
Reactant: C=CCOC(=N)C(Cl)(Cl)Cl
Reactant: COC(=O)[C@H](CO)NC(=O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCCCC1
Product: C=CCOC[C@H](NC(=O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O)C(=O)OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Dissolve N-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-L-serine, methyl ester (25 g, 63 mmol) in methylene chloride/cyclohexane (1:1, 600 mL). Add allyl trichloroacetimidate (26 g, 128 mmol) and trifluoromethanesulfonic acid (5 mL), 56.6 mmol). Stir at room temperature under a nitrogen atmosphere for 5 hours and dilute with methylene chloride. Wash with saturated aqueous sodium hydrogen carbonated water, dry (MgSO4) and evaporate the solvent in vacuo. Purify by silica gel chromatography (gradient 20% ethyl acetate/hexane to 35% ethyl acetate/hexane) to give the title compound; mp 95°-97° C.
Reaction SMILES: [CH3:1][O:2][C:3]([O:19][CH3:20])([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[CH:8]=1)[CH:4]([OH:6])[CH3:5].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[CH3:28][S:29]([O:6][CH:4]([CH3:5])[C:3]([O:19][CH3:20])([O:2][CH3:1])[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[CH:8]=1)(=[O:31])=[O:30]
Reactant: COc1ccc2cc(C(OC)(OC)C(C)O)ccc2c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2cc(C(OC)(OC)C(C)OS(C)(=O)=O)ccc2c1
Temperature: 5 °C

Procedure:
The crude oil, 1,1-dimethoxy-1-(6-methoxy-2-naphthyl)propan-2-ol, from Example 8 is dissolved in 200 ml of methylene chloride and to that mixture is added 13.2 g of triethylamine. The reaction mixture is cooled to 5° C. and 11.0 g of methanesulfonyl chloride is added slowly, maintaining the temperature between 5°-10° C. The precipitation of triethylamine hydrochloride crystals is observed. After the addition of the methanesulfonyl chloride has been completed, the reaction mixture is stirred for an additional one-half hour. Then the solution is filtered to remove the triethylamine hydrochloride crystals and the filtrate is poured into 200 ml of water. The organic layer is separated and dried over magnesium sulfate. Evaporation of the organic layer under reduced pressure yields 30.4 g of crude 1,1-dimethoxy-1-(6-methoxy-2-naphthyl)prop-2-yl methanesulfonate as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([F:17])=[C:6]([C:9]([CH:15]=[O:16])=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[C:7]#[N:8])[CH3:2].C(OCC)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[CH2:1]([O:3][C:4]1[C:5]([F:17])=[C:6]([C:9]([CH2:15][OH:16])=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[C:7]#[N:8])[CH3:2]
Reactant: CCOc1cc(C=O)c(C#N)c(F)c1OCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOc1cc(CO)c(C#N)c(F)c1OCC
Temperature: 40 °C
Reaction time: 8 h

Procedure:
3,4-Diethoxy-2-fluoro-6-formylbenzonitrile (5.90 kg, 24.87 mol) and ethyl acetate (59.0 L) were transferred to a reaction vessel under a nitrogen atmosphere, and while stirring, sodium triacetoxyborohydride (NaB(OAc)3H) (11.70 kg) was added. After 30 minutes of stirring, the internal temperature was heated up to 40° C., and the reaction solution was stirred for another 2 hours. The reaction solution was cooled, and at 15° C. internal temperature, water (2 L) was slowly added in drops, and excess sodium triacetoxyborohydride was degraded. Then more water (27.5 L) was added. The insoluble material was dissolved by increasing the outer bath temperature to 40° C., and the solution was separated after cooling. Following separation, the obtained organic layer was washed twice with an aqueous sodium bicarbonate solution and then with brine. The obtained organic layer was cooled in a 10° C. outer bath, and left to stand overnight.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.C(=O)(O)[O-].[Na+].[C:17]1([N:23]2[C:27](=[O:28])[CH:26]([C:29](=O)[CH2:30][C:31](=O)[CH3:32])[C:25]([CH3:35])=[N:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:29]([C:26]3[C:25]([CH3:35])=[N:24][N:23]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:27]=3[OH:28])=[CH:30][C:31]([CH3:32])=[N:11]2)=[CH:6][CH:5]=1
Reactant: COc1ccc(NN)cc1
Reactant: CC(=O)CC(=O)C1C(=O)N(c2ccccc2)N=C1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-n2nc(C)cc2-c2c(C)nn(-c3ccccc3)c2O)cc1
Reaction time: 0.17 h

Procedure:
To (4-methoxyphenyl)-hydrazine hydrochloride (0.083 g, 0.48 mmol) in ethanol (5 ml) add sodium bicarbonate (0.067 g, 0.80 mmol) after which stir the mixture for 10 min. Add 1-[1-phenyl-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-4-yl]-butane-1,3-dione (0.103 g, 0.40 mmol. The mixture was heated at reflux for 1.5 hours after which it was evaporated to dryness. Chromatography on silica gel, eluting with 50 to 100% ethyl acetate/heptane provided 0.071 g of the title compound.