Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[C:8]=2[Cl:15])[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[Cl:18][CH2:19][CH2:20][CH2:21][C:22](Cl)=[O:23]>C(#N)C>[Cl:18][CH2:19][CH2:20][CH2:21][C:22]([NH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[C:8]=2[Cl:15])[N:5]=[CH:4][C:3]=1[C:16]#[N:17])=[O:23]
Reactant: N#Cc1cnn(-c2ccc(Cl)c(Cl)c2Cl)c1N
Reactant: O=C(Cl)CCCCl
Solvent: CC#N
Product: N#Cc1cnn(-c2ccc(Cl)c(Cl)c2Cl)c1NC(=O)CCCCl
Temperature: 25 °C
Reaction time: 24 h
Yield: 29.4 %

Procedure:
A mixture of 5-amino-4-cyano-1-(2,3,4-trichlorophenyl)pyrazole (12.47 g) and 4-chlorobutyryl chloride (12.3 g) in dry acetonitrile (200 ml) was stirred and gently warmed to effect dissolution. The solution was cooled to room temperature and stirred, after 48 hours a further quantity of 4-chlorobutyryl chloride (6.15 g) was added and stirring continued for 24 hours. The solution was evaporated under reduced pressure to give an oil which was chromatographed using dichloromethane-ethyl acetate (19:1) as eluent. Evaporation of the eluate containing the fastest moving component gave 5-(4-chlorobutyramido)-4-cyano-1-(2,3,4-trichlorophenyl)pyrazole (5 g), m.p. 173°-174° C., after crystallisation from toluene, in the form of pale yellow crystals.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[C@@H:11]2[C@H:7]1[CH:8]=[CH:9][C@:10]2([NH2:22])[C:12]([O:14]CC1C=CC=CC=1)=[O:13])=[O:5])C.O[Li].O.Cl>C1COCC1.O.CO>[NH2:22][C@:10]1([C:12]([OH:14])=[O:13])[CH:9]=[CH:8][C@@H:7]2[C@H:11]1[C@H:6]2[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)[C@H]1[C@@H]2C=C[C@](N)(C(=O)OCc3ccccc3)[C@@H]21
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: N[C@]1(C(=O)O)C=C[C@H]2[C@H](C(=O)O)[C@H]21
Temperature: 23 °C
Yield: 95.3 %

Procedure:
A solution of (1S,2R,5R,6S)-2-amino-bicyclo[3.1.0]hex-3-ene-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (XXVII) (19 mg, 0.063 mmol) and LiOH.H2O (8 mg, 0.19 mmol) in THF (2 mL), H2O (0.5 mL) and MeOH (0.2 mL) was stirred at 23° C. for 10 h. The solution was acidified with conc. HCl and evaporated to dryness. The remaining pale yellow solid was suspended in EtOH, filtered, washed with more EtOH and the filtrate was evaporated to dryness. The residue was dissolved in EtOH (1 mL) and propylene oxide (1 mL) and refluxed for 3 min, whereupon the amino acid precipiated. After cooling to 23° C., the product was filtered off, washed with ether and dried to give (1S,2R,5R,6S)-2-amino-bicyclo[3.1.0]hex-3-ene-2,6-dicarboxylic acid (I-10) (11 mg, 95%) as a white solid. 1H-NMR (250 MHz, D2O) □1.59 (1H, t,J=3 Hz), 2.32 (1H, m), 2.60 (1H, m), 5.44 (1H, d, J=5.5 Hz), 6.37 (1H, dd,J=5.5, 2 Hz); MS[ISN] 182 [(M-H)- ]; mp>250° C.;
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH2:6][NH:7][CH2:8][CH2:9][NH2:10])=[N:2]1.[CH3:11][N:12]([CH3:18])[CH2:13][CH2:14][N:15]=[C:16]=[S:17]>>[CH3:11][N:12]([CH3:18])[CH2:13][CH2:14][NH:15][C:16]([NH:10][CH2:9][CH2:8][NH:7][CH2:6][C:3]1[CH:4]=[CH:5][NH:1][N:2]=1)=[S:17]
Reactant: CN(C)CCN=C=S
Reactant: NCCNCc1cc[nH]n1
Product: CN(C)CCNC(=S)NCCNCc1cc[nH]n1

Procedure:
Treating N-(3-pyrazolylmethyl)ethylenediamine with 2-dimethylaminoethyl isothiocyanate by the procedure of Example 40 gives the title compound.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:7]=[C:8]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>CC(C)=O.O>[O:18]1[CH2:19][CH2:20][N:15]([C:8]2[CH:9]=[CH:10][C:11]([N+:12]([O-:14])=[O:13])=[C:6]([CH:7]=2)[CH:2]=[O:1])[CH2:16][CH2:17]1
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)cc1C1OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=Cc1cc(N2CCOCC2)ccc1[N+](=O)[O-]

Procedure:
4-(3-(1,3-Dioxolan-2-yl)-4-nitrophenyl)morpholine (15.9 g, 56.7 mmol) was dissolved in a mixture of acetone and water (100 mL/100 mL). Then p-toluenesulfonic acid (2.0 g) was added and the mixture was heated to reflux for 4 hours. Ethyl acetate was added and the organic phase was washed with saturated sodium bicarbonate and brine, and then dried over anhydrous sodium sulfate, evaporated to afford the crude product 5-morpholino-2-nitrobenzaldehyde, which was used for the next step without purification.
Reaction SMILES: [N+](=[CH2:3])=[N-].[C:4]([NH:12][CH:13]1[C:25](=[O:26])[N:15]2[C:16]([C:22]([OH:24])=[O:23])=[C:17]([CH3:21])[CH2:18][S:19](=[O:20])[C@H:14]12)(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>ClCCl>[C:4]([NH:12][CH:13]1[C:25](=[O:26])[N:15]2[C:16]([C:22]([O:24][CH3:3])=[O:23])=[C:17]([CH3:21])[CH2:18][S:19](=[O:20])[C@H:14]12)(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC(=O)c3ccccc3)[C@H]2S(=O)C1
Reactant: C=[N+]=[N-]
Solvent: ClCCl
Product: COC(=O)C1=C(C)CS(=O)[C@@H]2C(NC(=O)c3ccccc3)C(=O)N12
Temperature: 0 °C
Yield: 86.6 %

Procedure:
An excess of an ethereal diazomethane solution was added to an ice-cooled suspension of 5 gm of 7-benzamido-3-methyl-3-cephem-4-carboxylic acid-1-oxide in 150 ml of dichloromethane and the mixture was stirred for half an hour. Then, excess diazomethane was destroyed with acetic acid and methanol was added. The mixture was evaporated to dryness in vacuo and the residue was crystallized from methanol to obtain 4.5 gm (86.6% yield) of methyl 7-benzamido-3-methyl-3-cephem-4-carboxylate-1-oxide.
Reaction SMILES: [I-].C[N+](C)(C)[CH2:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([OH:12])=[C:7]([O:13][CH3:14])[CH:6]=1.[P:17]([O:22]C)([O:20][CH3:21])[O:18][CH3:19]>C1(C)C(C)=CC=CC=1>[OH:12][C:8]1[C:9]([CH3:11])=[CH:10][C:5]([CH2:4][P:17](=[O:22])([O:20][CH3:21])[O:18][CH3:19])=[CH:6][C:7]=1[O:13][CH3:14]
Reactant: COc1cc(C[N+](C)(C)C)cc(C)c1O
Reactant: COP(OC)OC
Agent: [I-]
Solvent: Cc1ccccc1C
Product: COc1cc(CP(=O)(OC)OC)cc(C)c1O
Yield: 82 %

Procedure:
Trimethyl(4-hydroxy-3-methoxy-5-methylbenzyl)ammonium iodide (1 g, 3.0 mmol) was suspended in 8 ml xylene, trimethyl phosphite (0.52 ml, 4.4 mmol) was added dropwise and the resulting mixture was refluxed for 14 h. The solid formed was filtered and the solvent and excess of phosphite were evaporated under vacuum to yield dimethyl (4-hydroxy-3-methoxy-5-methylbenzyl)phosphonate as a viscous oil (0.64 g, 83%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][CH:12]([NH2:20])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[CH2:13]([CH:12]1[NH:20][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[CH2:9][CH2:10][CH2:11]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NC(CCCc1ccccc1CBr)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: c1ccc(CC2CCCc3ccccc3CN2)cc1
Temperature: 25 °C

Procedure:
To a solution of 30k (crude 1.58 mmol) in THF (10 mL) was added K2CO3 (436 mg, 3.16 mmol). The mixture was left to stir at rt until LC-MS analysis indicated the total consumption of the SM. Then the solid was removed by filtration and the solution was concentrated under reduced pressure to obtain the crude desired product. It was used without further purification in the next step.
Reaction SMILES: [B].[CH2:2]([O:9][CH:10]([CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[CH2:11][CH:12]=[CH2:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[BH4-].[Na+].[OH-:25].[Na+].OO>O1CCCC1.O>[CH2:2]([O:9][CH:10]([CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=1)[CH2:11][CH2:12][CH2:13][OH:25])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C=CCC(COc1ccc(F)cc1)OCc1ccccc1
Reactant: [OH-]
Agent: OO
Agent: [BH4-]
Agent: [B]
Solvent: O
Solvent: C1CCOC1
Product: OCCCC(COc1ccc(F)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A solution of boron trifluoroide.etherate (2.1 ml., 16.7 millimole) in dry tetrahydrofuran (15 ml.) is added dropwise to a stirred mixture of 4-benzyloxy-5-(4-fluorophenoxy)-1-pentene (2.86 g., 10 millimole) and sodium borohydride (0.47 g., 12.5 millimole) in dry tetrahydrofuran (25 ml.) maintained at 0°-5° C. under a nitrogen atmosphere. The resulting reaction mixture is warmed to 25° C. and maintained at 25° C. for 15 hours. After cooling to 0°-5° C., the reaction mixture is treated cautiously via successive dropwise additions of water (2 ml.), 5 N sodium hydroxide (4 ml.) and 30% hydrogen peroxide (8 ml.). After stirring at 25° C. for 1/2 hour, the resulting mixture is diluted with ice water and extracted with chloroform three times. The combined organic extract is washed with saturated aqueous brine, dried over magnesium sulfate, and filtered. Evaporation of the filtrate in vacuo provides the title compound as a viscous oil (3.0 g., 100%); pmr (CCl4) δ1.4-1.9 (4 H, m), 3.2-4.2 (6H, m), 4.58 (2H, broad s), 6.6-7.1 (4H, m) and 7.20 (5H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([Cl:11])[C:3]=1[S:12][C:13]1[S:14][C:15]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:16]=2[N:17]=1.O.O.[Sn](Cl)(Cl)(Cl)Cl.[OH-].[Na+]>CCOC(C)=O>[Cl:11][C:4]1[CH:5]=[C:6]([NH2:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[S:12][C:13]1[S:14][C:15]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:18][C:16]=2[N:17]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Sc2nc3cc(C(F)(F)F)ccc3s2)c(Cl)c1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1cc(Cl)c(Sc2nc3cc(C(F)(F)F)ccc3s2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 96.5 %

Procedure:
To a solution of 2-(2,6-dichloro-4-nitro-phenylsulfanyl)-5-trifluoromethyl-benzothiazole (258) (840 mg, 1.98 mmol) in EtOAc (20 mL) was added tin chloride dihydrate (Aldrich, 2.15 g, 9.52 mmol) and the resulting mixture was heated to reflux for 3 hours. After cooled to room temperature, to the mixture was added excess of 4N aqueous NaOH solution and the resulting mixture was stirred for 20 minutes. The mixture was filtered through Celite pad and washed with EtOAc. The organic layer was separated, washed twice with a brine solution, dried over Na2SO4, and concentrated under vacuum to give compound 270 (755 mg, 96%) product as a pale yellow solid, which was used in the next reaction without further purification.
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][N:2]1[C:12]1[CH:21]=[C:20]([CH2:22][CH2:23][C:24]([O:26]C)=[O:25])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1.[OH-].[Na+].Cl>CO>[CH2:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][N:2]1[C:12]1[CH:21]=[C:20]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1
Reactant: COC(=O)CCc1cc(N2CCCc3ccccc3C2)nc2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCc1cc(N2CCCc3ccccc3C2)nc2ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.6 %

Procedure:
To a solution of methyl 3-[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]propanoate (1.4 g, 3.89 mmol) in methanol (10 mL) was added an aqueous solution of sodium hydroxide (4 N, 16 mL) and the resulting mixture was stirred at room temperature for 4 hours. The reaction was acidified to pH 4 with 5 N hydrochloric acid, and then extracted with ethyl acetate (10 mL×3). The organic layer was dried over sodium sulfate and concentrated in vacuo to give a residue which was purified by flash column chromatography to afford 1.1 g of product as a white solid (yield was 82%). MS obsd. (ESI+) [(M+H)+] 347.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[C:13]1[N:14]=[C:15]([N:19]([CH:23]([CH2:33][CH2:34][CH3:35])[C:24]2[CH:29]=[CH:28][C:27]([C:30]([OH:32])=[O:31])=[CH:26][CH:25]=2)[CH2:20][CH2:21][CH3:22])[S:16][C:17]=1[CH3:18].[CH3:36]O>>[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[C:13]1[N:14]=[C:15]([N:19]([CH:23]([CH:33]2[CH2:35][CH2:34]2)[C:24]2[CH:25]=[CH:26][C:27]([C:30]([O:32][CH3:36])=[O:31])=[CH:28][CH:29]=2)[CH2:20][CH2:21][CH3:22])[S:16][C:17]=1[CH3:18]
Reactant: CCCC(c1ccc(C(=O)O)cc1)N(CCC)c1nc(-c2ccc(Cl)cc2Cl)c(C)s1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: CCCN(c1nc(-c2ccc(Cl)cc2Cl)c(C)s1)C(c1ccc(C(=O)OC)cc1)C1CC1
Temperature: 40 °C
Yield: 79 %

Procedure:
200 mg of thionyl chloride are added to 390 mg of the compound of Example 1 dissolved in 100 ml of anhydrous methanol and the solution is then maintained at 40° C. under argon for 16 hours. After evaporation under vacuum, the residue is purified on a column of silica, using a mixture of cyclohexane and ethyl acetate (10:1 v/v) as eluent. 4-(2,4-Dichlorophenyl)-5-methyl-2-{N-[α-cyclopropyl-4-(methoxycarbonyl)benzyl]-N-propylamino}thiazole is thus obtained.
Reaction SMILES: C(C1C=C(B(O)O)C=CC=1)#N.BrC1C=C(C=C(C)C=1)C(OC)=O.[C:24]([C:26]1[CH:27]=[C:28]([C:32]2[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([C:39]([O:41][CH3:42])=[O:40])[CH:33]=2)[CH:29]=[CH:30][CH:31]=1)#[N:25].C1C(=O)N(Br)C(=O)C1.[OH:51][C:52]1[CH:53]=[C:54]([CH:57]=[CH:58][CH:59]=1)[C:55]#[N:56]>>[C:24]([C:26]1[CH:27]=[C:28]([C:32]2[CH:37]=[C:36]([CH2:38][O:51][C:52]3[CH:59]=[CH:58][CH:57]=[C:54]([C:55]#[N:56])[CH:53]=3)[CH:35]=[C:34]([C:39]([O:41][CH3:42])=[O:40])[CH:33]=2)[CH:29]=[CH:30][CH:31]=1)#[N:25]
Reactant: COC(=O)c1cc(C)cc(-c2cccc(C#N)c2)c1
Reactant: N#Cc1cccc(O)c1
Agent: COC(=O)c1cc(C)cc(Br)c1
Agent: N#Cc1cccc(B(O)O)c1
Agent: O=C1CCC(=O)N1Br
Product: COC(=O)c1cc(COc2cccc(C#N)c2)cc(-c2cccc(C#N)c2)c1

Procedure:
Analogously to Example 1, by reaction of 3-cyanophenylboronic acid with methyl 3-bromo-5-methylbenzoate the compound methyl 3′-cyano-5-methylbiphenyl-3-carboxylate is obtained. By bromination with NBS and reaction with 3-hydroxybenzonitrile, methyl 3′-cyano-5-(3-cyanophenoxymethyl)biphenyl-3-carboxylate is obtained. Reaction with hydroxylamine and reduction using H2/Raney Ni affords the compound methyl 3′-carbamimidoyl-5-(3-carbamimidoylphenoxymethyl)biphenyl-3-carboxylate. By hydrolysis of the ester with aqueous NaOH, 3′-carbamimidoyl-5-(3-carbamimidoylphenoxymethyl)biphenyl-3-carboxylic acid
Reaction SMILES: [O:1]([C:8]1[CH2:13][CH2:12][CH:11]([C:14](=O)[CH:15]=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10](=O)[CH:9]=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)=O.CCO>[O:1]([C:8]1[CH2:13][CH2:12][C:11]2[C:14]([CH:15]=[CH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:26][NH:27][C:10]=2[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(C=Cc1ccccc1)C1CCC(Oc2ccccc2)=CC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: C(=Cc1n[nH]c2c1CCC(Oc1ccccc1)=C2)c1ccccc1
Temperature: 70 °C
Yield: 36.4 %

Procedure:
To a stirred solution of 3-phenoxy-6-(3-phenyl-acryloyl)-cyclohex-2-enone (1.13 g, 3.55 mmol) in 20 mL of HOAc/EtOH (1:1) was added hydrazine monohydrate (0.21 mL, 4.3 mmol). The reaction was heated at 70° C. for 3 h, cooled and poured cautiously into saturated NaHCO3 solution and extracted with EtOAc (2×). The combined organic layers were washed with saturated NaCl solution, dried (MgSO4) and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting hexanes/EtOAc (2:1) to give 6-phenoxy-3-styryl-4,5-dihydro-1H-indazole (3) as an off-white solid (406 mg, 36%): 1H NMR (DMSO-d6) δ 2.64 (t, 2H, J=8.0 Hz), 2.95 (t, 2H, J=8.0 Hz), 5.46 (s,1H), 7.04 (AB, 2H, J=16.8 Hz), 7.15 (d, 2H, J=8.1 Hz), 7.25 (m, 2H), 7.42 (m, 4H), 7.55 (d, 2H, J=7.7 Hz), 12.44 (s, 1H). Anal. Calc. for C2H18N2O.0.2H2O: C, 79.32; H, 5.83, N, 8.81. Found: C, 79.36; H, 5.85; N, 8.84.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N+:15]([O-:17])=[O:16])[C:8]([O:13][CH3:14])=[C:9]([CH:12]=1)[CH:10]=[O:11])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].[Cl-].[NH4+]>CO>[C:1]([C:5]1[CH:6]=[C:7]([N+:15]([O-:17])=[O:16])[C:8]([O:13][CH3:14])=[C:9]([CH2:10][OH:11])[CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(C=O)cc(C(C)(C)C)cc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: COc1c(CO)cc(C(C)(C)C)cc1[N+](=O)[O-]
Reaction time: 0.25 h
Yield: 96.7 %

Procedure:
A solution of 5-tert-butyl-2-methoxy-3-nitrobenzaldehyde (0.500 g, 2.10 mmol) in methanol (10.5 mL) was cooled to 0° C., and sodium borohydride (0.088 g, 2.31 mmol) was added thereto, followed by stirring the mixture for 15 minutes. Saturated aqueous ammonium chloride solution was added to the reaction solution and the mixture was stirred at room temperature for 10 minutes. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, hexane/ethyl acetate=10/90-50/50) to obtain 0.486 g of captioned compound (96% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[I:9])N.C(ON=O)CC(C)C.[CH2:18]([S:20]SCC)[CH3:19]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:20][CH2:18][CH3:19])[CH:6]=[CH:7][C:8]=1[I:9]
Reactant: Nc1ccc(I)c(Cl)c1
Reactant: CCSSCC
Agent: CC(C)CCON=O
Solvent: CC#N
Product: CCSc1ccc(I)c(Cl)c1

Procedure:
A solution of 3-chloro-4-iodo-aniline (5.6 g), isoamylnitrite (8.8 ml) and ethyldisulphide (13.4 ml) in acetonitrile (100 ml) was heated at 60° C. for 24 h. The solvent was removed under reduced pressure and the residue purified by chromatography on silica eluting with 1% ethylacetate/isohexane. Yield 4.02 g
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH:15]3[CH2:16][CH2:17][CH:11]2[CH2:12][N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]3)=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH:11]3[CH2:17][CH2:16][CH:15]2[CH2:14][N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:12]3)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CC2CCC(C1)N2c1ccc([N+](=O)[O-])nc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC2CCC(C1)N2c1ccc(N)nc1
Yield: 99.9 %

Procedure:
To a solution of tert-butyl 8-(6-nitropyridin-3-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (330 mg, 987 umol) in 10 ml of Methanol was added 10% Palladium in carbon (10 mg. The reaction mixture was hydrogenated 2 hr under 50 psi hydrogen. The reaction mixture was filtered through pack of celite and concentrated to afford 300 mg (100%) of tert-butyl 8-(6-aminopyridin-3-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate as colorless oil. This product was used in subsequent steps without further purification.
Reaction SMILES: [C:1]1([C:7]([CH2:9][CH3:10])=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[H][H].Cl>[Cl-].[Cl-].[Ti+2].C1(C)C=CC=CC=1>[C:1]1([CH:7]([CH2:9][CH3:10])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=C(CC)c1ccccc1
Reactant: [H][H]
Agent: [Ti+2]
Agent: Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CCC(C)c1ccccc1
Reaction time: 40 h
Yield: 42 %

Procedure:
(1R,7S)-1,3,10,10-Tetramethyltricyclo-[5.2.1 .02,6 ]-deca-2,5-dienyl)(η5 -cyclopentadienyl)titanium dichloride (21 mg, 0.05 mmol, prepared as in Example 6) together with 2-phenyl-1-butene (132 mg, 1 mmol) and freshly distilled toluene (5 ml) were placed into a 50 ml round-bottomed flask. After degassing with three freeze/thaw cycles the vessel was filled with hydrogen (3 evacuate/refill cycles). n-Butyllithium (0.2 ml, 22.5 M, 0.5 mmol) was then added via syringe at room temperature and the resulting dark grey/green reaction mixture was stirred under a pressure of 20 p.s.i. hydrogen, while excluding light, for 40 hours. The hydrogen pressure was vented and the reaction vessel opened to air. Aqueous hydrochloric acid (2 ml, 5 M) was added and mixture was stirred for 5 minutes. The organic phase was separated and the aqueous phase extracted with ether (3×5 ml). The combined organic phases were dried (sodium sulphate) and the solvents removed iii vacuo to provide 2-phenylbutane (56 mg, 0.42 mmol) of 10.3% ee (assessed using gas chromatography, Astec α-DA column, 65° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[C:21](Cl)[C:20]=1[Cl:29].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[C:21]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH3:17])[C:20]=1[Cl:29]
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(N)cc12
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCCC1Cc1c[nH]c2ccc(Nc3c([N+](=O)[O-])ccc(Cl)c3Cl)cc12
Temperature: 125 °C
Yield: 60 %

Procedure:
(R)-5-Amino-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole and 1,2,3-trichloronitrobenzene were used. Sodium carbonate was used as base, N,N-dimethylformamide was used as solvent, and the reaction was heated at 125° C. for 3 hours. Column chromatography afforded the title compound (60%) as a red solid: Rf =0.4 in 9:1:0.1 [methylene chloride/methanol/ammonium hydroxide]; 1H NMR (CDCl3) δ 8.59 (br s, NH), 8.36 (br s, NH), 7.96 (d, J=9.1 Hz, 1H), 7.23 (d, J=8.6 Hz, 1H), 7.09 (s, 1H), 7.07 (d, J=9.1 Hz, 1H), 6.99 (d, J=1.9 Hz, 1H), 6.81 (dd, J=8.6 and 2.1 Hz, 1H), 3.15-3.05 (m, 2H), 2.54 (dd, J=13.8 and 9.6 Hz, 1H), 2.46-2.33 (m, 1H), 2.40 (s, 3H), 2.22 (dd, J=17.4 and 9.3 Hz, 1H), 1.84-1.48 (m, 4H); FAB HRMS calculated for [C20H20Cl2N4O2.H] 419.1044, found 419.1046.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[CH3:12][N:13]1[C:17]([CH3:18])=[C:16](B2OC(C)(C)C(C)(C)O2)[C:15]([CH3:28])=[N:14]1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O>[CH3:12][N:13]1[C:17]([CH3:18])=[C:16]([C:2]2[CH:10]=[C:9]3[C:5]([CH2:6][CH2:7][C:8]3=[O:11])=[CH:4][CH:3]=2)[C:15]([CH3:28])=[N:14]1
Reactant: Cc1nn(C)c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: O=C1CCc2ccc(Br)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1nn(C)c(C)c1-c1ccc2c(c1)C(=O)CC2
Temperature: 100 °C
Reaction time: 3 h

Procedure:
6-Bromo-indan-1-one (0.94 mmol) was dissolved in DME/H2O 1/1 (10 mL) under argon atmosphere. 1,3,5-Trimethyl-1H-pyrazole-4-boronic acid pinacol ester (1.42 mmol), K2CO3 (2.82 mmol), and tetrakis-(triphenylphosphine)palladium (5 mol %, 0.047 mmol) were added and the reaction mixture was stirred at 100° C. for 3 h. The reaction mixture was evaporated to dryness, then dissolved in CHCl3 and filtered through Celite® to give the crude product 6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-indan-1-one. The crude was purified by flash column chromatography (AcOEt-Cyclohexane as eluents) by using a CombiFlash Companion™ system to yield the title compound (84%). MS [MH]+=240
Reaction SMILES: C([O:3][C:4](=[O:30])[C:5]([CH3:29])([CH3:28])[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:27])[CH2:19][CH2:20][CH2:21][N:22]2[CH:26]=[CH:25][N:24]=[CH:23]2)=[CH:13][CH:12]=1)C.[OH-].[Na+]>CO>[N:22]1([CH2:21][CH2:20][CH2:19][C:18]([NH:17][C:14]2[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]([CH3:28])([CH3:29])[C:4]([OH:30])=[O:3])=[CH:12][CH:13]=2)=[O:27])[CH:26]=[CH:25][N:24]=[CH:23]1
Reactant: CCOC(=O)C(C)(C)CCCCOc1ccc(NC(=O)CCCn2ccnc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(CCCCOc1ccc(NC(=O)CCCn2ccnc2)cc1)C(=O)O

Procedure:
1.0 g of Ethyl-6-[p-[4-(1-imidazolyl)-butyramido]-phenoxy]-2,2-dimethylhexanoate obtained from EXAMPLE 35 was stirred in 10 ml of methanol and 10 ml of 1N-aqueous sodium hydroxide solution at 40° C. for 16 hours. Ethanol was removed from the reaction mixture. The resulting mixture was washed with chloroform and then neutralized with 10 ml of 1N-aqueous hydrochloric acid solution. The precipitated crystals were collected by filtration, and recrystallized from 2-propanol to give 6-[p-[4-(1-imidazolyl)butyramido]phenoxy]-2,2-dimethyl hexanoic acid, as white crystals.