Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:21])([C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[CH2:3][CH2:4][S:5]([CH2:8][C:9]#[N:10])(=[O:7])=[O:6].N1CCCC1C(O)=O.C1O[C:33]2([CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]2)[O:32]C1>C1(C)C=CC=CC=1>[O:32]=[C:33]1[CH2:38][CH2:37][CH:36]([CH:8]([S:5]([CH2:4][CH2:3][C:2]([F:1])([F:21])[C:11]([F:19])([F:20])[C:12]([F:17])([F:18])[C:13]([F:14])([F:15])[F:16])(=[O:7])=[O:6])[C:9]#[N:10])[CH2:35][CH2:34]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: N#CCS(=O)(=O)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: O=C(O)C1CCCN1
Solvent: Cc1ccccc1
Product: N#CC(C1CCC(=O)CC1)S(=O)(=O)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.7 %

Procedure:
A mixture of 5.40 g of (3,3,4,4,5,5,6,6,6-nonafluorohexylsulfonyl)acetonitrile, 60 ml of toluene, 0.18 g of DL-proline and 2.77 g of 1,4-cyclohexanedione monoethylene ketal was heated and stirred for 3 hours under the reflux condition. After 40 ml of toluene was distilled off, the reaction mixture was cooled to room temperature. The mixture was cooled to 0° C. and then 0.61 g of sodium borohydride was added thereto. To the reaction mixture was added 3 ml of N,N-dimethylformamide. The mixture was stirred at room temperature for 6 hours and then cooled to 0° C. Thereto 50 ml of water and 50 ml of ethyl acetate were added. While the reaction mixture was stirred, 20 ml of an aqueous 1N hydrochloric acid solution was added dropwise, followed by extraction with 100 ml of ethyl acetate twice. An organic layer was washed with 100 ml of an aqueous saturated sodium hydrogen carbonate solution, 100 ml of an aqueous saturated sodium chloride solution and 100 ml of water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolve to 14 ml of acetic acid and 6 ml of water. The mixture was heated to 100° C. and stirred for 8 hours. After the reaction mixture was cooled to room temperature, 100 ml of ethyl acetate was added thereto. The mixture was added slowly into 100 ml of an aqueous saturated sodium hydrogen carbonate solution. The solution was stirred for 1 hour, followed by extraction with 100 ml of ethyl acetate twice. Organic layers were combined, washed with 100 ml of an aqueous saturated sodium hydrogen carbonate solution and 100 ml of an aqueous saturated sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 2.94 g of 2-(4-oxocyclohexyl)-2-(3,3,4,4,5,5,6,6,6-nonafluorohexylsulfonyl)acetonitrile (hereinafter, referred to as the present compound (62)) represented by the formula:
Reaction SMILES: [Br-:1].[Br:2][C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[CH2:5][CH2:6][SH+:7][CH2:8][C:9]1([OH:27])[CH2:14][CH2:13][CH:12](O)[CH:11]([O:16][CH3:17])[CH:10]1[C:18]1([CH3:26])[O:25][CH:19]1[CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23].[Cl:32][CH2:33][C:34]([N:36]=[C:37]=[O:38])=[O:35].[OH2:39]>ClCCl>[Br-:2].[Br:1][C:30]1[CH:29]=[CH:28][C:4]([CH2:5][CH2:6][SH+:7][CH2:8][C:9]2([OH:27])[CH2:14][CH2:13][CH:12]([O:39][C:37](=[O:38])[NH:36][C:34](=[O:35])[CH2:33][Cl:32])[CH:11]([O:16][CH3:17])[CH:10]2[C:18]2([CH3:26])[O:25][CH:19]2[CH2:20][CH:21]=[C:22]([CH3:23])[CH3:24])=[CH:3][CH:31]=1
Reactant: COC1C(O)CCC(O)(C[SH+]CCc2ccccc2Br)C1C1(C)OC1CC=C(C)C
Reactant: O
Reactant: O=C=NC(=O)CCl
Agent: [Br-]
Solvent: ClCCl
Product: COC1C(OC(=O)NC(=O)CCl)CCC(O)(C[SH+]CCc2ccc(Br)cc2)C1C1(C)OC1CC=C(C)C
Yield: 44 %

Procedure:
To a solution of 1-(2-bromobenzyl)methylsulfoniomethyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy- 1,4-cyclohexanediol bromide (150 mg) in dichloromethane (2 ml) was added dropwise, under ice-cooling, chloroacetylisocyanate (40 ml), then the mixture was stirred for 30 minutes. To the reaction mixture was added water to suspend the reaction. The product was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous saline solution, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography (carrier 10 g, developing solvent : chloroform-methanol=20:1) to give 1-(4-bromobenzyl)methylsulfoniomethyl-4-(N-chloroacetylcarbamoyloxy)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxycyclohexanol bromide (80 mg: yield 44%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[C:7]([N+:11]#[C-:12])([CH3:10])([CH3:9])[CH3:8].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH:18]=O>Cl(O)(=O)(=O)=O>[C:7]([NH:11][C:12]1[N:6]2[C:2]([S:3][CH:4]=[CH:5]2)=[N:1][C:18]=1[C:17]1[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:15]([O:14][CH3:13])[CH:16]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: COc1ccc(C=O)cc1OC
Reactant: [C-]#[N+]C(C)(C)C
Reactant: Nc1nccs1
Agent: [O-][Cl+3]([O-])([O-])O
Product: COc1ccc(-c2nc3sccn3c2NC(C)(C)C)cc1OC

Procedure:
Compound 26 was prepared in accordance with the general synthesis instructions from 1.0 ml (0.1 mmol) 2-amino thiazole solution (0.1 M, MC), 0.575 ml (0.115 mmol) tert-butylisonitrile solution (0.2 M, MC), 0.500 ml (0.15 mmol) 3,4-dimethoxybenzaldehyde solution (0.3 M, MC) and 10 μl perchloric acid (w=20%) in a substance library.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[OH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[C:7]=1[C:8]([O-:10])=[O:9].[C:16](O)(=O)C>>[OH:5][C:6]1[C:14]([N+:1]([O-:4])=[O:2])=[CH:13][CH:12]=[C:11]([OH:15])[C:7]=1[C:8]([O:10][CH3:16])=[O:9]
Reactant: CC(=O)O
Reactant: O=C([O-])c1c(O)cccc1O
Reactant: O=[N+]([O-])O
Product: COC(=O)c1c(O)ccc([N+](=O)[O-])c1O
Reaction time: 2 h

Procedure:
1M HNO3 in acetic acid (10 mL, 10.0 mmol) was added dropwise to a solution of 2,6-dihydroxybenzoate (1.68 g, 10.0 mmol) in acetic acid (10 mL) at ambient temperature. The reaction mixture was stirred for 2 hours. The precipitant was filtered and washed with water and acetone, dried to provide the titled compound (1.08 g). MS (ESI(−)) m/e 212 (M−H)+; 1H NMR (300 MHz, DMSO-d6) δ 11.71(bs, 1H), 10.93 (bs, 1H), 8.04 (d, J=9.5 Hz, 1H), 6.60(d, J=9.5 Hz, 1H).
Reaction SMILES: N1(C(C)C[NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[O:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)=[CH:12][C:11]=2[N+:25]([O-])=O)CCOCC1.[H][H].[O:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>[C].[Pd]>[N:9]1([CH2:10][CH2:11][CH2:12][NH:25][C:11]2[CH:12]=[C:13]([C:16]3[O:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)[CH:14]=[CH:15][C:10]=2[NH2:9])[CH2:34][CH2:35][O:31][CH2:32][CH2:33]1
Reactant: C1CCOC1
Reactant: CC(CNc1ccc(-c2nc3ccccc3o2)cc1[N+](=O)[O-])N1CCOCC1
Reactant: [H][H]
Agent: [Pd]
Product: Nc1ccc(-c2nc3ccccc3o2)cc1NCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 99 %

Procedure:
To a solution of 2-(N-(2-(morpholin-4-yl)-n-propyl)-2-nitroanilin-4-yl)benzoxazole (see Working Example 96-1) (665 mg, 1.74 mmol) in tetrahydrofuran (10 mL) was added 10% palladium-carbon (70 mg). A hydrogen atmosphere was then substituted in the flask, and this was stirred at room temperature for 17 hours. After the reaction was finished, this was filtered through Celite, and the filtrate was concentrated to yield the title compound (605 mg, 99% yield).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:5]=1[CH3:12]>C(Cl)(Cl)(Cl)Cl.[W]>[Cl:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:5]=1[CH2:12][Br:1]
Reactant: BrBr
Reactant: Cc1c(F)ccc(F)c1Cl
Agent: [W]
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(F)c(CBr)c1Cl
Temperature: 0 °C
Yield: 81.9 %

Procedure:
A solution of bromine (24.4 g) in carbon tetrachloride (50 ml) was added slowly over a period of 2 hours 45 minutes to a vigorously stirred solution of 2-chloro-3,6-difluorotoluene (24.4 g) in carbon tetrachloride (150 ml) irradicated by a 200 watt tungsten lamp maintained at 0° C. The solvent was removed by evaporation under reduced pressure and the residual oil distilled to yield 2-chloro-3,6-difluorobenzyl bromide (29.7 g) b.p 96°-101°/0.7 cm Hg.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:23]=[O:24])[C:8]([OH:22])=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18](F)(F)F)=[CH:13][CH:12]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:26]1[C:27](O)=[C:28](C=[C:32](C(C)(C)C)[CH:33]=1)C=O.O(C1C=CC(B(O)O)=CC=1)C1C=CC=CC=1>>[C:1]([C:5]1[CH:6]=[C:7]([CH:23]=[O:24])[C:8]([OH:22])=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:28]=[CH:27][CH:26]=[CH:33][CH:32]=3)=[CH:13][CH:12]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(Br)c(O)c(C=O)c1
Reactant: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(OC(F)(F)F)cc2)c1
Agent: OB(O)c1ccc(Oc2ccccc2)cc1
Product: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(Oc3ccccc3)cc2)c1

Procedure:
5-(tert-Butyl)-2-hydroxy-4′-phenoxy-[1,1′-biphenyl]-3-carbaldehyde was prepared as an orange oil using the procedure described in Intermediate 5 from 3-bromo-5-(tert-butyl)-2-hydroxybenzaldehyde (Intermediate 4) and 4-phenoxyphenylboronic acid.
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1)=[O:3].[C:15]([N:19]=[N:20][C:21]([C:27]#[N:28])([CH2:23][CH2:24][CH2:25][OH:26])[CH3:22])([CH3:18])([CH3:17])[CH3:16].N1C=CC=CC=1>CCOCC>[C:15]([N:19]=[N:20][C:21]([C:27]#[N:28])([CH3:22])[CH2:23][CH2:24][CH2:25][O:26][C:2]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1)=[O:3])([CH3:18])([CH3:16])[CH3:17]
Reactant: O=C(Cl)c1ccc2c(c1)C(=O)OC2=O
Reactant: CC(C)(C)N=NC(C)(C#N)CCCO
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(C)(C)N=NC(C)(C#N)CCCOC(=O)c1ccc2c(c1)C(=O)OC2=O
Reaction time: 0.25 h

Procedure:
To a solution of 2.1 g. (0.01 m) of 4-chloroformylphthalic anhydride in 25 ml ether in a 50 ml 4-neck round bottom flask equipped with a condenser containing a CaCl2 drying tube, a thermometer, a magnetic stirring bar and a dropping funnel was added a solution of 2.0 g. (0.01 m) 2-t-butylazo-2-cyano-5-hydroxypentane (from XIV) and 0.8 g. (0.01 m) pyridine in 10 ml ether. This solution was added dropwise with stirring over 15 minutes holding the temperature between 15° and 22° C with a water bath. The reaction was stirred an additional hour after the addition was completed and the pyridine hydrochloride filtered off. The ether filtrate was dried over anhydrous Na2SO4, filtered and evaporated to dryness leaving 3.1 g. (84%) of a viscous liquid. The infrared spectrum contained 3 carbonyl bands and no OH bands.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([O:22][CH3:23])=[N:17][N:16]=[C:15]3I)=[O:11])[CH:6]=[CH:7][CH:8]=1.C([O-])([O-])=O.[K+].[K+].O.[C:34]1(B(O)O)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=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.CO.C1(C)C=CC=CC=1>[F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([O:22][CH3:23])=[N:17][N:16]=[C:15]3[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1nnc(I)c2cc(C(=O)Nc3cccc(C(F)(F)F)c3)ccc12
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1nnc(-c2ccccc2)c2cc(C(=O)Nc3cccc(C(F)(F)F)c3)ccc12
Temperature: 65 °C
Yield: 80.8 %

Procedure:
A mixture of 4-iodo-1-methoxy-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide (0.123 g, 0.26 mmol), K2CO3 (0.072 g, 0.52 mmol), water (0.5 mL), toluene (3 mL), methanol (3 mL), phenylboronic acid (0.035 g, 0.286 mmol), Pd(PPh3)4 (0.09 g, 0.078 mmol) was heated to 65° C. for 1 hour. The reaction was cooled, filtered through celite, rinsed with methanol and concentrated. The residue was taken up in EtOAc, washed with sat. aq. NaHCO3 and dried (Na2SO4). Chromatography (Hex/EtOAc) afforded 1-methoxy-4-phenyl-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide (89 mg), m/z 424.05.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].C(N(CC)CC)C.Br[CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]2[O:23][CH2:22][C:21](=[O:24])[NH:20][C:19]=2[CH:25]=1>CN(C)C=O>[CH2:1]([NH:4][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]2[O:23][CH2:22][C:21](=[O:24])[NH:20][C:19]=2[CH:25]=1)[CH2:2][CH3:3]
Reactant: O=C1COc2ccc(CCBr)cc2N1
Reactant: CCCN
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCNCCc1ccc2c(c1)NC(=O)CO2

Procedure:
In a round-bottomed flask equipped with a mechanical stirrer and a calcium chloride guard tube, 0.01 mol of n-propylamine and 0.015 mol of triethylamine are added to a solution of 6-(2-bromoethyl)-3-oxo-2,3-dihydro-1,4-benzoxazine in 40 cm3 of dimethylformamide. The mixture is heated to reflux for 15 hours and the precipitate formed is drained in the heated state. The residue is evaporated under vacuum and the product is recrystallized.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2C(O)=O)=[CH:5][CH:4]=1.C(N(CC)CC)C.CN([C:28]([O:32]N1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH:47]1[CH2:52][CH:51]=[C:50]([C:53]2[CH:54]=[C:55]([CH:58]=[CH:59][CH:60]=2)[C:56]#[N:57])[CH2:49][CH2:48]1>CN(C=O)C>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:14][C:15]([C:28]([N:47]3[CH2:48][CH:49]=[C:50]([C:53]4[CH:54]=[C:55]([CH:58]=[CH:59][CH:60]=4)[C:56]#[N:57])[CH2:51][CH2:52]3)=[O:32])=[CH:16][CH:17]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccccc2C(=O)O)cn1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: N#Cc1cccc(C2=CCNCC2)c1
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc(C(=O)N3CC=C(c4cccc(C#N)c4)CC3)cc2)cn1
Temperature: 35 °C
Reaction time: 1.5 h

Procedure:
6-Methoxypyridin-3-ylbenzoic acid (0.7 g, 2.6 mmol) is treated with triethyl amine (0.7 ml, 5 mmol) and TBTU (0.95 g, 3.0 mmol) in DMF (5 ml). 3-(1,2,3,6-Tetrahydropyridin-4-yl)benzonitrile (0.9 g), prepared as above, is added to this suspension and the reaction mixture is heated to 35° C. with stirring for 1.5 h. Solvent is removed, the residue is dissolved in ethyl acetate, and the solution is washed with 1N HCl (2×5 ml). The precipitated solid, 3-{1-[4-(6-methoxypyridin-3-yl)-benzoyl]-1,2,3,6-tetrahydropyridin-4 yl}benzonitrile, is collected (0.60 g); a second crop (0.15 g) is obtained by saturating the organic layer with HCl. 1H NMR (DMSO) δ 8.53 (s, 1H), 8.10 (d, 1H), 7.90 (s, 1H), 7.75 (m, 4H), 4.30 (m, 3H), 6.95 (d, 1H), 6.3 (br, 1H), 4.2 (br, 2H), 3.87 (s, 3H), 3.5 (br, 2H), 2.6 (br, 2H). Ion spray MS M++1: 396.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=O)[CH:2]=1.CN.CO.CC(O)=O.[BH3-][C:22]#[N:23].[Na+]>CO>[CH3:22][NH:23][CH2:11][C:3]1[CH:2]=[N:1][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: O=Cc1cnc2ccccc2c1
Reactant: [BH3-]C#N
Agent: CN
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNCc1cnc2ccccc2c1
Yield: 48.2 %

Procedure:
A solution of 3-quinolinecarboxaldehyde (1.5 g, 10 mmole), 2.0 M CH3NH2/MeOH (10 mL, 20 mmole), glacial AcOH (0.6 mL, 10 mmole), and NaBH3CN (0.35 g, 11 mmole) in MeOH (20 mL) was stirred at RT overnight, then was concentrated in vacuo. The residue was diluted with 5% NaOH and extracted with CH2Cl2. The combined organic extracts were washed with brine, dried over MgSO4, and concentrated. Flash chromatography on silica gel (10% MeOH/CH2Cl2) gave the tide compound (0.83 g, 24%) as a slightly yellow viscous oil: MS (ES) m/e 173 (M+H)+.
Reaction SMILES: C([NH:8][CH:9]1[CH2:18][CH2:17][C:12]2([O:16][CH2:15][CH2:14][O:13]2)[CH2:11][CH2:10]1)C1C=CC=CC=1.C(Cl)Cl>CO.[OH-].[Pd+2].[OH-]>[O:13]1[C:12]2([CH2:17][CH2:18][CH:9]([NH2:8])[CH2:10][CH2:11]2)[O:16][CH2:15][CH2:14]1
Reactant: c1ccc(CNC2CCC3(CC2)OCCO3)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: NC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 24 h
Yield: 109.5 %

Procedure:
A mixture of N-benzyl-1,4-dioxaspiro[4.5]decan-8-amine (3 g, 12.2 mmol) and Palladium hydroxide (0.9 g) in MeOH (120 mL) was hydrogenated under 50 psi of H2 at room temperature. The mixture was stirred at room temperature for 24 h. TLC (CH2Cl2:MeOH=10:1) showed the reaction was complete. The mixture was filtered and the filtrated was concentrated in vacuo to give 1,4-dioxaspiro[4.5]decan-8-amine (2.1 g, 110%) as a brown oil.
Reaction SMILES: [C:1]1([CH2:7][S:8]([Cl:11])(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:12]1[C:20]2[CH:19]=[CH:18][N:17]=[C:16]([N:21]3[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]3)[C:15]=2[CH:14]=[CH:13]1>>[ClH:11].[C:1]1([CH2:7][S:8]([N:12]2[C:20]3[CH:19]=[CH:18][N:17]=[C:16]([N:21]4[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]4)[C:15]=3[CH:14]=[CH:13]2)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccc3[nH]ccc23)CC1
Product: Cl
Product: O=S(=O)(Cc1ccccc1)n1ccc2c(N3CCNCC3)nccc21

Procedure:
Phenyl-methanesulfonyl chloride (24.6 mg) was added to tert-butyl 4-(1H-pyrrolo[3,2-c]pyridin-4-yl)piperazine-1-carboxylate the title compound (0.2 mg). LC/MS RT: 1.007 (System 10 till 40% MeCN over 1.5 min, ACE C8), Purity. 90%. MS: 357 (M+1).
Reaction SMILES: C([O:8][C:9](=[O:31])[CH2:10][C@H:11]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:12][N:13]1[C:18](=[O:19])[CH2:17][CH2:16][C:15]([F:21])([F:20])[C:14]1=[O:22])C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:27]([O:26][C:24]([NH:23][C@H:11]([CH2:12][N:13]1[C:18](=[O:19])[CH2:17][CH2:16][C:15]([F:20])([F:21])[C:14]1=[O:22])[CH2:10][C:9]([OH:31])=[O:8])=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)CN1C(=O)CCC(F)(F)C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)CN1C(=O)CCC(F)(F)C1=O
Yield: 106 %

Procedure:
(S)-3-t-butoxycarbonylamino-4-(3,3-difluoro-2,6-dioxo-piperidin-1-yl)-butyric acid benzyl ester (310 mg, 0.70 mmol) synthesized in Section (2) was dissolved in methanol and 10% Pd/C (31 mg, 0.1 eq) was added thereto. The mixture was stirred for 1 hour under 1 atm hydrogen gas. After the reaction was complete, a solid material was removed by celite filtration to afford 260 mg of the crude title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:25](=[O:35])[NH:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([OH:34])[CH:29]=2)=[CH:20][C:21]=1[CH:22]([CH3:24])[CH3:23])=[O:16])[CH2:5][NH:6]C(OC(C)(C)C)=O.[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]>C(Cl)Cl>[F:40][C:39]([F:42])([F:41])[C:37]([OH:43])=[O:38].[CH3:1][O:2][C:3](=[O:36])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:25](=[O:35])[NH:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([OH:34])[CH:29]=2)=[CH:20][C:21]=1[CH:22]([CH3:24])[CH3:23])=[O:16])[CH2:5][NH2:6]
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H](CN)NC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-3-tert-Butoxycarbonylamino-2-{[5-(3-hydroxy-benzylcarbamoyl)-3-isopropyl-thiophene-2-carbonyl]-amino}-propionic acid methyl ester (0.085 g, 0.16 mmol) in DCM (5 mL) was added TFA (1.0 mL). The mixture was stirred at room temperature 1 h and evaporated. Isolate 0.067 g of crude product which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[CH:4]=[N:5][OH:6].Cl[O-].[Na+].[CH3:15][C:16]1[S:17][C:18]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C@@H:27]([OH:38])[CH2:28][N:29]3[CH2:34][CH2:33][N:32]([CH:35](C)[CH3:36])[CH2:31][CH2:30]3)=[CH:21][C:19]=2[N:20]=1.[CH2:39](N(CC)CC)C>ClCCl.CO>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]1[CH:39]=[C:36]([CH2:35][N:32]2[CH2:31][CH2:30][N:29]([CH2:28][C@H:27]([OH:38])[CH2:26][O:25][C:22]3[CH:23]=[CH:24][C:18]4[S:17][C:16]([CH3:15])=[N:20][C:19]=4[CH:21]=3)[CH2:34][CH2:33]2)[O:6][N:5]=1
Reactant: CCN(CC)CC
Reactant: ON=Cc1cccc(Cl)c1Cl
Reactant: Cc1nc2cc(OC[C@@H](O)CN3CCN(C(C)C)CC3)ccc2s1
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Solvent: CO
Product: Cc1nc2cc(OC[C@@H](O)CN3CCN(Cc4cc(-c5cccc(Cl)c5Cl)no4)CC3)ccc2s1
Reaction time: 0.07 h

Procedure:
To a solution of 2,3 dichlorobenzaldehyde oxime (136 mg, 0.725 mmol) in 1 ml of dichloromethane was added aqueous sodium hypochlorite solution (>4%, 1.35 ml, 0.725 mmol). The reaction was sealed in a reaction vessel with a stirbar. The vessel was subjected to microwave under the following conditions: temperature=60° C., time=240(s), high absorbance, fixed hold time=on, pre-stir=10(s). After 4 minutes (2S)-1-(2-methylbenzothiazol-5-yloxy)-3-(4-prop-2-ylpiperazinyl)propan-2-ol (50 mg, 0.145 mmol) in 1 ml of dichloromethane was added, followed by triethylamine (0.022 ml, 0.145 mmol). The reaction vessel was again subjected to microwave under the following conditions: temperature=110° C., time=240(s), high absorbance, fixed hold time=on, pre-stir=10(s). After 4 minutes, thin layer chromatography (10:1 dichloromethane:methanol) showed consumption of starting material and product formation. The solution was evaporated under reduced pressure and purified by preparative thin layer chromatography (10:1 dichloromethane:methanol) followed by HPLC to yield (2S)-3-(4-{[3-(2,3-dichlorophenyl)isoxazol-5-yl]methyl}piperazinyl)-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol (20). (M+1=533.21)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)(=O)=O)[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[N:3]=1.[CH2:26]([OH:28])[CH3:27].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:28][CH2:26][CH3:27])[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[N:3]=1
Reactant: CCO
Reactant: COc1cc(-c2nc(N)nc(S(C)(=O)=O)c2C#N)cc(OC)c1OC
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: CCOc1nc(N)nc(-c2cc(OC)c(OC)c(OC)c2)c1C#N

Procedure:
From 2-amino-4-methanesulfonyl-6-(3,4,5-trimethoxy-phenyl)-pyrimidine-5-carbonitrile, ethanol and DBU in DME. ES-MS m/e (%): 331 (M+H+, 100).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:22][CH2:23][OH:24])[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=[O:5])[CH3:2].C(N(CC)CC)C.[S:32](Cl)([OH:35])(=O)=[O:33].[CH4:37]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:22][CH2:23][O:24][S:32]([CH3:37])(=[O:35])=[O:33])[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1CCO
Reactant: O=S(=O)(O)Cl
Reactant: C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1CCOS(C)(=O)=O
Reaction time: 0.5 h

Procedure:
A solution of 3.4 g. of 5-chloro-2-(2-hydroxyethyl)-3-phenylisoindole-1-carboxylic acid ethyl ester and 3.4 ml. of triethylamine in 60 ml. of methylene chloride is treated dropwise at 15°-20° C. with 1.6 ml. of methane sulfochloride. The mixture is subsequently left standing for 30 minutes at room temperature, then diluted with methylene chloride to three times the volume. The solution is washed successively with water, 0.5-N hydrochloric acid, 5% sodium bicarbonate solution and again with water. After drying over sodium sulfate and evaporation of the solution, there is obtained 5-chloro-2-{2-[(methylsulfonyl)oxy]ethyl}-3-phenylisoindole-1-carboxylic acid ethyl ester; melting point 125°-127° C. Recrystallization from methylene chloride/hexane does not increase the melting point.