Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH3:1].C1COCC1.[CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=1.[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=1.O1CCCC1>O1CCCC1>[CH:7]1([BH:1][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: B
Reactant: C1=CCCCC1
Solvent: C1CCOC1
Product: B(C1CCCCC1)C1CCCCC1
Temperature: 0 °C

Procedure:
A 250 ml, three-necked round-bottom flask was sparged with nitrogen and equipped with a 50 ml dropping funnel, a thermometer, a stir bar, and a septum. The flask was charged with 38.38 ml (38.38 mmol) BH3.THF adduct and cooled to 0° C. in an ice bath. The dropping funnel was charged with 7.78 ml (76.7 mmol) cyclohexene and 36 ml tetrahydrofuran (THF). The cyclohexene/THF mixture was added dropwise over 45 min. A white solid (dicyclohexylborane) formed. The reaction mixture was stirred for one hour at 0° C. The dropping funnel was then charged with 13.0 g (202.0 mmol) poly(methylvinyl)silazane, [(MeSiHNH)0.8 (MeSiViNH)0.2 ]x and 36 ml THF and added to the reaction mixture over 30 min. After the polysilazane addition was complete, the reaction mixture was stirred for 30 min at 0° C. and then warmed to room temperature. The white solid disappeared and a clear solution was formed. The boron-substituted polysilazane, Polymer III, contained about 2.1 wt % boron bound to the polymer backbone. This solution was used in the following example.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[OH:12].I[CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:14]([O:12][C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[CH3:15]
Reactant: CCI
Reactant: COc1ccc([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1cc([N+](=O)[O-])ccc1OC
Yield: 94 %

Procedure:
A mixture of 2-methoxy-5-nitrophenol (5.3 g, 31.3 mmol), iodoethane (14.6 g, 93.9 mmol), and potassium carbonate (43.2 g, 310 mmol) in acetone (100 mL) was heated to reflux for 4 hours. The reaction mixture was cooled, and the solvent was evaporated in vacuo. The residue was dissolved in water (250 mL) and extracted with ethyl acetate (3×75 mL). The combined organic extracts were washed with water (3×75 mL) and dried (MgSO4), and the solvent was evaporated under vacuum, providing 5.8 g of the product, in 99% yield: 1H NMR (CDCl3) δ 1.51 (t, J=7.0 Hz, 3H), 3.97 (s, 3H), 4.18 (q, J=7.0 Hz, 2H), 6.22 (dd, J=8.4 Hz, J=2.4 Hz, 1H), 6.31 (d, J=2.4 Hz, 1H), 6.70 (d, J=8.4 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:34])[C:3]1[CH:33]=[CH:32][C:6]([C:7]([C:9]2[CH:10]=[C:11]([NH:15]C(C3C=CN4C=3CSC4C3C=NC=CC=3)=O)[CH:12]=[CH:13][CH:14]=2)=[O:8])=[CH:5][CH:4]=1.CN(C)C1C=CC(C(=O)C2C=CC=C([N+]([O-])=O)C=2)=CC=1.Cl.[OH-].[Na+]>O.C(O)(C)C.C(O)C>[NH2:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[C:7]([C:6]1[CH:32]=[CH:33][C:3]([N:2]([CH3:34])[CH3:1])=[CH:4][CH:5]=1)=[O:8]
Reactant: CN(C)c1ccc(C(=O)c2cccc(NC(=O)c3ccn4c3CSC4c3cccnc3)c2)cc1
Agent: CN(C)c1ccc(C(=O)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CC(C)O
Product: CN(C)c1ccc(C(=O)c2cccc(N)c2)cc1
Temperature: 79 °C
Reaction time: 0.5 h

Procedure:
The 3-amino-4'-dimethylaminobenzophenone may be prepared as follows: Stannous chloride in the dihydrate form (29.3 g) is added, at a temperature between 44° and 79° C., to a suspension of 4'-dimethylamino-3-nitrobenzophenone (11.4 g) in a mixture of concentrated hydrochloric acid (45 cc) and ethanol (120 cc), in the course of 35 minutes. The solution obtained is heated at a temperature in the vicinity of 79° C. for 3 hours. The suspension obtained is concentrated under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 50° C. The residue obtained is suspended in distilled water (350 cc) and an aqueous 10N sodium hydroxide solution (100 cc) is added, at a temperature in the vicinity of 5° C., to the suspension obtained and the mixture is stirred at a temperature in the vicinity of 20° C. for 30 minutes. The crystals formed are separated by filtration, washed 3 times with distilled water (60 cc in total) and air-dried. The crude product obtained is dissolved in boiling isopropanol (30 cc) and the solution obtained is cooled at a temperature in the vicinity of 4° C. for 2 hours. The crystals formed are separated by filtration, washed twice with isopropanol cooled to a temperature in the vicinity of 4° C. (20 cc in total) and twice with diethyl ether (40 cc) and then dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 20° C. in the presence of potassium hydroxide pellets. 3-amino-4'-dimethylaminobenzophenone (8.4 g) in the form of beige-coloured crystals, m.p. 110° C., is thereby obtained.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH2:13])([C:10]([OH:12])=[O:11])[NH:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(N(C(C)C)CC)(C)C.[C:23](Cl)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>ClCCl.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][C:2]1[C:3]([NH:13][C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)([C:10]([OH:12])=[O:11])[NH:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC1=C(C)C(N)(C(=O)O)NC=C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC1=C(C)C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)(C(=O)O)NC=C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 88.7 %

Procedure:
1.70 g of methyl 2-amino-4-methoxy-picolinic acid (compound C6) are dissolved in 44 ml of dichloromethane. Subsequently, 1.92 ml of diisopropylethylamine, 690 mg of tetrabutylammonium iodide, and 3.12 g of trityl chloride are added. The solution is stirred for 48 h at room temperature. Thereafter, the mixture is extracted three times each with 50 ml of sat sodium hydrogencarbonate solution. The organic layer is dried using sodium sulphate, filtered with suction and concentrated in vacuum. The crude product (5.38 g) is purified by chromatography (eluent: toluene/ethyl acetate 5:1) to afford 3.49 g of the title compound as a colorless oil. TSP-MS: 425.2 [MH+]. TLC: Rf=0.37 (toluene/ethyl acetate 5:1).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([S:9](Cl)(=[O:11])=[O:10])=[C:4]([F:13])[CH:3]=1.[CH:14]([NH2:17])([CH3:16])[CH3:15]>ClCCl>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([S:9]([NH:17][CH:14]([CH3:16])[CH3:15])(=[O:11])=[O:10])=[C:4]([F:13])[CH:3]=1
Reactant: O=S(=O)(Cl)c1cc(F)c(Br)cc1F
Reactant: CC(C)N
Solvent: ClCCl
Product: CC(C)NS(=O)(=O)c1cc(F)c(Br)cc1F

Procedure:
According to general procedure C, 4-Bromo-2,5-difluorobenzenesulfonyl chloride (0.20 g, 0.68 mmol) and isopropylamine were stirred together in dichloromethane (1 mL) for 16 hours. The reaction afforded 4-bromo-2,5-difluoro-N-isopropylbenzenesulfonamide (0.16 g) after purification. HPLC purity 96.6% at 210-370 nm, 10.7 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min. HRMS: calcd for C9H10BrF2NO2S−H+, 311.95109; found (ESI-FTMS, [M−H]1−), 311.95114
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13]2[CH:21]=[C:22]([C:25]#[N:26])[CH:23]=[CH:24][C:12]=2[N:11]=1)[CH3:9])(C)(C)C>C(O)(C(F)(F)F)=O>[NH2:7][C@H:8]([C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13]2[CH:21]=[C:22]([C:25]#[N:26])[CH:23]=[CH:24][C:12]=2[N:11]=1)[CH3:9]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(C#N)cc2n1-c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)c1nc2ccc(C#N)cc2n1-c1ccccc1

Procedure:
A solution of [(S)-1-(6-cyano-1-phenyl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tertbutyl ester (1.97 mmol) in TFA (3 mL) was stirred at RT for 30 min. Volatiles were removed under reduced pressure and the resulting residue was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 2M NH3/MeOH. The product was further purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM) affording 2-((S)-1-Aminoethyl)-3-phenyl-3H-benzoimidazole-5-carbonitrile as white crystalline solid (415 mg, 80% over two steps). LCMS: RT 1.99 min [M+H]+ 263.2
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:32])[C:19]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([Cl:31])[CH:26]=2)([OH:24])[C:20]([F:23])([F:22])[F:21])=[C:14]([Cl:33])[CH:13]=1)C(OCC)=O)[CH3:2].[Na+].[Cl-].O>CS(C)=O>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:32])[C:19]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([Cl:31])[CH:26]=2)([OH:24])[C:20]([F:21])([F:23])[F:22])=[C:14]([Cl:33])[CH:13]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(C(C)C(O)(c2ccnc(Cl)c2)C(F)(F)F)c(Cl)c1)C(=O)OCC
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)CCc1ccc(C(C)C(O)(c2ccnc(Cl)c2)C(F)(F)F)c(Cl)c1
Temperature: 140 °C

Procedure:
To a mixture of 2-{3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-benzyl}-malonic acid diethyl ester (214 mg) and NaCl (29 mg) in DMSO (4 mL) was added a small amount of water (0.011 mL). The mixture was then heated to 140° C. for 7 days. The mixture was poured into water and extracted with ethyl acetate. The organic extracts were washed with brine, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (silica gel, gradient of ethyl acetate in heptane) to give the title compound as a colorless, viscous oil (127 mg). MS (m/e)=450.1 (MH+).
Reaction SMILES: [CH3:1][CH:2]([CH3:8])/[CH:3]=[CH:4]/[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.Cl.[CH2:41]([C:43]1[C:44]([NH:50][CH2:51][CH2:52][NH2:53])=[N:45][CH:46]=[N:47][C:48]=1[CH3:49])[CH3:42]>CN(C=O)C.C(#N)C.C(OCC)(=O)C>[CH2:41]([C:43]1[C:44]([NH:50][CH2:51][CH2:52][NH:53][C:5](=[O:7])/[CH:4]=[CH:3]/[CH:2]([CH3:1])[CH3:8])=[N:45][CH:46]=[N:47][C:48]=1[CH3:49])[CH3:42]
Reactant: CCc1c(C)ncnc1NCCN
Reactant: CC(C)/C=C/C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCc1c(C)ncnc1NCCNC(=O)/C=C/C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(E)-4-Methylpent-2-enoic acid (46 mg, 0.4 mmol), HBTU (152 mg, 0.4 mmol) and triethylamine (82 μl, 0.6 mmol) were dissolved in a 1:1 mixture of anhydrous DMF and anhydrous acetonitrile (2 ml), after 20 minutes N-(5-ethyl-6-methyl-pyrimidin-4-yl)ethane-1,2-diamine hydrochloride (40 mg, 0.185 mmol) was added. The mixture was stirred at room temperature for 2 hours and left to stand at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was purified by preparative HPLC (gradient of water containing 0.1% NH3 and acetonitrile) to yield 9 mg (0.033 mmol, 18%).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([C:8]([NH:10][CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([S:19]([NH2:22])(=[O:21])=[O:20])[CH2:15][CH2:14]2)=[O:9])[C:5](=[O:23])[N:4]([CH3:24])[C:3]1=[O:25].[C:26]12([N:36]=[C:37]=[O:38])[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH2:27]1)[CH2:33]2.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:26]12([NH:36][C:37]([NH:22][S:19]([N:16]3[CH2:17][CH2:18][CH:13]([CH2:12][CH2:11][NH:10][C:8]([C:6]4[C:5](=[O:23])[N:4]([CH3:24])[C:3](=[O:25])[N:2]([CH3:1])[CH:7]=4)=[O:9])[CH2:14][CH2:15]3)(=[O:21])=[O:20])=[O:38])[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH2:27]1)[CH2:33]2
Reactant: Cn1cc(C(=O)NCCC2CCN(S(N)(=O)=O)CC2)c(=O)n(C)c1=O
Reactant: O=C=NC12CC3CC(CC(C3)C1)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1cc(C(=O)NCCC2CCN(S(=O)(=O)NC(=O)NC34CC5CC(CC(C5)C3)C4)CC2)c(=O)n(C)c1=O
Yield: 40 %

Procedure:
A mixture of 380 mg. (0.001 mole) of 4-[2-(1,3-dimethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione-5-carboxamido)ethyl]-1-piperidinesulfonamide, 220 mg. (0.001 mole) of 1-adamantyl isocyanate and 310 mg. (0.002 mole) of anhydrous potassium carbonate in 30 ml. of acetone was refluxed for a period of 20 hours. At the end of this time, the spent reaction mixture was cooled and the excess potassium carbonate subsequently removed therefrom by means of suction filtration. The resulting filtrate was then slowly acidified with 1N aqueous hydrochloric acid causing a white precipitate to form. The latter material was subsequently recovered by suction filtration and thereafter recrystallized from acetonitrile-methanol to afford 220 mg (38%) of pure 1-(1-adamantyl)3-{4-[2-(1,3-dimethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione-5-carboxamido)ethyl]-1-piperidinesulfonyl}urea, m.p. 224°-226° C.
Reaction SMILES: [C:1]([CH:6]([NH:15][CH:16]1[C:22](=[O:23])[NH:21][C:20]2[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=2[O:18][CH2:17]1)[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([O:3][CH2:4][CH3:5])=[O:2].[OH-].[K+].Br[CH2:31][C:32]([O:34][CH3:35])=[O:33]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[C:1]([CH:6]([NH:15][CH:16]1[C:22](=[O:23])[N:21]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[C:20]2[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=2[O:18][CH2:17]1)[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)C(CCc1ccccc1)NC1COc2ccccc2NC1=O
Reactant: COC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CCc1ccccc1)NC1COc2ccccc2N(CC(=O)OC)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
An ice cold mixture of 81 mg of 3-[N-(1-carboethoxy-3-phenylpropyl)amino]-2,3-dihydro-1,5-benzoxazepin-4(5H)-one, 15 mg of powdered potassium hydroxide and 6.5 mg of tetrabutylammonium bromide in 3 ml of dry tetrahydrofuran is treated with 32 mg of methyl bromoacetate. The reaction is allowed to stir for 3 hr at room temperature. At this time the solution is filtered and concentrated and the residue is dissolved in 20 ml of ethyl acetate. This is washed with 5 ml of water and dried over potassium carbonate. Concentration under reduced pressure affords 3-[N-(1-carboethoxy-3-phenylpropyl)amino]-5-carbomethoxymethyl-2,3-dihydro-1,5-benzoxazepin-4(5H)-one; NMR (CDCl3) δ 6.35-8.00 (m, 10), 4.30-4.80 (m, 3), 3.67 (s, 3), 1.20 (t, 3); IR (neat) 3300 (NH), 1730 (C=O, ester), 1685 (C=O, lactam) cm-1.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[O:25][N:24]=[C:23]([C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)[N:22]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[O:25][N:24]=[C:23]([C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)[N:22]=2)[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccncc3)no2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cc(-c2noc(C3CCNCC3)n2)ccn1
Reaction time: 2.5 h

Procedure:
Trifluoroacetic acid (20 ml) was added to a stirred solution of 4-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-yl)piperidine-1-carboxylic acid tert-butyl ester (Example 2, 1.64 g, 4.96 mmol) in CH2Cl2 (35 ml). After 2.5 h at rt, the solvent was evaporated under reduced pressure. The residual solid was suspended in EtOAc (150 ml) and washed with saturated aqueous Na2CO3 (20 ml). The aqueous was separated and extracted with EtOAc (3×30 ml). The combined organic extracts were dried (MgSO4) and evaporated under reduced pressure to afford the title compound: RT=3.48 min, m/z (ES+)=231.2 [M+H]+.
Reaction SMILES: Cl.[O:2]([CH2:6][CH2:7][NH2:8])[N+:3]([O-:5])=[O:4].C[O-].[Na+].[C:12]([N:14]=[C:15]([C:20]1[CH:21]=[N:22][C:23]([NH2:26])=[CH:24][CH:25]=1)OCCC)#[N:13]>CN(C=O)C>[NH2:26][C:23]1[N:22]=[CH:21][C:20]([C:15](=[N:8][CH2:7][CH2:6][O:2][N+:3]([O-:5])=[O:4])[NH:14][C:12]#[N:13])=[CH:25][CH:24]=1
Reactant: CCCOC(=NC#N)c1ccc(N)nc1
Reactant: NCCO[N+](=O)[O-]
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CNC(=NCCO[N+](=O)[O-])c1ccc(N)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.2 %

Procedure:
To a solution of 2-nitroxyethylamine hydrochloride (1.36 g, 9.54 mmol) in DMF (3.5 ml) was added sodium methoxide (470 mg, 8.7 mmol) followed by a solution of propyl N-cyano-6-amino-3-pyridinecarboximidate (355 mg, 1.74 mmol) in DMF (2 ml) described in Example 5 of Experimental Example 1, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction mixture was evaporated under reduced pressure. The residue was suspended in water and extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography with a mixed solvent of methanol and chloroform as an eluent to give the title compound (284 mg, yield 74%) as colorless crystals.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][OH:8])([CH3:3])[CH3:2].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[CH:1]([NH:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8])([CH3:3])[CH3:2]
Reactant: CC(C)Nc1ccccc1CO
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: CC(C)Nc1ccccc1C=O
Yield: 80.1 %

Procedure:
To a solution of 9.6 g of 2-isopropylaminobenzyl alcohol in 200 ml of dioxane was added 13.2 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in several portions, followed by stirring for an hour. The solvent was evaporated, the reaction solution was concentrated, and methylene chloride was added thereto, followed by filtration. The filtrate was concentrated, and the resulting oily substance was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1) to give 7.6 g of 2-isopropylaminobenzaldehyde.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:20]3[CH:21]=[N:22][CH:23]=[CH:24][C:19]=3[N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]=2Cl)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:32][C:33]1[CH:34]=[CH:35][C:36]([CH3:40])=[C:37]([OH:39])[CH:38]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:20]3[CH:21]=[N:22][CH:23]=[CH:24][C:19]=3[N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]=2[O:39][C:37]2[CH:38]=[C:33]([F:32])[CH:34]=[CH:35][C:36]=2[CH3:40])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2c(Cl)n(-c3ccccc3)c3ccncc23)CC1
Reactant: Cc1ccc(F)cc1O
Product: Cc1ccc(F)cc1Oc1c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c2cnccc2n1-c1ccccc1

Procedure:
The title compound was prepared from the compound of step 5 (187 mg, 424 μmol) and 5-fluoro-2-methylphenol analogously as described in example 1, step 6. Yield: 173 mg.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:26]2[CH:31]=[CH:30][C:29]([S:32]([N:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)(=[O:34])=[O:33])=[CH:28][CH:27]=2)[C:8]([NH:10][C:11]2[S:12][C:13]3[C:18]([N:19]=2)=[CH:17][CH:16]=[C:15]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:14]=3)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:41](O)=O>C=O>[CH:1]1([CH2:6][C@H:7]([C:26]2[CH:27]=[CH:28][C:29]([S:32]([N:35]3[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]3)(=[O:34])=[O:33])=[CH:30][CH:31]=2)[C:8]([NH:10][C:11]2[S:12][C:13]3[C:18]([N:19]=2)=[CH:17][CH:16]=[C:15]([N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)[N:14]=3)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=CO
Reactant: O=C(Nc1nc2ccc(N3CCOCC3)nc2s1)C(CC1CCCC1)c1ccc(S(=O)(=O)N2CCNCC2)cc1
Agent: C=O
Product: CN1CCN(S(=O)(=O)c2ccc([C@@H](CC3CCCC3)C(=O)Nc3nc4ccc(N5CCOCC5)nc4s3)cc2)CC1
Temperature: 70 °C

Procedure:
Title compound H, 3-Cyclopentyl-N-(5-morpholin-4-yl-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(piperazine-1-sulfonyl)-phenyl]-propionamide (0.21 g, 0.354 mmol was suspended in formaldehyde (2 mL) to which 1 mL of formic acid was added. The mixture was heated to 70° C. for 7 h before being cooled and subsequently quenched into 2N NaOH and extracted with ethyl acetate. The combined organic layer was dried over MgSO4, filtered and evaporated to provide a brown foam which was purified over silica (0-20% EtOAc: methanol) to afford a white foam. This material was purified on a Chiracel column to afford pure (R)-3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-N-(5-morpholin-4-yl-thiazolo[5,4-b]pyridin-2-yl)-propionamide as a white solid. 1H NMR (400 MHz, DMSO) δ 1.14 (m, 2H) 1.43 (d, J=4.80 Hz, 2H) 1.57 (d, J=8.34 Hz, 3H) 1.72 (d, J=5.05 Hz, 2H) 1.75-1.83 (m, 1H) 2.10 (s, 3H) 2.16 (m, 1H) 2.33 (d, J=4.04 Hz, 4H) 2.87 (s, 4H) 3.41-3.49 (m, 4H) 3.67-3.74 (m, 4H) 4.07 (t, J=7.58 Hz, 1H) 6.97 (d, J=9.09 Hz, 1H) 7.64-7.69 (m, 2H) 7.69-7.75 (m, 2H) 7.87 (d, J=8.84 Hz, 1H)
Reaction SMILES: [Cl:1][C:2]1[C:6]([S:7]([CH3:10])(=[O:9])=[O:8])=[CH:5][S:4][C:3]=1[C:11]([NH:13][CH2:14][C:15]1[CH2:20][C@@H:19]([N+:21]([O-])=O)[C@H:18]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[Cl:31])[CH2:17][CH:16]=1)=[O:12]>[Zn].CO.C(O)(=O)C>[NH2:21][C@@H:19]1[CH2:20][C:15]([CH2:14][NH:13][C:11]([C:3]2[S:4][CH:5]=[C:6]([S:7]([CH3:10])(=[O:9])=[O:8])[C:2]=2[Cl:1])=[O:12])=[CH:16][CH2:17][C@H:18]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[Cl:31]
Reactant: CS(=O)(=O)c1csc(C(=O)NCC2=CC[C@@H](c3ccc(Cl)cc3Cl)[C@H]([N+](=O)[O-])C2)c1Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: CS(=O)(=O)c1csc(C(=O)NCC2=CC[C@@H](c3ccc(Cl)cc3Cl)[C@H](N)C2)c1Cl
Yield: 65.7 %

Procedure:
To a solution of Example 12D (40 mg, 0.077 mmol) in mixture of methanol/acetic acid (0.5 mL/0.5 mL), Zn powder (50 mg, 0.77 mmol) was added at room temperature. The reaction mixture was stirred for thirty minutes, filtered, concentrated under reduced pressure, and purified by high pressure liquid chromotography (eluting with 0-70% acetonitrile/water and 0.1% trifluoroacetic acid) to provide the title compound (25 mg, 66%). 1H NMR (400 MHz, methanol-d4) δ ppm 8.45 (s, 1H), 8.03 (s, 1H), 7.54 (s, 1H), 7.35-7.47 (m, 2H), 5.82 (m, 1H), 3.82-4.06 (m, 3H), 3.49-3.61 (m, 1H), 3.18 (s, 3H), 2.43-2.62 (m, 2H), 2.24-2.42 (m, 2H). MS (ESI) m/z 493 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([CH3:22])[N:17]([CH3:23])[C:16]2=[O:24])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[I:25]I.[N+]([O-])(O)=O>C(O)(=O)C>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([I:25])=[C:18]([CH3:22])[N:17]([CH3:23])[C:16]2=[O:24])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: Cc1cc(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)n1C
Reactant: II
Solvent: CC(=O)O
Solvent: O=[N+]([O-])O
Product: Cc1c(I)c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)n1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.50 g of isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-3,4-dimethyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate in 10 ml of acetic acid are treated with 0.70 g of iodine and the reaction mixture is stirred for 1 hour at room temperature. Subsequently the reaction mixture is treated with 0.67 g of 100% nitric acid and stirred at room temperature for 3 hours. The reaction mixture is poured into 150 ml of ice/water and extracted with 100 ml of ethyl acetate. The organic phase is washed with 150 ml of water, thereafter with 150 ml of aqueous sodium bicarbonate solution and finally with 150 ml of saturated aqueous sodium bisulphite solution. The upper phase is dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The residue is recrystallized from methylene chloride/n-hexane. Isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-3,4-dimethyl-5-iodo-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, m.p. 147°-150° C., is obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([O:11][CH2:12][O:13][CH3:14])[CH3:10])=[CH:4][CH:3]=1.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]Br)=[CH:18][CH:17]=1>>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([O:11][CH2:12][O:13][CH3:14])[CH3:10])=[CH:4][CH:3]=2)=[CH:18][CH:17]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: COCOC(C)Cc1ccc(Br)cc1
Product: COCOC(C)Cc1ccc(Cc2ccc(Br)cc2)cc1

Procedure:
In accordance with Example 19-(2), but using 1-bromo-4-[2-(methoxymethoxy)propyl]benzene instead of tert-butyl 5-(benzyloxy)-2-{[1-(5-bromopyridin-2-yl)piperidin-4-yl]methyl}-6-methylpyrimidine-4-carboxylate, and 1-bromo-4-(bromomethyl)benzene instead of tert-butyl[(4-iodobenzyl)oxy]dimethylsilane, a crude product of 1-bromo-4-{4-[2-(methoxymethoxy)propyl]benzyl}benzene was afforded as a yellow oil.