Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH:13]([C:33]#[C:34][CH3:35])[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[NH4+:37]>CCO>[NH2:37][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH:13]([C:33]#[C:34][CH3:35])[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC#CC1CN(S(=O)(=O)c2ccc(Cl)nc2)CCN1c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: CC#CC1CN(S(=O)(=O)c2ccc(N)nc2)CCN1c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 120 °C
Yield: 88.2 %

Procedure:
A 20-mL sealed tube was charged with 2-(4-(4-((6-chloro-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.340 g, 0.627 mmol), concentrated ammonium hydroxide (5.00 mL, 38.5 mmol) and EtOH (5 mL). The reaction mixture was heated in an Initiator (Biotage, AB, Uppsala, Sweden) at 120° C. for 1 h. The reaction mixture was further heated in a heating block at 110° C. for 5 h. The reaction mixture was concentrated and purified by column chromatography (25 g of silica, 30 to 80% EtOAc in hexanes) to afford 2-(4-(4-((6-amino-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.289 g) as a mixture of two enantiomers.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][C:19]([N:21]1[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22]1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>O>[CH2:11]([O:18][C:19]([N:21]1[CH2:25][CH2:24][C:23](=[O:26])[CH2:22]1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(OCc1ccccc1)N1CCC(O)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C1CCN(C(=O)OCc2ccccc2)C1

Procedure:
150 ml of oxalic acid chloride was added to 2 liters of dichloromethylene. 245 ml of dimethylsulfoxide was gradually added at -70° to -50° C. in a stream of argon. 70.67 g of N-(N-(benzyloxycarbonyl)-3-pyrrolidinol dissolved in dichloromethylene was dropped. After gradual dropping of 720 ml of triethylamine, the mixture was raised to room temperature. After completion of the reaction, the reaction solution was poured into water and extracted with dichloromethylene, followed by removal of the solvent by distillation under reduced pressure. The residue was purified by column chromatography (eluting solvent: hexane-ethyl acetate), thereby obtaining 66.55 g of the intended compound.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:12]([NH:14][CH2:15][C:16]([NH2:18])=[O:17])=[O:13])[CH:5]=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32].Cl.N[CH2:35]C(N)=O>>[NH2:18][C:16]([C@@H:15]([NH:14][C:12](=[O:13])[C:11]1[CH:19]=[CH:20][C:21]([CH3:22])=[C:9]([N:6]2[C:7](=[O:8])[C:2]([Cl:1])=[C:3]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[F:32])[N:4]=[CH:5]2)[CH:10]=1)[CH3:35])=[O:17]
Reactant: NCC(N)=O
Reactant: Cc1ccc(C(=O)NCC(N)=O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O
Agent: Cl
Product: Cc1ccc(C(=O)N[C@@H](C)C(N)=O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O

Procedure:
The title compound was prepared using a procedure similar to that used in Step 4 of the synthesis of 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-N-[1-(aminocarbonyl)methyl]-4-methylbenzamide by substituting L-alaninamide HCl for glycineamide HCl. 1H NMR (CD3OD/400 MHz) δ8.32 (s, 1H), 7.96 (m, 1H), 7.82 (m, 1H), 7.61 (q, 1H, J=6.4 Hz), 7.53 (d, 1H, J=8.0 Hz), 7.02 (m, 2H), 5.60 (m, 2H), 4.55 (q, 1H, J=6.0 Hz), 2.20 (s, 3H), 1.45 (d, 3H, J=6.0 Hz). ESHRMS m/z 477.1141 (M+H calculated for C22H20ClF2N4O4 requires 477.1136).
Reaction SMILES: [C:1]1([CH3:29])[C:2]([S:7]([O:10][C:11]2[CH2:17][CH:16]3[N:13]([C:14](=[O:18])[CH2:15]3)[C:12]=2[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.C([N-]C(C)C)(C)C.[Li+].[F:38][C:39]([F:43])([F:42])[CH:40]=[O:41].[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[F:38][C:39]([F:43])([F:42])[CH:40]([CH:15]1[C:14](=[O:18])[N:13]2[CH:16]1[CH2:17][C:11]([O:10][S:7]([C:2]1[C:1]([CH3:29])=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:9])=[O:8])=[C:12]2[C:19]([O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:20])[OH:41]
Reactant: Cc1ccccc1S(=O)(=O)OC1=C(C(=O)OCc2ccccc2)N2C(=O)CC2C1
Reactant: O=CC(F)(F)F
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccccc1S(=O)(=O)OC1=C(C(=O)OCc2ccccc2)N2C(=O)C(C(O)C(F)(F)F)C2C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of benzyl 3-toluenesulfonyloxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (41 mg) in anhydrous THF (0.5 ml) is added dropwise over 5 mins to a stirring solution of lithium diisopropylamide (from 15.5 μl of diisopropylamine and 70 μl of 1.6N BuLi) in anhydrous THF (1.5 ml) at -78°. The resulting solution is stirred under a N2 atm at -78° for 10 mins and then trifluoroacetaldehyde (50 mg) is added all at once. After 1 more min, saturated aqueous NH4Cl solution (1.5 ml) is added and the mixture is allowed to warm to room temperature. The mixture is diluted with EtOAc (20 ml), washed with water and brine, dried with MgSO4, filtered, and evaporated in vacuo. The benzyl 6-(2,2,2-trifluoro-1-hydroxyethyl)-3-toluenesulfonyloxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH:12]([CH:14]=[CH2:15])=[O:13].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC>>[C:1]1(=[O:11])[N:5]([CH2:15][CH2:14][CH:12]=[O:13])[C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C=CC=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Product: O=CCCN1C(=O)c2ccccc2C1=O

Procedure:
3-Phthalimidopropanal was prepared by addition of phthalimide to acrolein in the presence of tetrabutylammonium hydroxide according to the procedure described by R. O. Atkinson & F. Poppelsdorf, J Chem. Soc. (1952) 2448. 1H-NMR (CDCl3, 400 MHz): δ 9.82 (t,1H,J=2); 7.85 (m,2H); 7.72 (m,2H); 4.04 (t,2H,J=7); 2.88 (dt,2H,J=2,7). 13C-NMR (CDCl3, 100 MHz): δ 199.36, 167.98, 134.10, 131.95, 123.36, 42.35, 31.67.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:18][CH3:19])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([C:12](N(C)OC)=[O:13])[O:7][CH2:6][CH2:5]2.CC(C[AlH]CC(C)C)C>C1COCC1>[Br:1][C:2]1[C:3]([O:18][CH3:19])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([CH:12]=[O:13])[O:7][CH2:6][CH2:5]2
Reactant: COc1c(Br)ccc2c1CCOC2C(=O)N(C)OC
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: COc1c(Br)ccc2c1CCOC2C=O
Temperature: -30 °C
Reaction time: 2 h

Procedure:
To a solution of 6-bromo-N-methyl-N,5-bis(methyloxy)-3,4-dihydro-1H-isochromene-1-carboxamide (300 mg, 0.9 mmol) in 20 mL of anhydrous THF was cooled to −30° C. and then DIBAL-H (1.3 mL, 1.3 mmol, 1M) was added. The mixture was stirred at −30° C. for 2 hours. The reaction was quenched with water and extracted with DCM. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The crude 6-bromo-5-(methyloxy)-3,4-dihydro-1H-isochromene-1-carbaldehyde was used for next step without purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[CH:6]=[CH:5]2.C(N(CC)CC)C.[C:27]([O:31][CH3:32])(=[O:30])[CH:28]=[CH2:29].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[OH:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2](/[CH:29]=[CH:28]/[C:27]([O:31][CH3:32])=[O:30])[CH:11]=[CH:10]2
Reactant: C=CC(=O)OC
Reactant: OCCCCCCOc1ccc2cc(Br)ccc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1ccc2cc(OCCCCCCO)ccc2c1

Procedure:
A mixture of 5.2 g of 6-bromo-2-(6-hydroxyhexyloxy)naphthalene, 25 ml of triethylamine, 4.3 ml of methyl acrylate, 0.072 g of palladium acetate and 0.392 g of tri-o-tolylphosphine was heated under reflux for 16 hrs. In order to complete the reaction, a further 0.177 g of palladium acetate, 2.5 g of tetrabutylammonium bromide, 10 ml of dimethylformamide and 2 ml of methyl acrylate were added and the mixture was heated to reflux for a further 24 hrs. Thereafter, the reaction mixture was cooled, partitioned between ethyl acetate and water, the organic phase was washed with water, and dried over magnesium sulphate, filtered and evaporated. The residue was chromatographed on 250 g of silica gel with toluene/ethyl acetate (3:1 to 1:1) and subsequently crystallized twice from toluene. This gave 0.63 g of methyl (E)-3-[6-(6-hydroxyhexyloxy)naphthalen-2-yl]acrylate as a colorless solid, λmax. (CH2Cl2): 326 nm (ε=27660).
Reaction SMILES: [Br:1][C:2]1[C:7]([Br:8])=[C:6]([Br:9])[C:5]([Br:10])=[C:4]([Cl:11])[C:3]=1[CH3:12].BrC1C(C)=C(Br)C(Br)=C(Br)C=1Br.C1C[NH2+]CC1.C1[O:34]C2OC1C2(C(I)I)CCC1(C(I)I)C2OC1CO2>>[Br:1][C:2]1[C:7]([Br:8])=[C:6]([Br:9])[C:5]([Br:10])=[C:4]([Cl:11])[C:3]=1[CH:12]=[O:34]
Reactant: IC(I)C1(CCC2(C(I)I)C3COC2O3)C2COC1O2
Reactant: Cc1c(Cl)c(Br)c(Br)c(Br)c1Br
Agent: C1CC[NH2+]C1
Agent: Cc1c(Br)c(Br)c(Br)c(Br)c1Br
Product: O=Cc1c(Cl)c(Br)c(Br)c(Br)c1Br

Procedure:
When 2,3,4,5-tetrabromo-6-chlorotoluene, mp 268-269°, was substituted for pentabromotoluene in Example 7 and the resultant dioxonium compound was hydrolyzed according to the procedure of Example 35 an essentially quantitative yield of the title compound was obtained. The structure of the novel high melting compound was confirmed by infrared and nuclear magnetic resonance spectroscopy as well as by elemental analysis.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:24])[C:13]2[NH:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH3:23])=[CH:19][C:20]=3[N:21]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].C[O-].[Na+:27].CO>C(C(C)=O)C>[CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:24])[C:13]2[N-:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH3:23])=[CH:19][C:20]=3[N:21]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].[Na+:27]
Reactant: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCC(C)=O
Product: COc1ccc2[n-]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Temperature: 27 °C

Procedure:
A solution of esomeprazole (19.5 g, 56.5 mmol; 1.3% sulfone, 1.05% R-enantiomer) in methyl ethyl ketone (120 mL) was cooled to 15° C. 30% sodium methoxide in methanol (10.7 mL, 57.6 mmol) was added in 15 min. Subsequently, the solution was stirred at 27° C. A solid started to crystallize. The resulting slurry was stirred overnight at room temperature. The solid was collected by filtration, rinsed with methyl ethyl ketone (2×20 mL) and dried under reduced pressure at 50° C. to yield esomeprazole sodium. Yield: 12.4 g (60%). Sulfone content: 0.06%. R-enantiomer content: 0.00%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([OH:15])[CH2:12][C:13]#[N:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[NH2:14][CH2:13][CH2:12][CH:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[OH:15]
Reactant: COc1ccc(C(O)CC#N)cc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(O)CCN)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
A solution of 3-(3,4-dimethoxyphenyl)-3-hydroxypropiononitrile (1.25 g, 6.02 mM) in dried tetrahydrofuran (25 ml) was dropped into a solution of lithium aluminum hydride (0.55 g, 14.48 mM) in dried tetrahydrofuran (40 ml) at 0° C. This was gradually warmed to room temperature and stirred for 1 hour. Next, the reaction solution was again cooled to 0° C., water was carefully added to it, then the mixture was stirred at room temperature for 30 minutes. Next, the solution was filtered through Celite, the filtrate was dried over anhydrous sodium sulfate, then the solvent was removed in vacuo to obtain a crude product of 3-amino-1-(3,4-dimethoxyphenyl)-1-propanol (1.27 g). The crude product obtained here had a sufficient purity even without purification, so could be used as it was for the next reaction.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:20])[NH:5][C:6](=[O:19])[NH:7][C:8]=1[C:9](=[O:18])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([F:30])[CH:29]=1)[CH2:25]Br>>[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([F:30])[CH:29]=1)[CH2:25][N:7]1[C:8]([C:9](=[O:18])[C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:20])[NH:5][C:6]1=[O:19]
Reactant: CCc1c(C(=O)c2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: Fc1cc(F)cc(CBr)c1
Product: CCc1c(C(=O)c2cc(C)cc(C)c2)n(Cc2cc(F)cc(F)c2)c(=O)[nH]c1=O
Yield: 59.2 %

Procedure:
5-Ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 3,5-difluorobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (236 mg, yield: 59.2%).
Reaction SMILES: [C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([C@@H:23]([CH:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:24][CH:25]=O)[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].O1CCCC1.[OH-].[NH4+:38].II>O>[C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([C@@H:23]([CH:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:24][C:25]#[N:38])[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:4])([CH3:5])[CH3:3]
Reactant: [NH4+]
Reactant: CC(C)(C)C(=O)OCn1ccc2c(-c3cnn([C@H](CC=O)C4CCCC4)c3)ncnc21
Agent: II
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C(=O)OCn1ccc2c(-c3cnn([C@H](CC#N)C4CCCC4)c3)ncnc21
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 86.8 %

Procedure:
A solution of (1R)-(4-(1-(1-cyclopentyl-3-oxopropyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate ((R)-37, 169 mg, 0.399 mmol) in tetrahydrofuran (THF, 1.2 mL, 15 mmol) at room temperature was added a 14.3 M solution of ammonium hydroxide (NH4OH) in water (1.2 mL), followed by iodine (I2, 112 mg, 0.439 mmol, 1.1 equiv). The resulting reaction mixture was stirred at room temperature for 25 min. When LCMS showed that the reaction was deemed complete, the reaction mixture was quenched with 10% aqueous Na2S2O3 (10 mL) before being extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine, dried over magnesium sulfate (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by Combiflash (SiO2) with 0-60% EtOAc/hexane gradient elution to afford (R)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate ((R)-12, 145.6 mg, 167.8 mg theoretical, 86.8% yield) as a colorless foam.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5]>CO.[Rh]>[Cl:1][CH2:2][CH2:3][C@H:4]([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[OH:5]
Reactant: O[C@H](CCCl)c1ccccc1
Agent: [Rh]
Solvent: CO
Product: O[C@H](CCCl)C1CCCCC1
Reaction time: 6.5 h
Yield: 52.5 %

Procedure:
A solution of 4.25 g (25 mmol) of (R)-3-chloro-1-phenyl-1-propanol in 20 mL of methanol, containing 0.75 g of 5% rhodium-on-alumina, was hydrogenated at 60-65 psig at RT on a Parr shaker for 6.5 hours. The solution was filtered and concentrated, and the crude product was purified by chromatography on silica to give 2.32 g (55%) of (R)-3-chloro-1-cyclohexyl-1-propanol. NMR (DMSO-d6) δ0.8-1.3 (m, 5H), 1.5-1.9 (m, 6H), 3.30 (m, 1H), 3.68 (2 overlapping t, J=5.2 and 7.0, 2H), 4.48 (d, J=5.9, 1H, exchanges).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][P:11](=[O:17])([CH:14]([CH3:16])[CH3:15])[CH2:10][CH2:9]1)C1C=CC=CC=1.C(O)C.O.O.[C:23]([OH:28])(=[O:27])[C:24]([OH:26])=[O:25]>O.[Pd]>[C:23]([OH:28])(=[O:27])[C:24]([OH:26])=[O:25].[CH3:15][CH:14]([P:11]1(=[O:17])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[CH3:16]
Reactant: CC(C)P1(=O)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: O=C(O)C(=O)O
Solvent: CCO
Solvent: O
Product: CC(C)P1(=O)CCNCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.5 %

Procedure:
A 10 L auto clave was charged with the product of Step 2 (200.0 g, 796.8 mmol), ethanol (4000 mL) and oxalic acid dihydrate (100.4 g, 797.0 mmol) in water (1000 ml). To the reaction mixture was added palladium on carbon (10% w/w, 99.6 g) and stirred at room temperature under H2 pressure (50 psi) for 16 h. After completion, the reaction mixture filtered and concentrated. Obtained solid was triturated with hot ethanol (250 mL) and kept in a cold room for 90 minutes, filtered, washed with diethylether and hexane to give 4-(propan-2-yl)-1,4-azaphosphinane 4-oxide oxalate salt (105 g, 53%) as a colorless solid. Mp 223-224° C. LC ESI: [M]+ m/z 162. HPLC (ELSD method)=99.9%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19]OS(C)(=O)=O)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[NH:25]([CH2:29][CH2:30][OH:31])[CH2:26][CH2:27][OH:28]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19][N:25]([CH2:29][CH2:30][OH:31])[CH2:26][CH2:27][OH:28])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)OCC#Cc1ccc2c(-c3ccc(Cl)cc3)nsc2c1
Reactant: OCCNCCO
Product: OCCN(CC#Cc1ccc2c(-c3ccc(Cl)cc3)nsc2c1)CCO

Procedure:
In analogy to example 16.1, Methanesulfonic acid 3-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl ester and Diethanolamine (2×2 equivalents) were converted to yield 2-[{3-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl}-(2-hydroxy-ethyl)-amino]-ethanol as white solid, MS: 387 (MH+, 1Cl).
Reaction SMILES: [NH2:1]/[C:2](/[CH3:8])=[CH:3]\[C:4]([O:6][CH3:7])=[O:5].C([O:11][C:12]([N:14]=[C:15]=[O:16])=O)C>C(OCC)C>[OH:11][C:12]1[N:14]=[C:15]([OH:16])[C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([CH3:8])[N:1]=1
Reactant: COC(=O)/C=C(/C)N
Reactant: CCOC(=O)N=C=O
Solvent: CCOCC
Product: COC(=O)c1c(C)nc(O)nc1O
Reaction time: 4 h
Yield: 49.7 %

Procedure:
To a suspension of methyl 3-aminocrotonate (2.0 g) in diethyl ether (15 mL) was added a solution of ethoxycarbonylisocyanate (2 g) in diethyl ether (5 mL) in a dropwise manner under ice-cooling, and the mixture was stirred at the same temperature for 4 hours. The insoluble material was collected by filtration, and the collected material was washed with diethyl ether, and dried under reduced pressure. To this material was added 25% aqueous triethylamine solution (20 mL), and the mixture was stirred at 50° C. overnight, and then stirred at 60° C. for 4 hours. The reaction mixture was concentrated under reduced pressure. The residual crystals were suspended in methylene chloride, and collected by filtration. The collected crystals were washed with methylene chloride, and dried under reduced pressure to give the title compound (1.59 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)[C:12]([NH2:14])=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].Cl.[NH2:26][C:27]1[S:31][N:30]=[C:29]([CH3:32])[CH:28]=1.C([O-])([O-])=O.[K+].[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:8]([C:7]1[CH:6]=[CH:5][C:4]([NH:10][C@H:11]([CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)[C:12]([NH2:14])=[O:13])=[CH:3][C:2]=1[NH:26][C:27]1[S:31][N:30]=[C:29]([CH3:32])[CH:28]=1)#[N:9]
Reactant: Cc1cc(N)sn1
Reactant: N#Cc1ccc(N[C@H](Cc2c[nH]c3ccccc23)C(N)=O)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(Nc2cc(N[C@H](Cc3c[nH]c4ccccc34)C(N)=O)ccc2C#N)sn1
Reaction time: 18 h
Yield: 96 %

Procedure:
A mixture of (R)-2-(3-bromo-4-cyanophenylamino)-3-(1H-indol-3-yl)propanamide (96 mg, 0.250 mmol), 5-amino-3-methylisothiazole hydrochloride (60 mg, 0.398 mmol), K2CO3 (120 mg, 0.869 mmol), BINAP (40 mg, 0.064 mmol) and Pd(OAc)2 (20 mg, 0.089 mmol) in dioxane (2 mL) was degassed with argon, then was stirred at 120 C for 18 h. Water and EtOAc were added. The organic phase was separated, dried over Na2SO4, concentrated in vacuo to give (R)-2-(4-cyano-3-(3-methylisothiazol-5-ylamino)phenylamino)-3-(1H-indol-3-yl)propanamide (100 mg)
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:13](=O)[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=3)[C:11]([OH:12])=[C:6]2[CH:5]=[N:4]1)[CH3:2].Cl.[NH2:24]O>N1C=CC=CC=1>[CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]3[C:13]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=4)=[N:24][O:12][C:11]3=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: NO
Reactant: CCn1ncc2c(O)c(C(=O)c3cccc(OC)c3)cnc21
Agent: Cl
Solvent: c1ccncc1
Product: CCn1ncc2c3onc(-c4cccc(OC)c4)c3cnc21

Procedure:
1-Ethyl-4-hydroxy-5-(3-methoxybenzoyl)-1H-pyrazolo-[3,4-b]pyridine was refluxed overnight in 75 ml of pyridine containing 7.0 g of hydroxylamine hydrochloride. The pyridine was evaporated and the residue triturated with 5% hydrochloric acid. The product thus obtained was recrystallized from methanol to give 5.94 g, mp 130°-131° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][N:12]2[N:15]=[C:16]([CH3:34])[C:17]([C:18]3[S:19][C:20]([C:29]4[NH:33][CH:32]=[N:31][N:30]=4)=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:22]=3)=[C:11]2[CH:10]=1)C1C=CC=CC=1>O1CCCC1.CO.C(O)C.[C].[Pd]>[CH3:34][C:16]1[C:17]([C:18]2[S:19][C:20]([C:29]3[NH:33][CH:32]=[N:31][N:30]=3)=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:22]=2)=[C:11]2[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][N:12]2[N:15]=1
Reactant: Cc1nn2ccc(OCc3ccccc3)cc2c1-c1nc(-c2ccccc2)c(-c2nnc[nH]2)s1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1nn2ccc(O)cc2c1-c1nc(-c2ccccc2)c(-c2nnc[nH]2)s1
Temperature: 25 °C
Reaction time: 31 h
Yield: 38.6 %

Procedure:
To a solution of 5-(benzyloxy)-2-methyl-3-[4-phenyl-5-(4H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]pyrazolo[1,5-a]pyridine (220 mg, 0.47 mmol) produced in Example 30(x) in tetrahydrofuran (20 mL) and methanol (10 mL) was added 10% palladium-carbon (50% wet with water, 110 mg). Under a hydrogen atmosphere (1 atm), the mixture was stirred at room temperature for 31 hr, and 10% palladium-carbon was filtered off. The filtrate was concentrated under reduced pressure, the obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=50/50→100/0), and the obtained solution was concentrated under reduced pressure. The obtained residue was washed with tetrahydrofuran/ethyl acetate. The obtained crude product was dissolved in ethanol, and concentrated under reduced pressure. The obtained residue was crystallized from ethanol and ethyl acetate to give the title compound (68 mg, 38%) as a pale yellow-brown solid.
Reaction SMILES: [C:1]1([N:7]2[CH2:13][CH2:12][C:11]([CH2:14][CH2:15][O:16][Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:10][CH:9]([CH2:34][C:35]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:36])[C:8]2=[O:45])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:1]1([N:7]2[CH2:13][CH2:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]([CH2:34][C:35]([O:37][CH2:38][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)=[O:36])[C:8]2=[O:45])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)[Si](OCCC1=CC(CC(=O)OCc2ccccc2)C(=O)N(c2ccccc2)CC1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(CC1C=C(CCO)CCN(c2ccccc2)C1=O)OCc1ccccc1
Yield: 66.3 %

Procedure:
Compound (11) (388 mg, 0.628 mmol) was dissolved in tetrahydrofuran (3 mL) and treated at room temperature with 1.26 mL of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran for 4 h. The reaction mixture was then evaporated at reduced pressure and the residue purified by flash chromatography (silica gel, 2.5×20 cm, 65% ethyl acetate/hexane) to yield the title compound (12) (158 mg, 66%). Compound (12): 1H NMR (CDCl3) δ 1.77-3.27 (7H, m), 3.40-3.73 (1H, m), 3.67 (2H, t, J=6 Hz), 4.20-4.77 (2H, m), 5.07-5.40 (3H, m), 7.07-7.58 (10H, m); TLC Rf 0.33 (silica gel, 1:3 hexane:ethyl acetate).