Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[S:14]1[C:18]([CH:19]=O)=[CH:17][N:16]=[CH:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[S:14]1[C:18]([CH2:19][N:11]2[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]2)=[CH:17][N:16]=[CH:15]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1cncs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2cncs2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 51.1 %

Procedure:
N-Boc-piperazine (0.900 g, 4.86 mmol, 1.1 eq) was dissolved in 1,2-DCE (12 mL). To this solution, 5-thiazolecarboxaldehyde (0.500 g, 4.42 mmol, 1 eq) in 1,2-DCE (2 mL) was added followed by the portionwise addition of sodium triacetoxyborohydride (1.310 g, 6.19 mmol, 1.4 eq). The reaction mixture was stirred at room temperature for 17 h and then washed with a saturated aqueous solution of NaHCO3. The organic layer was dried (MgSO4), the solvent removed in vacuo and the crude product was purified by column chromatography on a Biotage SP1 system (DCM/EtOAc; v/v 1:1) to give the title compound as a light yellow oil (0.640 g, 51%); 1H-NMR (500 MHz, CDCl3): δ 1.46 (s, 9H, C(CH3)3), 2.43 (t, J=4.5 Hz, 4H, piperazine N(CH2)2), 3.44 (t, J=5.0 Hz, 4H, piperazine N(CH2)2), 3.77 (s, 2H, NCH2), 7.72 (s, 1H, thiazole 4-H), 8.76 (s, 1H, thiazole 2-H); LC (Method B)-MS (ESI, m/z): Rt=2.04 min—284 [(M+H)+, 100%].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5](=[N:7][OH:8])[NH2:6].[C:12](Cl)(=O)[CH3:13]>N1C=CC=CC=1>[CH3:12][C:13]1[O:8][N:7]=[C:5]([C:4]2[CH:3]=[C:2]([OH:1])[CH:11]=[CH:10][CH:9]=2)[N:6]=1
Reactant: NC(=NO)c1cccc(O)c1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: Cc1nc(-c2cccc(O)c2)no1

Procedure:
3-(5-Methyl-[1,2,4]oxadiazol-3-yl)-phenol was prepared using 3-hydroxybenzamidoxime (1 g, 6.6 mM) and acetyl chloride (0.52 g, 6.7 mM) in pyridine (4 mL) according to Preparation 62 to provide 0.66 g of a white powder; m.p., 87-89° C.
Reaction SMILES: C1([NH2+]C2CCCCC2)CCCCC1.[CH2:14]([O:21][C:22]([N:24]([CH3:37])[C@@H:25]([CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:26]([O-])=[O:27])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN(CC)CC.ClC(OCC(C)C)=O.[BH4-].[Na+]>C1COCC1.O>[CH2:14]([O:21][C:22]([N:24]([CH3:37])[C@H:25]([CH2:26][OH:27])[CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:34])[CH3:35])=[O:31])=[O:23])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CN(C(=O)OCc1ccccc1)[C@@H](CC(=O)OC(C)(C)C)C(=O)[O-]
Agent: C1CCC([NH2+]C2CCCCC2)CC1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)OCc1ccccc1)[C@H](CO)CC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
To a mixture of (S)-2-((benzyloxycarbonyl)(methyl)amino)-4-tert-butoxy-4-oxobutanoic acid dicyclohexylammonium salt (20 g, 0.0386 mol) and Et3N (7.90 mL, 0.0579 mol) in THF (500 mL) was added isobutyl chloroformate (6.05 mL, 0.0463 mol) at 0° C. The reaction mixture was stirred for 1 h, and filtered to remove TEA salt. To the filtrate was added a solution of NaBH4 (2.19 g, 0.0579 mol) in THF (50 mL) and water (100 mL) at 0-5° C. The reaction mixture was stirred at RT for 1 h and quenched with saturated NH4Cl solution. The reaction mixture was concentrated to remove most of THF and extracted with EtOAc (700 mL×3). The organic layers were washed with water, NaHCO3 and brine, dried over Na2SO4, and concentrated to give (S)-tert-butyl 3-((benzyloxycarbonyl)(methyl)amino)-4-hydroxybutanoate (10 g), which was used without further purification. LRMS (M+Na+) m/z 346.1.
Reaction SMILES: ClC1N=C(N[C@@H]2[C@@H]3C[C@@H](C=C3)[C@@H]2C(N)=O)C(Cl)=CN=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:37]=[CH:36][CH:35]=[CH:34][C:29]=2[C:30]([NH:32][CH3:33])=[O:31])[C:24]([Cl:38])=[CH:23][N:22]=1.COC1C(N)=CC2CCC(N3CCOCC3)CCC=2C=1.[CH3:59][O:60][C:61]1[CH:62]=[CH:63][C:64]2[CH2:70][CH2:69][CH:68]([N:71]3[CH2:76][CH2:75][O:74][CH2:73][CH2:72]3)[CH2:67][CH2:66][C:65]=2[C:77]=1[NH2:78]>>[Cl:38][C:24]1[C:25]([NH:27][C:28]2[CH:37]=[CH:36][CH:35]=[CH:34][C:29]=2[C:30]([NH:32][CH3:33])=[O:31])=[N:26][C:21]([NH:78][C:77]2[C:65]3[CH2:66][CH2:67][CH:68]([N:71]4[CH2:72][CH2:73][O:74][CH2:75][CH2:76]4)[CH2:69][CH2:70][C:64]=3[CH:63]=[CH:62][C:61]=2[O:60][CH3:59])=[N:22][CH:23]=1
Reactant: COc1ccc2c(c1N)CCC(N1CCOCC1)CC2
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: COc1cc2c(cc1N)CCC(N1CCOCC1)CC2
Agent: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Product: CNC(=O)c1ccccc1Nc1nc(Nc2c(OC)ccc3c2CCC(N2CCOCC2)CC3)ncc1Cl

Procedure:
Prepared in an analogous fashion to Example 1047 replacing (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide with 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide and 3-Methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine was replaced with 2-Methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-1-ylamine to afford 2-[5-Chloro-2-(2-methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-1-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide. LC/MS (ESI): 537.20. 1H NMR (400 MHz, DMSO, d6) δ 8.71 (m, 2H), 8.14 (m, 1H), 7.79 (m, 1H), 7.70 (m, 1H), 6.89 (m, 2H), 3.69 (s, 3H), 3.51 (m, 4H), 3.11 (m, 6H), 2.79 (m, 1H), 2.71 (s, 3H), 2.33 (m, 4H), 1.44 (m, 2H).
Reaction SMILES: [CH2:1]([NH:15][C:16]1[CH:17]=[C:18]([CH:22]([CH2:27][CH3:28])[C:23]([O:25][CH3:26])=[O:24])[CH:19]=[CH:20][CH:21]=1)[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[OH:29][CH2:30][CH:31](CO)[OH:32]>>[CH2:1]([NH:15][C:16]1[CH:17]=[C:18]([CH:22]([CH2:27][CH3:28])[C:23]([O:25][CH2:26][CH:31]([OH:32])[CH2:30][OH:29])=[O:24])[CH:19]=[CH:20][CH:21]=1)[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCC=CCCCNc1cccc(C(CC)C(=O)OC)c1
Reactant: OCC(O)CO
Product: CCCCCCCCCC=CCCCNc1cccc(C(CC)C(=O)OCC(O)CO)c1
Temperature: 180 °C

Procedure:
A mixture of 2.25 g. of methyl 3-(4-tetradecenylamino)phenylbutyrate, 280 mg. of glycerol, and 1.37 g. of p-touluenesulfonic acid is heated at 180° C. for 18 hours and then is partitioned between ether and 3% aqueous sodium carbonate solution. The ether layer is separated, dried, and evaporated to yield the product as a white solid.
Reaction SMILES: Br[CH:2]([CH3:26])[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)[S:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.Cl.[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH3:41])[CH2:36][NH:35][CH2:34][CH2:33]2>>[CH3:25][O:24][C:18]1[CH:17]=[C:16]([CH:7]([S:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:26][N:35]2[CH2:34][CH2:33][C:32]3[C:37](=[CH:38][C:39]([O:40][CH3:41])=[C:30]([O:29][CH3:28])[CH:31]=3)[CH2:36]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: COc1ccc(C(CCCCC(C)Br)Sc2ccc(C)cc2)cc1OC
Reactant: COc1cc2c(cc1OC)CNCC2
Agent: Cl
Product: COc1ccc(C(CCCCCCN2CCc3cc(OC)c(OC)cc3C2)Sc2ccc(C)cc2)cc1OC
Yield: 38 %

Procedure:
The procedure of Example 49 is repeated using 5.22 g of 4-[6-bromo-1-[(4-methylphenyl)thio]heptyl]-1,2-dimethoxybenzene, 3.29 g of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride. This affords 2.49 g of the desired product as a yellow gum.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][NH:6]1.C(=O)(O)[O-].[Na+].[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>ClCCl>[CH3:2][O:3][C:4](=[O:11])[C@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)[C@H]1C[C@@H](O)CN1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@H]1C[C@@H](O)CN1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
This ester was added in portions to a stirred mixture of 1500 mL of 1 N aqueous sodium bicarbonate and 500 mL of dichloromethane at 0-5° C., then 80 mL (97 g, 0.69 mol) of benzoyl chloride was added dropwise at 0-5° C., and the mixture was stirred at room temperature overnight. The phases were separated and the aqueous phase was extracted with dichloromethane (twice with 250 mL). The organic phases were combined, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was triturated with toluene to afford 112.98 g (90.7% from cis-4-hydroxy-D-proline) of N-benzoyl-cis-4-hydroxy-D-proline methyl ester as a white powder.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=1.C(OC(=O)C)(=[O:13])C>CC(O)=O>[CH:1]([C:2]1[S:3][C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=1)=[O:13]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nc2cnccc2s1
Solvent: CC(=O)O
Product: O=Cc1nc2cnccc2s1
Yield: 35.5 %

Procedure:
A mixture of 2-methylthiazolo[4,5-c]pyridine [prepared according to the procedure of T. Takahashi et al., Pharm. Bull. (Japan) 2, 196 (1954)] (635 mg, 4.2 mmoles), 2.55 g of SeO2, 10 ml of CH3COOH and 10 ml of acetic anhydride was heated at 90 100° C. for 2.5 hours, and the reaction mixture then was filtered to remove insolubles. The filtrate was evaporated in vacuo, and purified by a column of SiO2 (50 ml) to give 248 mg (35.5%) of the title compound. Mp. 96.5°~98° C.
Reaction SMILES: [OH:1][C:2]1[C:7]2[O:8][CH:9]([CH2:12][OH:13])[CH2:10][O:11][C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:16]I>O>[CH3:16][O:1][C:2]1[C:7]2[O:8][CH:9]([CH2:12][OH:13])[CH2:10][O:11][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: OCC1COc2cccc(O)c2O1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cccc2c1OC(CO)CO2
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A mixture of 8-hydroxy-1,4-benzodioxan-2-ylmethanol (10 g--prepared in a similar manner to that described in U.S. Pat. No. 3,101,354), sodium hydroxide (2.2 g) and water (150 ml) was stirred for 30 minutes, then cooled to 0° C. Methyl iodide (3.42 ml) was added dropwise, then the mixture was heated to 80° C. and stirred for 4 hours. The mixture was cooled to ambient temperature and stirred for 16 hours. The product was extracted into ethyl acetate (2×200 ml), and the combined extracts were washed with saturated sodium thiosulphate solution (2×200 ml), dried over magnesium sulphate, and the solvent removed in vacuo to yield 1-(8-methoxy-1,4-benzodioxan-2-yl)methanol as a solid (6.89 g)
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH2:4]O.[C:7]([O-:13])([O-])([O:9][CH2:10][CH3:11])[CH3:8]>C(O)C>[CH3:1][C:2]([CH3:6])([CH:3]=[CH2:4])[CH2:8][C:7]([O:9][CH2:10][CH3:11])=[O:13]
Reactant: CC(C)=CCO
Reactant: CCOC(C)([O-])[O-]
Solvent: CCO
Product: C=CC(C)(C)CC(=O)OCC
Yield: 51.7 %

Procedure:
A mixture of 4.3 g of 3-methyl-2-buten-1-ol and 8.1 g of ethyl orthoacetate was heated with stirring. The temperature was increased slowly from room temperature to 165° over 2 hours, during which 2.21 g of ethanol was collected. The temperature was maintained at 165° for 26 hours, during which time an additional 1.52 g of ethanol was collected. The reaction mixture was then allowed to cool and diluted with diethyl ether. The ether solution was washed successively with dilute hydrochloric acid, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The washed solution was dried over magnesium sulfate and distilled to give 4.03 g (52% yield) of ethyl 3,3-dimethyl-4-pentenoate, b.p. 80°-85°/52 mm.
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3C[CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])[CH:5]=1.C1(C2C3C=CC=CC=3N(CC(C3CCCC3)=O)C(=O)N(CC(O)=O)N=2)CCCCC1.NC1C=C(N(C)[C:78]2[N:79]=[N:80][N:81]([CH2:83][O:84][C:85](=[O:90])[C:86]([CH3:89])([CH3:88])[CH3:87])[N:82]=2)C=CC=1.C1(C2C3C=CC=CC=3N(CC(=O)C(C)(C)C)C(=O)N(CC(O)=O)N=2)CCCCC1.COC(=O)C1C=CC=C(N)C=1>>[CH:20]1([C:18]2[C:17]3[CH:16]=[CH:29][CH:28]=[CH:27][C:26]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:33])([CH3:35])[CH3:34])[C:14](=[O:37])[N:13]([CH2:12][C:11]([NH:10][C:6]3[CH:5]=[C:4]([C:78]4[N:79]=[N:80][N:81]([CH2:83][O:84][C:85](=[O:90])[C:86]([CH3:88])([CH3:87])[CH3:89])[N:82]=4)[CH:9]=[CH:8][CH:7]=3)=[O:38])[N:19]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CN(c1cccc(N)c1)c1nnn(COC(=O)C(C)(C)C)n1
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Agent: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)O)N=C(C2CCCCC2)c2ccccc21
Agent: COC(=O)c1cccc(N)c1
Agent: O=C(O)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C2CCCC2)C1=O
Product: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)Nc2cccc(-c3nnn(COC(=O)C(C)(C)C)n3)c2)N=C(C2CCCC2)c2ccccc21

Procedure:
The title compound was obtained by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1), except that [5-cyclohexyl-1-(2-cyclopentyl-2-oxo-ethyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 22, step a) and 2,2-dimethyl-propionic acid 5-[(3-amino-phenyl)-methyl-amino]-tetrazol-2-ylmethyl ester were used in place of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 1, step d) and 3-amino-benzoic acid methyl ester respectively in step e, followed by reaction of the product obtained, in place of 2,2-dimethyl-propionic acid 5-(3-{2-[5-cyclopentyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-phenyl)-tetrazol-2-ylmethyl ester (Example 10, step a), according to the method of Example 10, step b. 1H NMR (DMSO-d6) 9.85 (1H, s), 7.56-7.48 (3H, m), 7.30-7.20 (3H, m), 7.15 (1H, d), 7.06 (1H, d), 7.00 (1H, br m), 6.65 (1H, br m), 4.65 (2H, br m), 4.25 (1H, br d), 3.95 (1H, br d), 3.40 (3H, s), 3.05-2.85 (2H, m), 1.90-1.40 (9H, m), 1.40-0.95 (9H, m). The compound was further characterised as the N-methyl-D-glucamine salt. Found: C, 56.42; H, 7.05; N, 16.27%; C31H37N9O3.C7H17NO5.1.5CH3CO2H requires C, 56.67; H, 6.96; N, 16.12%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][CH:10]=[CH2:11])=[CH:7][CH:6]=[CH:5][C:4]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19].[OH-].[K+]>CO>[CH3:1][O:2][C:3]1[C:8]([CH:9]=[CH:10][CH3:11])=[CH:7][CH:6]=[CH:5][C:4]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19]
Reactant: C=CCc1cccc(Oc2ccccc2Cl)c1OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC=Cc1cccc(Oc2ccccc2Cl)c1OC
Yield: 90.2 %

Procedure:
2-Chlorophenyl 2-methoxy-3-allylphenyl ether (21.50 g) was added to methanol (100 ml) saturated with potassium hydroxide, and the mixture was treated in a similar manner to that of Example 3-(2) and recrystallized from methanol to give colorless crystals of 2-chlorophenyl 2-methoxy-3-(1-propenyl)phenyl ether (19.40 g). mp 61°-62° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]#[C:11][C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([N+:21]([O-])=O)[CH:19]=2)[NH:14][N:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(OCC)(=O)C.CCO.[Pd]>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([NH2:21])[CH:19]=2)[NH:14][N:13]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCC#Cc1n[nH]c2ncc([N+](=O)[O-])cc12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCCCc1n[nH]c2ncc(N)cc12
Reaction time: 8 h
Yield: 57.1 %

Procedure:
10% (wt.) Pd on activated carbon (0.017 g, 0.016 mmol) was added to a solution of 3-(3-(tert-butyldimethylsilyloxy)prop-1-ynyl)-5-nitro-1H-pyrazolo[3,4-b]pyridine (0.053 g, 0.160 mmol) in a mixture of ethyl acetate/EtOH (1:1, 6 mL). The reaction mixture was purged with nitrogen for 5 minutes and then stirred under a hydrogen balloon overnight. The reaction mixture was filtered through GF/F paper. The filter cake was rinsed with ethyl acetate, and the filtrate was concentrated. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (2:1), hexanes/ethyl acetate (1:1) to give 3-(3-(tert-butyldimethylsilyloxy)propyl)-1H-pyrazolo[3,4-b]pyridin-5-amine (0.028 g, 57%) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:47]=[CH:46][C:45]([S:48]([N:51]2[CH2:56][CH2:55][O:54][CH2:53][CH2:52]2)(=[O:50])=[O:49])=[CH:44][CH:43]=1>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:47]=[CH:46][C:45]([S:48]([N:51]6[CH2:52][CH2:53][O:54][CH2:55][CH2:56]6)(=[O:49])=[O:50])=[CH:44][CH:43]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: O=S(=O)(c1ccc(Br)cc1)N1CCOCC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(S(=O)(=O)N4CCOCC4)cc3)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (44 mg) and 4-(4-bromo-benzenesulfonyl)-morpholine (prepared from 4-bromobenzenesulfonyl chloride, morpholine and pyridine in acetonitrile, 51 mg) instead of 4-bromobenzoic acid methyl ester in Example 1-D-08, in the same manner as Example 1-D-08, a crude product of bis-(4-methoxy-benzyl)-(5-{7-[4-(morpholine-4-sulfonyl)-phenyl]-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}-pyrimidin-2-yl)-amine was obtained, and then the PMB groups were removed according to the above Deprotection method 1, to obtain the desired compound (D-87) as a yellow powder (53 mg, 68%).
Reaction SMILES: [O-]Cl.[Na+].CS.C(=O)C.[CH3:9][CH:10]([CH3:22])[C:11]([O:13][CH:14]([O:18][C:19]([CH3:21])=[S:20])[CH:15](C)C)=[O:12]>P([O-])([O-])([O-])=O>[CH3:21][C:19]([O:18][C@H:14]([O:13][C:11](=[O:12])[CH:10]([CH3:22])[CH3:9])[CH3:15])=[S:20]
Reactant: CC(=S)OC(OC(=O)C(C)C)C(C)C
Agent: CC=O
Agent: CS
Agent: O=P([O-])([O-])[O-]
Product: CC(=S)O[C@@H](C)OC(=O)C(C)C

Procedure:
A 20-L, multi-necked, cylindrical reactor, fitted with a mechanical stirrer, a nitrogen inlet and an outlet connected to an oxidation bath, and a bleach bath (14% NaOCl) to oxidize librated methanethiol and acetaldehyde is charged with racemic 2-methyl-1-methylthiocarbonyloxypropyl 2-methylpropanoate (2b) (5.32 kg, 25.8 mol) and 0.8 M phosphate buffer (10 L, pH 7.0). Solid supported Candida antarctica lipase A (125 g, NOVOZYME® 735, NOVOZYME®; CHIRAZYME™ L-5, Roche Diagnostics; or other suppliers) is slowly added while stirred. The reaction mixture is stirred at room temperature (22-24° C.) for ca. 18 hours.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[NH2:27][C:28]1[CH:41]=[CH:40][C:31]([CH2:32][CH:33]2[S:37][C:36](=[O:38])[NH:35][C:34]2=[O:39])=[CH:30][CH:29]=1.N1CCCCC1.CCO.O>CN(C=O)C>[O:38]=[C:36]1[NH:35][C:34](=[O:39])[CH:33]([CH2:32][C:31]2[CH:30]=[CH:29][C:28]([NH:27]/[C:16](=[C:6]3\[C:5](=[O:26])[NH:4][C:12]4[C:7]\3=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=4)/[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:41][CH:40]=2)[S:37]1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: Nc1ccc(CC2SC(=O)NC2=O)cc1
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Solvent: O
Product: O=C1NC(=O)C(Cc2ccc(N/C(=C3\C(=O)Nc4ccc([N+](=O)[O-])cc43)c3ccccc3)cc2)S1

Procedure:
Prepared by reacting 1-acetyl-3-{1-ethoxy-1-phenylmethylidene}-5-nitro-2-indolinone with 1.2 equivalents of 5-(4-amino-benzyl)-thiazolidin-2,4-dione in DMF (120° C., 1 hour), subsequent treatment with 6.7 equivalents of piperidine (20° C., 1 hour), evaporation in vacuo and trituration with EtOH/water (1:1).
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([CH3:13])=[C:8]([C:10]([OH:12])=O)[CH:9]=1)=[O:4].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[CH3:47][O:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]2[CH:60]=[CH:59][C:58]([NH2:61])=[CH:57][CH:56]=2)=[CH:51][CH:50]=1>CN(C)C=O.C(OCC)(=O)C>[CH3:47][O:48][C:49]1[CH:50]=[CH:51][C:52]([C:55]2[CH:60]=[CH:59][C:58]([NH:61][C:10]([C:8]3[CH:9]=[C:5]([C:3]([OH:2])=[O:4])[O:6][C:7]=3[CH3:13])=[O:12])=[CH:57][CH:56]=2)=[CH:53][CH:54]=1
Reactant: COc1ccc(-c2ccc(N)cc2)cc1
Reactant: COC(=O)c1cc(C(=O)O)c(C)o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc(NC(=O)c3cc(C(=O)O)oc3C)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.4 %

Procedure:
To a solution of 5-methyl-furan-2,4-dicarboxylic acid-2-methyl ester (23) (100 mg) in N,N-dimethylformamide (3.0 mL) was added O—(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (228 mg), diisopropylethylamine (0.56 mL) and 4′-methoxy-biphenyl-4-ylamine (120 mg). The resulting solution was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate (20 mL) and washed successively with water (2×20 mL), 0.1M hydrochloric acid (20 mL), water (20 mL), saturated sodium hydrogen carbonate (10 mL) and brine (10 mL). This solution was dried and concentrated in vacuo. The residue (170 mg) was dissolved in dichloromethane (5 mL), treated with triethylamine (0.3 mL) and a scavenger resin PS-TsCl (0.6 g) and the mixture shaken for 3 hours at room temperature. The reaction mixture was filtered and concentrated in-vacuo. The residue was dissolved in methanol/tetrahydrofuran (1:3 by volume) (20 mL), treated with 1.0 M aqueous lithium hydroxide solution (2.0 mL) and allowed to stir at room temperature for 4 hours. The pH of the reaction mixture was adjusted to between pH 4 and pH 5 by careful addition of 1.0 M hydrochloric acid (1.0 mL) and partly concentrated in vacuo. The residue was then partitioned between ethyl acetate (2×25 mL) and water (25 mL) and the combined organic extracts were washed with brine (35 mL), dried (Na2SO4), and concentrated in vacuo afforded compound 24 as beige solid (58 mg). LC/MS System D: Rt=7.23 mins, m/z (ES+)=351 (MH+ for C20H17NO5).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:10]([P:13](Cl)(Cl)=[O:14])([CH3:12])[CH3:11]>CC1CCCCC1>[CH:10]([P:13]1(=[O:14])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][N:2]1[CH3:1])([CH3:12])[CH3:11]
Reactant: CC(C)P(=O)(Cl)Cl
Reactant: CNCc1ccccc1
Solvent: CC1CCCCC1
Product: CC(C)P1(=O)c2ccccc2CN1C

Procedure:
The procedure of Example 30 was employed utilizing N-methyl-N-benzylamine and isopropyl phosphonic dichloride. The reaction of the dilithio compound and the isopropyl phosphonic dichloride was conducted at -72° C. The crude product produced as a result of the chromatographic separation was slurried in methylcyclohexane to yield a pale solid. The solid was recrystallized from diethyl ether and petroleum ether to yield 1-isopropyl-2-methyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide as a crystalline precipitate. A second crop was obtained to give a total yield of 2.35 g (19% yield) of 1-isopropyl-2-methyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide having a melting point of 72°-74° C. and the following analysis: