Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(N[C@@H:12]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)[C:13]([NH:15][C@@H:16]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]([OH:19])=O)=[O:14])=O)C1C=CC=CC=1.[CH3:32][O:33][C:34](=[O:42])[C@@H:35]([NH2:41])[CH2:36][CH2:37][CH2:38][CH2:39][OH:40].[CH3:43]N(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH3:32][O:33][C:34](=[O:42])[C@@H:35]([NH:41][C:17](=[O:19])[C@@H:16]([NH:15][C:13](=[O:14])[C@@H:12]([CH3:43])[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([OH:31])=[CH:29][CH:30]=1)[CH2:20][CH:21]([CH3:22])[CH3:23])[CH2:36][CH2:37][CH2:38][CH2:39][OH:40]
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)CCCCO
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CCCCO)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](C)Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.6 %

Procedure:
To a suspension of (S)-2-[(S)-2-benzyloxycarbonylamino-3-(4-hydroxy-phenyl)-propionylamino]-4-methyl pentanoic acid (Bachem) (5.44 mmol, 1.36 g, 1 eq) and methyl ester 82 (5.44 mmol, 0.91 g) in DMF was added HATU (5.98 mmol, 1.41 g, 1.1 eq). DIPEA (0.12 mol, 1.62 g, 2.1 eq) was added and the reaction mixture was stirred at room temperature overnight. EtOAc (l 00 mL) was added the mixture was washed with 1M hydrochloric acid, saturated aqueous NaHCO3 and brine. The organic layer was dried over MgSO4 and the solvent was removed in vacuo. The crude product was purified by recrystallisation from EtOAc to provide diol 83 as an oil (2.39 g, 76%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:10][CH2:11][S:12](Cl)(=[O:14])=[O:13].C(N(CC)CC)C.Cl>C1(C)C=CC=CC=1>[Cl:10][CH2:11][S:12]([NH:4][C:3]1[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:2]=1[Cl:1])(=[O:14])=[O:13]
Reactant: Nc1ccc(F)cc1Cl
Reactant: O=S(=O)(Cl)CCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=S(=O)(CCl)Nc1ccc(F)cc1Cl
Temperature: 7.5 °C
Yield: 75 %

Procedure:
72.8 g (0.5 mol) of 2-chloro-4-fluoroaniline were dissolved in 400 mL of toluene and cooled to 5-10° C., and then 79 g (0.53 mol) of chloromethylsulfonyl chloride were added slowly with stirring. The temperature was kept below 10-15° C. The mixture was then heated to 40° C. for 30 minutes and cooled again to 5-10° C. At this temperature, 101 g (1 mol) of triethylamine was added with stirring and cooling. After the addition was complete, the mixture was stirred at 40° C. for an additional 8 hours and then poured into 1050 mL of 6 N hydrochloric acid. The organic phase was separated and the aqueous phase was washed with toluene. The combined organic phases were poured with vigorous stirring into 12.5% sodium hydroxide solution. The basic aqueous phase was separated and the organic phase was washed with aqueous sodium hydroxide solution. The combined aqueous phases were treated with active carbon and filtered. 6 N hydrochloric acid was added with cooling until the pH was below 7. The precipitated product was filtered off, washed with water and dried to yield 96.8 g (75%) of the title compound as a solid melting at 83-85° C.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.N1C=CC=CC=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][O:33][C:34](Cl)=[O:35])=[C:27]([N+:37]([O-:39])=[O:38])[CH:26]=1.CC(O)C.N#N>C(Cl)Cl>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][O:33][C:34]([O:7][CH2:6][C@H:5]2[O:8][C@@H:1]([N:9]3[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]3=[O:11])[CH2:2][C@@H:3]2[OH:4])=[O:35])=[C:27]([N+:37]([O-:39])=[O:38])[CH:26]=1
Reactant: O=C(Cl)OCCc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: N#N
Solvent: CC(C)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](COC(=O)OCCc3ccc(Cl)cc3[N+](=O)[O-])O2)c(=O)[nH]c1=O
Temperature: -30 °C
Reaction time: 0.08 h
Yield: 75.2 %

Procedure:
Thymidine (150 mg, 0.62 mmol) was co-evaporated with pyridine (2×5 ml, pro analysi quality, additionally dried over molecular sieve 4 Å), dissolved in pyridine and cooled to -30° C. A solution of 2-(4-chloro-2-nitrophenyl)ethoxycarbonyl chloride (255 mg, 0.97 mmol) in CH2Cl2 (3 ml, dist. over CaH2) was added dropwise thereto for 5 min. After being stirred for 4 h in conditions of i-PrOH/N2 cooling (-30° to -15° C.), the mixture was diluted with CH2Cl2 (30 ml) and washed with H2O (30 ml). The aqueous phase was post-extracted with CH2Cl2 (2×30 ml). The combined organic phases were dried over MgSO4, filtered and co-evaporated with toluene (4×10 ml) and CH2Cl2 (20 ml). The crude product was purified by column chromatography (SiO2 15×3 cm, solvent: CH2Cl2 /MeOH 100:7 700 ml). 5'-O-(2-(4-chloro-2-nitrophenyl)ethoxycarbonyl)thymidine (219 mg, 75% ) was obtained as a colorless solid.
Reaction SMILES: C1[O:15][C:4]([CH3:14])([CH2:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]=O)=[CH:8][CH:7]=2)OC1.[C:16]([C:21](=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:22])([O:18][CH2:19][CH3:20])=[O:17]>O1CCCC1>[C:16]([C:21]([CH3:22])=[CH:12][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][C:4](=[O:15])[CH3:14])=[CH:11][CH:10]=1)([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC1(Cc2ccc(C=O)cc2)OCCO1
Solvent: C1CCOC1
Product: CCOC(=O)C(C)=Cc1ccc(CC(C)=O)cc1

Procedure:
A mixture of 4-formylphenylpropan-2-one-2-ethylene acetal (3.11 g) and 1-carboethoxyethylidenetriphenylphosphorane (5.47 g) was refluxed in tetrahydrofuran under nitrogen for 1 h. The solvent was evaporated and the residue chromatographed on alumina (200 g). Elution with dichloromethane gave the title compound as the ethylene acetal (1.7 g). This was dissolved in ethanol-2 N hydrochloric acid and stirred at ambient temperature until tlc showed no acetal present. The aqueous was extracted with ether (3×50 ml) and the combined ether layers washed with water (×2), sodium bicarbonate solution, and dried (MgSO4). Removal of the solvent gave the title compound (1.05 g). τ(CDCl3) 8.7 (3H, t, 3=7 Hz), 7.92 (3H, s), 7.9 (3H, s), 6.35 (2H, s), 5.8 (2H, q, J=7 Hz), 2.8 (2H, d, J=8 Hz), 2.6 (2H, d, J=8 Hz), 2.35 (1H, broad s).
Reaction SMILES: [ClH:1].[N:2]1([CH:7]2[CH2:11][CH2:10][NH:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH2:12]([C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>C(Cl)Cl.C(N(CC)CC)C>[ClH:1].[CH2:12]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([N:9]2[CH2:10][CH2:11][C@H:7]([N:2]3[CH2:6][CH2:5][CH2:4][CH2:3]3)[CH2:8]2)=[O:24])=[CH:26][CH:27]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C1CCN(C2CCNC2)C1
Reactant: O=C(O)c1ccc(Cc2ccccc2)cc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Cc2ccccc2)cc1)N1CC[C@H](N2CCCC2)C1
Reaction time: 16 h

Procedure:
A mixture of the HCl salt of 3-(pyrrolidino)pyrrolidine (0.44 g, 2.1 mmol) and 4-benzyl benzoic acid (0.34 g, 1.6 mmol) CH2Cl2 is treated sequentially at room temperature with 0.85 mL of triethylamine and solid benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (1.2 g, 2.4 mmol), stirred for 16 h under nitrogen, diluted with CH2Cl2, washed sequentially with water and brine, dried over MgSO4 and concentrated in vacuo. The concentrate is chromatographically purified. The purified material is treated with ethereal HCl to afford the title compound, identified by H1 NMR and mass spectral analyses.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1/[CH:18]=[CH:19]/[C:20]1[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][N:21]=1)[C:5]2=[O:29].[CH:30](=O)[CH3:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C1COCC1>[CH2:30]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1/[CH:18]=[CH:19]/[C:20]1[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][N:21]=1)[C:5]2=[O:29])[CH3:31]
Reactant: CC=O
Reactant: Nc1ccc2c(c1)C(=O)N(c1ccccc1/C=C/c1n[nH]c3ccccc13)C2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCNc1ccc2c(c1)C(=O)N(c1ccccc1/C=C/c1n[nH]c3ccccc13)C2=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 35.6 %

Procedure:
To a solution of (E)-5-amino-2-{2-[2-(1H-indazol-3-yl)vinyl]phenyl}isoindole-1,3-dione (40 mg, 0.11 mmol) obtained in Example 193 in THF (1.0 mL), acetaldehyde (5.2 μL, 0.12 mmol) and sodium triacetoxyborohydride (33 mg, 0.16 mmol) were added and stirred at room temperature for 2.5 hours. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate solution, extracted with ethyl acetate and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform to chloroform/methanol=90/10) to obtain Compound 201 (16 mg, 38%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH2:11][C:12]([OH:14])=[O:13].[CH2:15](O)[CH3:16]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O=C(O)Cc1n[nH]c2ccc(F)cc12
Reactant: CCO
Product: CCOC(=O)Cc1n[nH]c2ccc(F)cc12
Yield: 37.4 %

Procedure:
2-(5-Fluoro-1H-indazol-3-yl)acetic acid (1.12 g, 5.77 mmol) was dissolved in anhydrous ethanol (50 mL) concentrated sulfuric acid (1.5 mL), and heated under reflux for 16 hours. After concentrated under reduce pressure to remove most of ethanol, water (20 mL) was added, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and concentrated to obtain the product 0.48 g, at a yield of 37.4%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=2)[N:5]=[C:4]([NH2:16])[N:3]=1.[NH2:17][C:18]1[N:22]([CH3:23])[N:21]=[C:20]([CH2:24][CH2:25][CH3:26])[C:19]=1[C:27]([NH2:29])=[O:28]>>[NH2:16][C:4]1[N:3]=[C:2]([NH:17][C:18]2[N:22]([CH3:23])[N:21]=[C:20]([CH2:24][CH2:25][CH3:26])[C:19]=2[C:27]([NH2:29])=[O:28])[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=2)[N:5]=1.[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([S:14][CH3:15])=[CH:12][CH:13]=2)[N:5]=[C:4]([NH2:16])[N:3]=1
Reactant: CCCc1nn(C)c(N)c1C(N)=O
Agent: CSc1ccc(-c2cc(Cl)nc(N)n2)cc1
Product: CCCc1nn(C)c(Nc2cc(-c3ccc(SC)cc3)nc(N)n2)c1C(N)=O

Procedure:
5-[2-Amino-6-(4-methylsulfanylphenyl)pyrimidin-4-ylamino]-1-methyl-3-propyl-1H-pyrazole-4-carboxylic acid amide was prepared by treating 4-chloro-6-(4-methylsulfanylphenyl)pyrimidin-2-ylamine with 5-amino-1-methyl-3-propyl-1H-pyrazole-4-carboxylic acid amide according to the procedure described in step (iv) of Example 1. 4-Chloro-6-(4-methylsulfanylphenyl)pyrimidin-2-ylamine was prepared according to the procedure as described in Example 1 (Steps i-iii) using 4-methylsulfanylacetophenone in place of 4-methoxyacetophenone.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18](=[O:32])[N:19]([CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[CH:20]=[N:21]2)=[CH:16][C:15]=1[O:33][CH3:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:54][O:55][CH2:56][CH2:57][O:58][CH2:59][CH2:60]O>C(Cl)Cl>[CH3:34][O:33][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:14]=1[O:13][CH2:60][CH2:59][O:58][CH2:57][CH2:56][O:55][CH3:54])[N:21]=[CH:20][N:19]([CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:28])([CH3:29])[CH3:30])[C:18]2=[O:32]
Reactant: COCCOCCO
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COCCOCCOc1cc2ncn(COC(=O)C(C)(C)C)c(=O)c2cc1OC
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 106.7 %

Procedure:
Diethyl azodicarboxylate (864 μl, 5.5 mmol) was added dropwise to a mixture of 7-hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (1.2 g, 3.9 mmol) (prepared as described for the starting material in Example 12), triphenylphosphine (1.44 g, 5.5 mmol) and 2-(2-methoxyethoxy)ethanol (653 μl, 5.5 mmol) in methylene chloride (70 ml) cooled at 0° C. The mixture was stirred for 1.5 hours at ambient temperature and the solvent was removed by evaporation. The residue was purified by column chromatography eluting with a mixture of ethyl acetate/methylene chloride (50/50 followed by 80/20). The purified solid was suspended in ether, collected by filtration and dried under vacuum to give 6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (1.70 g, 100%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH2:16])=[N:14][CH:13]=[C:12](Br)[N:11]=2)=[O:9])=[CH:3][CH:2]=1.CC1(C)C(C)(C)OB([C:26]2[S:30][C:29]([CH2:31][N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:28][CH:27]=2)O1>>[N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH2:16])=[N:14][CH:13]=[C:12]([C:26]3[S:30][C:29]([CH2:31][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:28][CH:27]=3)[N:11]=2)=[O:9])=[CH:3][CH:2]=1
Reactant: CC1(C)OB(c2ccc(CN3CCCCC3)s2)OC1(C)C
Reactant: Nc1ncc(Br)nc1C(=O)Nc1ccncc1
Product: Nc1ncc(-c2ccc(CN3CCCCC3)s2)nc1C(=O)Nc1ccncc1

Procedure:
The reaction of 3-amino-6-bromo-pyrazine-2-carboxylic acid pyridin-4-ylamide (synthesis described for “A10”) with 1-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiophen-2-ylmethyl]-piperidine gives the compound “A13”;
Reaction SMILES: N[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH2:6]2.S(=O)(=O)(O)[OH:12].N([O-])=O.[Na+].NC(N)=O>O>[OH:12][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH2:6]2
Reactant: O=S(=O)(O)O
Reactant: Nc1cccc2c1CCC2
Agent: NC(N)=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Oc1cccc2c1CCC2
Temperature: 5 °C
Reaction time: 0.08 h

Procedure:
4-Aminoindan (3.0 g) was added to a solution of concentrated sulphuric acid (2.4 mL) in water (15 mL). More water (15 mL) was added and the mixture cooled to 5° C. A solution of sodium nitrite (1.71 g) in water (4.5 mL) was added portionwise to the mixture while maintaining the temperature below 5° C. After addition was complete the mixture was allowed to warm to room temperature and urea (0.29 g) was added. The mixture was stirred for a further 5 minutes before being heated at 45° C. for 30 minutes. The mixture was then cooled to room temperature and extracted with ethyl acetate. The combined organic extracts were washed with 2M aqueous sodium hydroxide (2×100 mL) and these aqueous extracts were then acidified with hydrochloric acid and extracted with ethyl acetate (3×100 mL). The combined organic extracts were then washed with brine and dried (Na2SO4) before being concentrated in vacuo. The resulting crude product was chromatographed over silica gel. Elution with ethyl acetate/hexanes (1:7) gave 4-hydroxyindan as an orange oil (1.0 g).
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:11]([CH:20]=[CH2:21])[C@H:10]([CH2:22][OH:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Si:24](Cl)([C:37]([CH3:40])([CH3:39])[CH3:38])([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.N1C=CN=C1>ClCCl>[C:1]([O:5][C:6]([C@@H:8]1[N:12]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C@H:11]([CH:20]=[CH2:21])[C@H:10]([CH2:22][O:23][Si:24]([C:37]([CH3:40])([CH3:39])[CH3:38])([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: C=C[C@@H]1[C@H](CO)C[C@H](C(=O)OC(C)(C)C)N1Cc1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C=C[C@@H]1[C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C[C@H](C(=O)OC(C)(C)C)N1Cc1ccccc1
Yield: 98 %

Procedure:
(±)-(2R,3R,5R)-1-Benzyl-2-vinyl-3-hydroxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester (30.8 g, 97.1 mmol) was reacted with t-butyldiphenylsilyl chloride (49.5 mL, 190.4 mmol) and imidazole in dichloromethane (650 mL) at 0° C. for 1 hour. The reaction was quenched methanol followed by extraction with dichloromethane (600 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 2/1: chloroform/hexane to provide the title compound (yield: 52.9 g, 98%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[NH:35][N:34]=[N:33][N:32]=2)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:24][C:25]4[CH:30]=[CH:29][C:28]([C:31]5[NH:35][N:34]=[N:33][N:32]=5)=[CH:27][CH:26]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: Oc1ccc(-c2nnn[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc(-c5nnn[nH]5)cc4)ncnc32)CC1
Yield: 12.7 %

Procedure:
4-{4-[4-(1H-Tetrazol-5-yl)-phenoxy]-pyrazolo[3,4-d]pyrimidin-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (5.3 mg, 13%) was prepared using the procedure described for the preparation of Example 41 by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 30 mg, 0.09 mmol) with 5-(4-hydroxyphenyl)tetrazole (Biofine International Inc., Blaine, Wash., USA; 15 mg, 0.09 mmol) in the presence of potassium carbonate (27 mg, 0.195 mmol).
Reaction SMILES: [CH:1]1([OH:5])[CH2:4][CH2:3][CH2:2]1.[C:6](Cl)(Cl)=[O:7].[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]([CH3:24])[CH2:19][C:20](=[O:23])[NH:21][N:22]=2)=[CH:13][CH:12]=1.O1CCCC1>CCOCC>[CH:1]1([O:5][C:6]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]([CH3:24])[CH2:19][C:20](=[O:23])[NH:21][N:22]=3)=[CH:13][CH:12]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)Cl
Reactant: OC1CCC1
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1CC(=O)NN=C1c1ccc(NC(=O)OC2CCC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.5 %

Procedure:
5.0 g (69.3 millimoles) of cyclobutanol, dissolved in 80 ml of absolute ether, are added dropwise to a stirred solution of 11.5 g (116.3 millimoles) of phosgene in 100 ml of absolute ether at 10°-15° C. The reaction solution is then stirred for 3 hours at room temperature. Thereafter, the excess phosgene is removed by means of a dry stream of nitrogen, and the ether is then removed under reduced pressure at room temperature. The cyclobutyl chloroformate which remains in mixed with 6.0 g (29.5 millimoles) of 6-(p-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone and 180 ml of absolute tetrahydrofuran and the mixture is kept for 20 hours at room temperature and then for 4 hours at 40°-45° C. The product is filtered off at 10° C., washed first with tetrahydrofuran and then with water, and recrystallized from dimethylformamide/water. 2.8 g (31% of theory) of 6-(p-cyclobutoxycarbonylaminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone are obtained as colorless crystals, of melting point 245°-246° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:11])=[CH:9][C:8](=[O:12])[C:4]([C:5]([OH:7])=[O:6])=[C:3]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+:20]>CO>[CH3:1][N:2]1[C:10]([CH3:11])=[CH:9][C:8](=[O:12])[C:4]([C:5]([O-:7])=[O:6])=[C:3]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Na+:20]
Reactant: Cc1cc(=O)c(C(=O)O)c(-c2ccccc2)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(=O)c(C(=O)[O-])c(-c2ccccc2)n1C

Procedure:
1.69 gms of 1,6-dimethyl-2-phenyl-4-oxonicotinic acid is suspended in approximately 50 mls of methanol. NaOH pellets (0.305 gms) are added with stirring. After both the acid and the sodium hydroxide dissolve the solution is evaporated to dryness in vacuo. Sodium 1,6-dimethyl-2-phenyl-4-oxonicotinate is then isolated as a glossy, somewhat hydroscopic solid. Yield=1.6 gms.
Reaction SMILES: N[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:8]2=[O:11])=[CH:4][CH:3]=1.CC1C=C([N+:29]([O-])=O)C=CC=1C(O)=O>>[NH2:29][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:2]=1)[C:8](=[O:11])[N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6]2
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(N)cc2C1=O
Reactant: Cc1cc([N+](=O)[O-])ccc1C(=O)O
Product: CC(C)(C)OC(=O)N1Cc2cc(N)ccc2C1=O

Procedure:
tert-Butyl 5-amino-1-oxoisoindoline-2-carboxylate was prepared following the same procedure used for the preparation of tert-butyl 6-amino-1-oxoisoindoline-2-carboxylate using 2-methyl-4-nitrobenzoic acid as starting material.
Reaction SMILES: [F:1][C:2]1[C:15]([N:16]2[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[NH:18][C:17]2=[O:27])=[CH:14][C:5]2[N:6]([CH:10]([CH2:12][CH3:13])[CH3:11])[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.[H-].[Na+].[N+:30](C1C=C([N+]([O-])=O)C=CC=1ON)([O-])=O.O>CN(C)C=O>[F:1][C:2]1[C:15]([N:16]2[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:24])([F:25])[F:26])[N:18]([NH2:30])[C:17]2=[O:27])=[CH:14][C:5]2[N:6]([CH:10]([CH2:12][CH3:13])[CH3:11])[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1
Reactant: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CCC(C)n1c(=O)sc2cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(C)n1c(=O)sc2cc(F)c(-n3c(=O)cc(C(F)(F)F)n(N)c3=O)cc21
Yield: 19.3 %

Procedure:
To a solution of 1-[6-fluoro-3-sec-butyl-2(3H)-benzothiazolon-5-yl]-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidine-2,6-dione (2.0 g) in dimethylformamide (10 g), sodium hydride (0.3 g) and 2,4-dinitrophenoxyamine (1.8 g) were added, and the resultant mixture was heated at 40 to 60° C. for 3 hours. After completion of the reaction, the reaction mixture was poured into water, extracted with ethyl acetate and concentrated. The residue was purified by silica gel column chromatography to give 1-[6-fluoro-3-sec-butyl-2(3H)-benzothiazolon-5-yl]-3-amino-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidine-2,6-dione (0.4 g).
Reaction SMILES: [Br:1][CH2:2][CH:3]=[CH:4][CH2:5]Br.[C:7]([O-:10])(=[O:9])[CH3:8].[Na+]>CN(C)C=O>[C:7]([O:10][CH2:5][CH:4]=[CH:3][CH2:2][Br:1])(=[O:9])[CH3:8]
Reactant: CC(=O)[O-]
Reactant: BrCC=CCBr
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCC=CCBr
Temperature: 100 °C
Reaction time: 1 h

Procedure:
93 g of 1,4-dibromobut-2-ene are treated in 250 ml of dimethylformamide with 35.5 g of anhydrous sodium acetate and stirred for 1 hour at 100°C. The mixture is extensively freed from dimethylformamide on a rotary evaporator and the residue is partitioned between water and methylene chloride. The methylene chloride phase is dried over calcium chloride, filtered and concentrated. The residue is distilled under a water-jet vacuum, whereby the fractions are collected between 95° and 105°C at 10-15 mm; nD25 =1.502. There is obtained 1-acetoxy-4-bromobut-2-ene as a colourless liquid.