Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([CH2:14][O:15]C(=O)C)[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][CH:22]=[N:23][C:24]=2[NH2:28])(=[O:3])[CH3:2].P([O-])([O-])([O-])=O.C(=O)(O)[O-].[Na+]>>[C:1]([O:4][C@H:5]1[C@H:9]([OH:10])[C@@H:8]([CH2:14][OH:15])[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][CH:22]=[N:23][C:24]=2[NH2:28])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: CC(=O)O[C@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(N)ncnc21

Procedure:
To a stirred suspension of 500 mg. of 9-(2,3,5-tri-O-acetyl-β-D-arabinofuranosyl)adenine (U.S. Pat. No. 3,651,045, supra) in 50 ml. of a 0.1M pH 7 phosphate buffer is added 500 mg. of Bacillus subtilis ATCC 6633 cell paste or lyophilizate (U.S. Pat. No. 3,304,236, Example 9) and the mixture is stirred for 22 hours at 35°-40° C., with periodic addition of saturated aqueous sodium bicarbonate to maintain the pH at 7.0 to 7.5. The incubated mixture is then poured into 150 ml. of methanol and the resulting mixture is filtered through diatomaceous earth and the filtrate evaporated at reduced pressure. The residue is passed through a 1 × 30 cm. column of dry silica gel, and the column is eluted sequentially with 5:95, 10:90 and 20:90 (v/w) methanol-chloroform. The eluate is collected in 10-ml. fractions and those that contain the desired product, as established by thin layer chromatography, are combined and evaporated at reduced pressure to give the desired product 9-(2-O-acetyl-β-D-arabinofuranosyl)adenine; λmaxCH3OH = 259 nm. The structure is confirmed by nmr spectra.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C:41]([CH3:62])([CH3:61])[C@H:42]([N:46]1[CH2:50][C:49](=[O:51])[N:48]([CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[C:55]([CH3:59])[N:54]=2)[C:47]1=[O:60])[C:43](O)=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:40][C:41]([CH3:62])([CH3:61])[C@H:42]([N:46]1[CH2:50][C:49](=[O:51])[N:48]([CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[C:55]([CH3:59])[N:54]=2)[C:47]1=[O:60])[C:43]([NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)=[O:44]
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: Cc1cccc(CN2C(=O)CN([C@H](C(=O)O)C(C)(C)C)C2=O)n1
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CC(=O)N(Cc2cccc(C)n2)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
A solution containing the product from Example 2C (0.020 g, 0.038 mmol) in THF (0.4 mL) was treated with the product from Example 46E (0.020 g, 0.046 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine (0.035 mL, 0.201 mmol), stirred at 25° C. for 1 hour, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-100% ethyl acetate/dichloromethane to give the title compound (0.020 g, 64% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.85 (s, 9 H), 0.88 (s, 9 H), 1.54 (m, 2 H), 2.41 (s, 3 H), 2.65 (m, 4 H), 3.08 (d, J=18.02 Hz, 1 H), 3.51 (s, 3 H), 3.72 (m, 1 H), 3.89 (m, 2 H), 4.17 (m, 2 H), 4.39 (s, 1 H), 4.67 (m, 3 H), 6.66 (d, J=9.93 Hz, 1 H), 7.06 (m, 7 H), 7.23 (d, J=8.46 Hz, 2 H), 7.31 (m, 1 H), 7.66 (t, J=7.54 Hz, 1 H), 7.87 (m, 6 H), 8.64 (d, J=4.41 Hz, 1 H).
Reaction SMILES: O.[NH2:2][NH2:3].[CH:4]1([C:7]2[N:8]=[N:9][S:10][C:11]=2[C:12]([O:14]C)=O)[CH2:6][CH2:5]1>C(O)C>[CH:4]1([C:7]2[N:8]=[N:9][S:10][C:11]=2[C:12]([NH:2][NH2:3])=[O:14])[CH2:6][CH2:5]1
Reactant: NN
Reactant: COC(=O)c1snnc1C1CC1
Solvent: O
Solvent: CCO
Product: NNC(=O)c1snnc1C1CC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 93.1 %

Procedure:
Hydrazine monohydrate (1.75 g; 35 mmols) was dissolved in ethanol (15 ml), and methyl 4-cyclopropyl-1,2,3-thiadiazole-5-carboxylate (1.29 g; 7 mmols) was added thereto, followed by stirring at room temperature for 10 hours. Ethanol was evaporated under reduced pressure and, after adding thereto water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, the solvent was evaporated. The residue was washed with a mixed solvent of hexane-ethyl acetate to obtain 1.2 g of 4-cyclopropyl-1,2,3-thiadiazole-5-carbohydrazide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl[CH2:16][CH2:17][CH:18]([OH:27])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)(C)C>C(O)CCC>[O:20]([CH2:19][CH:18]([OH:27])[CH2:17][CH2:16][N:12]1[CH2:13][CH2:14][N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:10][CH2:11]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: OC(CCCl)COc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Solvent: CC(C)O
Product: COc1ccc(N2CCN(CCC(O)COc3ccccc3)CC2)cc1

Procedure:
This compound was prepared according to the procedure of Example 78. A mixture of 4.8 g (0.025 mole) of 1-(4-methoxyphenyl)piperazine, 5.0 g (0.025 mole) of 4-chloro-1-phenoxy-2-butanol and 8.0 g (0.075 mole) of anhydrous sodium carbonate in 100 ml of 1-butanol gave 6.4 g (72%) of tan towder., m.p. 95°-97° C. Recrystallizing solvent used was isopropyl alcohol.
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([Si](C)(C)C)=[CH:9]2)(=[O:4])=[O:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][S:2]([CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2)(=[O:4])=[O:3]
Reactant: C[Si](C)(C)c1cc2cc(CS(C)(=O)=O)ccc2[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)Cc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
5-[(Methylsulfonyl)methyl]-2-(trimethylsilyl)-1H-indole (2) (1.5 g, 0.00534 mol) was dissolved in CH2Cl2 (70 mL). Trifluoroacetic acid (2 mL) was added and the mixture was stirred at RT for 2 h. The solvent was concentrated in vacuo and the residue was dissolved in EtOAc and extracted with sat. NaHCO3 and then with brine. The organic phase was dried over MgSO4, filtered and evaporate in vacuo. Silica gel chromatography (50-100% EtOAc gradient in hexane) of the concentrate gave the product 0.57 g, 51%) as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[N:12]=[C:11]3[CH3:26])=[N:4][C:3]=1[N:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:50](Br)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.ClCCl>C1COCC1>[CH2:50]([NH:1][C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[N:12]=[C:11]3[CH3:26])=[N:4][C:3]=1[N:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: COc1ccc(Cn2nc(C)c3cc(-c4nnc(N)c(N5CCN(C(=O)OC(C)(C)C)CC5)n4)ccc32)cc1
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(Cn2nc(C)c3cc(-c4nnc(NCc5ccccc5)c(N5CCN(C(=O)OC(C)(C)C)CC5)n4)ccc32)cc1
Temperature: 25 °C

Procedure:
To a solution of 6-amino-3-[N-(4-methoxybenzyl)-3-methylindazol-5-yl]-5-(4-Boc-piperazin-1-yl)-[1,2,4]triazine 111 (0.04 g, 0.0755 mmol) in anhydrous THF (2 mL), cooled at −78° C., was added a 1.0 M solution of lithium bis(trimethylsilyl)amide (0.083 mL) and benzyl bromide (0.001 mL dissolved in 0.1 mL THF). The reaction mixture was allowed to warm to room temperature. The reaction mixture was heated at 70° C. for 3 hours. Dichloromethane (50 mL) was added. The organic layer was washed with 1% citric acid, water and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure. The crude product was purified by RP-HPLC to yield the desired 6-benzylamino-3-[N-(4-methoxybenzyl)-3-methylindazol-5-yl]-5-(4-Boc-piperazin-1-yl)-[1,2,4]triazine 114 (0.027 g, 0.0435 mmol).
Reaction SMILES: C(O[C:6]([NH:8][C@@H:9]([CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[C@@H:10]([OH:18])[CH2:11][C@@H:12]([CH3:17])[C:13]([NH:15][CH3:16])=[O:14])=[O:7])(C)(C)C.Cl.[C:27]([O:31][C:32]([NH:34][C@H:35](C(O)=O)[CH2:36][C:37]1[N:38]=[CH:39][S:40][CH:41]=1)=[O:33])([CH3:30])([CH3:29])[CH3:28].C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCOCC1>[C:27]([O:31][C:32]([NH:34][C@H:35]([C:6]([NH:8][C@@H:9]([CH2:19][CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1)[C@@H:10]([OH:18])[CH2:11][C@@H:12]([CH3:17])[C:13]([NH:15][CH3:16])=[O:14])=[O:7])[CH2:36][C:37]1[N:38]=[CH:39][S:40][CH:41]=1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cscn1)C(=O)O
Reactant: CNC(=O)[C@H](C)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CNC(=O)[C@H](C)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
A mixture of 200 mg (0.56 mmole) of (2R, 4S, 5S)-5-(t-butoxycarbonyl)amino-6-cyclohexyl-4-hydroxy-2,N-dimethylhexanamide (prepared as described in Preparation 5) and 4 ml of a 4N solution of hydrogen chloride in dioxane was stirred at room temperature for 30 minutes. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was mixed with benzene; the solvent was then removed by distillation under reduced pressure. This operation was repeated three times in total. After drying the final residue in vacuo for 8 hours, the dried material was suspended in 10 ml of anhydrous tetrahydrofuran. 150 mg (1.68 mmole) of N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanine were then added to the suspension. After this, 0.1 ml (0.67 mmole) of 95% diethyl cyanophosphonate and 0.23 ml (1.68 mmole) of triethylamine were added to the mixture, whilst ice-cooling and under an atmosphere of nitrogen. The mixture was then stirred for 15 hours. At the end of this time, the reaction solvent was stripped from the mixture by distillation under reduced pressure and the residue was mixed with water. The precipitate which deposited was collected by filtration and washed with water. It was then dissolved in methylene chloride and the resulting solution was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, to afford 260 mg of the title compound as a pale yellow powder, melting at 158°-160° C.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.Cl.CN(C)CCCN=C=NCC.[O:33]1[CH2:37][CH2:36][O:35][CH:34]1[CH2:38][CH:39]([C:41]1([OH:45])[CH2:44][NH:43][CH2:42]1)[OH:40].C(OCC)(=O)C>CN(C)C1C=CN=CC=1.CN(C=O)C>[F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])=[C:4]([C:5]([N:43]2[CH2:42][C:41]([CH:39]([OH:40])[CH2:38][CH:34]3[O:33][CH2:37][CH2:36][O:35]3)([OH:45])[CH2:44]2)=[O:7])[CH:8]=[CH:9][C:10]=1[F:11]
Reactant: OC(CC1OCCO1)C1(O)CNC1
Reactant: O=C(O)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(c1ccc(F)c(F)c1Nc1ccc(I)cc1F)N1CC(O)(C(O)CC2OCCO2)C1
Reaction time: 0.17 h
Yield: 35.9 %

Procedure:
3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (287 mg, 0.730 mmol), prepared using procedures similar to those described in U.S. Pat. No. 7,019,033, 4-(dimethylamino)pyridine (178 mg, 1.46 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (168 mg, 0.88 mmol) were dissolved in DMF (3 mL). The mixture was stirred at ambient for 10 minutes and then 3-[2-(1,3-dioxolan-2-yl)-1-hydroxyethyl]azetidin-3-ol (0.729 mmol) in DMF (2 mL) was added and the mixture was stirred for 15 h. The mixture was partitioned between ethyl acetate and 5% lithium chloride. The organic portion was washed with 20% citric acid, saturated sodium bicarbonate and brine, then was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, gradient 90% ethyl acetate in hexanes to 100% ethyl acetate) gave 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[2-(1,3-dioxolan-2-yl)-1-hydroxyethyl]azetidin-3-ol (148 mg, 0.262 mmol, 36% yield): MS (EI) for C21H20F3IN2O5: 565 (MH+).
Reaction SMILES: [NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:2]([C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])[CH:3]([CH3:5])[CH3:4].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[NH2:38][C@H:39]([C:43]([C:45]([C:48]([F:51])([F:50])[F:49])([F:47])[F:46])=[O:44])[CH:40]([CH3:42])[CH3:41].Cl>C(Cl)Cl>[NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:2]([C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([NH:38][C@H:39]([C:43]([C:45]([C:48]([F:49])([F:50])[F:51])([F:46])[F:47])=[O:44])[CH:40]([CH3:41])[CH3:42])=[O:12])=[O:7])[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)O
Reactant: CC(C)[C@H](N)C(=O)C(F)(F)C(F)(F)F
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(=O)C(F)(F)C(F)(F)F)C(C)C
Temperature: -22 °C
Reaction time: 0.33 h
Yield: 78.6 %

Procedure:
Dissolve Boc-Val-Pro-OH (314 mg, 1.0 mmol) in methylene chloride (4 mL) and add N-methylmorpholine (252 mg, 2.5 mmol). Cool to -22° C. and add isobutylchloroformate (136 mg, 1.0 mmol). Stir for 20 minutes and add to H-Val-CF2CF3.hydrochloride (1.1 mmol). Stir for 1 hour at -22° C., allow to warm to room temperature and stir for 3 hours. Purify by silica gel chromatography (40% ethyl acetate/hexane) to give the title compound (405 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([CH2:14][OH:15])[CH2:12][OH:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.Cl>N1C=CC=CC=1>[CH3:26][C:16]1[CH:21]=[CH:20][C:19]([S:22]([O:13][CH2:12][CH:11]([CH2:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH2:14][O:15][S:22]([C:19]2[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=2)(=[O:24])=[O:23])(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=[N+]([O-])c1ccc(CC(CO)CO)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC(COS(=O)(=O)c2ccc(C)cc2)Cc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 89 %

Procedure:
A solution of 24 (6.43 g, 30.44 mmol) in pyridine (20 mL) was added dropwise to a solution of p-toluenesulfonyl chloride (14.51 g, 76.11 mmol) in pyridine (30 mL), with temperature being kept below 0° C. After complete addition, the reaction mixture was stirred at room temperature for 10 hours, and then it was poured into ice-cold aqueous 5 M HCl (100 mL). The aqueous phase was extracted with CH2Cl2 (3×100 mL). The combined organic phase was washed with brine (2×100 mL), dried over MgSO4, and evaporated under reduced pressure to afford pale yellow oil, which was crystallized from ethanol (100 mL) to give white solid 25 (14.08 g, 89% yield).
Reaction SMILES: [Br:1][C:2]1[CH:24]=[N:23][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3CCCC[O:16]3)[C:9](=[O:10])[C:4]=2[C:3]=1[CH:25](O)[C:26]1[CH:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=1>C(O)=O.[Zn]>[Br:1][C:2]1[CH:24]=[N:23][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]=[O:16])[C:9](=[O:10])[C:4]=2[C:3]=1[CH2:25][C:26]1[CH:27]=[N:28][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:31]=1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(C(F)(F)F)nc3)c(Br)cnc21
Agent: [Zn]
Solvent: O=CO
Product: Cn1c(=O)n(CCCOC=O)c(=O)c2c(Cc3ccc(C(F)(F)F)nc3)c(Br)cnc21
Temperature: 50 °C
Yield: 57 %

Procedure:
To a stirred solution of 6-bromo-5-(hydroxy(6-(trifluoromethyl)pyridin-3-yl)methyl)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (160 mg, 0.280 mmol) in formic acid (2 mL) was added Zinc dust (40.9 mg, 0.64 mmol). The reaction was heated at 50° C. for 2 h, cooled to RT and filtered. The filtrate was concentrated to a residue which was purified by chromatography eluted with PE/EA (10:1) to give 3-(6-bromo-1-methyl-2,4-dioxo-5((6-(trifluoromethyl)pyridin-3-yl)methyl)-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propylformate (80 mg, 57.1% yield). LCMS: MH+ 501 and TR=1.727 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:18])[C:15]([OH:17])=[O:16])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([Cl:13])[CH:10]=[N:9]1.C(=O)([O-])O.[Na+:23]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:18])[C:15]([O-:17])=[O:16])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([Cl:13])[CH:10]=[N:9]1.[Na+:23]
Reactant: CC(C(=O)O)c1ccc(-n2cc(Cl)cn2)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C(=O)[O-])c1ccc(-n2cc(Cl)cn2)c(Cl)c1
Yield: 91.2 %

Procedure:
2.85 g (10 mmoles) of 2-[3-chloro-4-(4-chloropyrazol-1-yl)phenyl]propionic acid are dissolved (on heating) in 10 ml of 1 N sodium hydrogen carbonate solution and extracted with diethyl ether; the aqueous phase is concentrated, the resulting residue is rubbed with chloroform and recrystallized from chloroform to yield 2.8 g (91.2% of theory) of sodium 2-[3-chloro-4-(4-chloropyrazol-1-yl)phenyl]propionate (m.p. 115° to 128° C.).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.[CH3:13][CH:14]1[CH2:16][O:15]1.O>O1CCCC1.CCOCC>[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH:14]([OH:15])[CH3:16])[CH:8]=[CH:7]2
Reactant: CC1CO1
Reactant: Brc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CC(O)Cn1ccc2cc(Br)ccc21
Reaction time: 1 h
Yield: 89 %

Procedure:
A suspension of 0.56 g of sodium hydride dispersion in 75 ml of tetrahydrofuran was treated with 2.95 g of 5-bromoindole at 0° C. and stirred at this temperature for 1 hour. After the addition of 2.1 ml of (RS)-methyloxirane the reaction mixture was stirred at room temperature for 60 hours and subsequently treated with 15 ml of water. The mixture was diluted with 750 ml of ether, washed twice with 250 ml of water and with 125 ml of saturated sodium chloride solution and the organic phase was dried over sodium sulfate. After removal of the solvent the residue was chromatographed over 120 g of silica gel with toluene-ethyl acetate (19:1). There were obtained 3.4 g (89%) of (RS)-1-(5-bromo-indol-1-yl)-propan-2-ol as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17]CC2C=CC=CC=2)=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:25])[NH:7][CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC(=O)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCC(=O)c1ccc(O)cc1

Procedure:
The compound of example 27b (6.0 g; 17.6 mmol) was dissolved in methanol (60 ml) and hydrogenated using 10% Pd—C (50 mg) at 40 psi for 2 h. The reaction mixture was filtered, concentrated and purified using flash chromatography (silica gel, 3% CH3CN in chloroform) to obtain the title compound. Yield, 2.6 g (59%); mp, 183-85° C.; MS (CI): 252 (M++1), 196, 178, 152; analysis: C13H17NO4 requires: C, 62.14; H, 6.82; N, 5.57; found: C, 62.23; H, 6.44; N, 5.57%.
Reaction SMILES: C([O:3][C:4](=[O:41])[C:5]([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([CH2:16][N:17]([C:24]2[S:28][C:27]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=3)=[N:26][C:25]=2[CH3:39])[CH2:18][C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)=[CH:11][C:10]=1[CH3:40])([CH3:7])[CH3:6])C.[OH-].[Na+]>CCO>[CH3:15][C:14]1[CH:13]=[C:12]([CH2:16][N:17]([C:24]2[S:28][C:27]([C:29]3[CH:30]=[CH:31][C:32]([C:35]([F:36])([F:37])[F:38])=[CH:33][CH:34]=3)=[N:26][C:25]=2[CH3:39])[CH2:18][C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)[CH:11]=[C:10]([CH3:40])[C:9]=1[O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:41])=[O:3]
Reactant: CCOC(=O)C(C)(C)Oc1c(C)cc(CN(Cc2ccsc2)c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(CN(Cc2ccsc2)c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc(C)c1OC(C)(C)C(=O)O
Yield: 26 %

Procedure:
To a solution of example 1 (300 mg, 0.5 mmol) in EtOH was added a 1N NaOH solution and the mixture was stirred to reflux for 1 hour and then the solvant was evaporated off. The residue was acidified with a 1N HCl solution and the precipitate was purified by flash chromatography using DCW/MeOH (90/10), to give the title compound (75 mg, 0.13 mmol) as crystals.
Reaction SMILES: [CH2:1]1[C:6]2[NH:7][C:8]3[C:13]([C:14](=[O:15])[C:5]=2[CH2:4][C:3]2[NH:16][C:17]4[C:22]([C:23](=[O:24])[C:2]1=2)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:12][CH:11]=[CH:10][CH:9]=3.[OH-].[Na+].[Na].OO>C1C2C(=O)C3C(=CC=CC=3)C(=O)C=2C=CC=1.O.CO>[CH:20]1[CH:21]=[C:22]2[C:23]([C:2]3[C:3]([NH:16][C:17]2=[CH:18][CH:19]=1)=[CH:4][C:5]1[C:14]([C:13]2[C:8]([NH:7][C:6]=1[CH:1]=3)=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:15])=[O:24]
Reactant: O=c1c2c([nH]c3ccccc13)Cc1c([nH]c3ccccc3c1=O)C2
Agent: O=C1c2ccccc2C(=O)c2ccccc21
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12
Temperature: 37.5 °C
Reaction time: 0.08 h
Yield: 97.9 %

Procedure:
A one liter flask equipped with a thermometer, stirrer and condenser was charged with 40 grams 6,13-dihydroquinacridone, 180 ml methanol and 40.9 grams 50% aqueous sodium hydroxide. The mixture was stirred under a slow flow of nitrogen at 30-45° C. for five minutes. 2.4 grams of the pigment additive prepared according to Example 4, followed by 0.5 grams anthraquinone mono sulfonic acid sodium salt as catalyst, were added and the reaction mixture was heated to reflux for one hour generating the sodium salt of 6,13-dihydroquinacridone. 73.5 grams of an aqueous 16.9% hydrogen peroxide solution were added into the reaction mixture with a peristaltic pump at a rate of 0.3 ml/minute while maintaining reflux under a slow nitrogen flow. The resulting reddish suspension was further stirred for 10 minutes at reflux then diluted with 100 ml cold water and filtered. The presscake was washed with hot water then dried, yielding 38.9 grams red quinacridone.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:15]1[N:20]([CH3:21])[C:19](=[O:22])[CH:18]=[C:17]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][C:24]=2[F:29])[N:16]=1>O1CCCC1>[F:29][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][C:23]=1[C:17]1[N:16]=[C:15]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[N:20]([CH3:21])[C:19](=[O:22])[CH:18]=1
Reactant: C1COCCN1
Reactant: Cn1c(Cl)nc(-c2ccncc2F)cc1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(N2CCOCC2)nc(-c2ccncc2F)cc1=O
Reaction time: 12 h
Yield: 94.8 %

Procedure:
To a solution of morpholine (3.2 g, 36.7 mmol) and triethylamine (10.2 g, 101 mmol) in tetrahydrofuran (80 ml) was added 2-chloro-6-(3-fluoropyridin-4-yl)-3-methyl-3H-pyrimidin-4-one (8.0 g, 32.4 mmol) portionwise and stirred for 12 hours. The resulting suspension was partitioned between chloroform and 1N sodium hydroxide and the aqueous layer was extracted with chloroform. The combined organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting 5-10% methanol in chloroform to furnish 6-(3-fluoropyridin-4-yl)-3-methyl-2-(morpholin-4-yl)-3H-pyrimidin-4-one (8.9 g, 30.7 mmol, 92%) as white crystals.