Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:42])[CH2:7][O:6][CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C@H:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C@:17](O)([CH2:18][C@@H:19]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH2:20][C@@H:21]3[O:29][CH2:30][O:31][CH3:32])[CH:16]=[CH:15]4)[CH2:12][CH2:11]2)[CH3:9])[O:4][CH2:3]1.C(O)(=O)C.[C:47](=[O:52])([O:50]C)[O:48][CH3:49]>>[CH3:42][C:2]1([CH3:1])[CH2:7][O:6][CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C@H:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C:17]([CH2:18][C@@H:19]([O:33][Si:34]([C:37]([CH3:38])([CH3:39])[CH3:40])([CH3:35])[CH3:36])[CH2:20][C@@H:21]3[O:29][CH2:30][O:31][CH3:32])=[CH:16][C@H:15]4[O:52][C:47]([O:48][CH3:49])=[O:50])[CH2:12][CH2:11]2)[CH3:9])[O:4][CH2:3]1
Reactant: COCO[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@]2(O)C=C[C@H]3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]12C
Reactant: COC(=O)OC
Solvent: CC(=O)O
Product: COCO[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CC2=C[C@@H](OC(=O)OC)[C@H]3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@]21C

Procedure:
In 10 ml of dimethyl carbonate was dissolved 400 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-3β-(tert-butyldimethylsilyl)oxy-1α-(methoxymethyl)oxypregn-6-en-5α-ol, followed by addition of 0.2 ml of acetic acid. The mixture was refluxed in an atmosphere of argon gas for 12 hours. The reaction mixture was then worked up in the same manner as Example 132 to give 120 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-3β-(tert-butyldimethylsilyl)oxy-1α-(methoxymethyl)oxy-7α-(methoxycarbonyl)oxypregn-5-ene showing the following physical properties.
Reaction SMILES: Cl[C:2]1[C:3]([F:22])=[CH:4][C:5]2[C:6]([CH:21]=1)=[N:7][C:8]1[N:9]([CH2:19][CH3:20])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>N1C=CC=CC=1>[CH2:19]([N:9]1[C:8]2[N:7]=[C:6]3[CH:21]=[C:2]([N:27]4[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]4)[C:3]([F:22])=[CH:4][C:5]3=[CH:14][C:13]=2[C:12](=[O:15])[C:11]([C:16]([OH:18])=[O:17])=[CH:10]1)[CH3:20]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Reactant: CN1CCNCC1
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCN(C)CC4)cc3nc21

Procedure:
1-Ethyl-7-fluoro-8-(4-methyl-1-piperazinyl)-4-oxo- 1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is prepared under the conditions of Example 5 but starting from 1.6 g of 8-chloro-1-ethyl-7-fluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid and 4.5 g of 4-methylpiperazine in 16 cm3 of pyridine. After recrystallizing 4 times from, in total, 120 cm3 of dimethylformamide, 1.2 g of 1-ethyl-7-fluoro-8-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid melting at 285°-286° C. solvated with 1% of water.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([N:17]2[CH:25]([CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH:24]3[C:19]([C:20]4[CH:34]=[CH:33][C:32]([C:35]([O:37][CH3:38])=[O:36])=[CH:31][C:21]=4[CH2:22][CH2:23]3)=[N:18]2)[CH:12]=[CH:13][C:14]=1[C:15]#[N:16])C1C=CC=CC=1.[H][H]>[Pd].C(OCC)(=O)C>[C:15]([C:14]1[CH:13]=[CH:12][C:11]([N:17]2[CH:25]([CH:26]3[CH2:27][CH2:28][CH2:29][CH2:30]3)[CH:24]3[C:19]([C:20]4[CH:34]=[CH:33][C:32]([C:35]([O:37][CH3:38])=[O:36])=[CH:31][C:21]=4[CH2:22][CH2:23]3)=[N:18]2)=[CH:10][C:9]=1[OH:8])#[N:16]
Reactant: [H][H]
Reactant: COC(=O)c1ccc2c(c1)CCC1C2=NN(c2ccc(C#N)c(OCc3ccccc3)c2)C1C1CCCC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(c1)CCC1C2=NN(c2ccc(C#N)c(O)c2)C1C1CCCC1
Yield: 53 %

Procedure:
A mixture of methyl 2-(3-(benzyloxy)-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylate, Example 30, (345 mg, 0.68 mmol), catalytic 10% palladium on carbon, and ethyl acetate was hydrogenated at 30 psi hydrogen for three hours. The mixture was filtered through Celite and concentrated. The solid was suspended in diethyl ether/hexanes, a small amount of methanol and filtered to give methyl 2-(4-cyano-3-hydroxyphenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylate (150 mg, 0.36 mmol, 53% yield). The title compound was largely present as (±)-(3RS,3aSR)-methyl 2-(4-cyano-3-hydroxyphenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10-1.58 (m, 7H), 1.60-1.90 (m, 2H), 2.06 (s, 1H), 2.16-2.30 (m, 1H), 2.79-2.95 (m, 1H), 3.05-3.15 (m, 1H), 3.58 (ddd, J=13.76, 9.47, 4.70 Hz, 1H), 3.86 (s, 3H), 4.77 (dd, J=9.67, 5.37 Hz, 1H), 6.70 (d, J=8.59 Hz, 1H), 6.82 (s, 1H), 7.36 (d, J=8.86 Hz, 1H), 7.82-7.93 (m, 2H), 8.02 (d, J=8.06 Hz, 1H), 10.70 (s, 1H). ES-MS m/z 416 (M+H).
Reaction SMILES: [NH2:1][C@H:2]([C:6]([O:8][CH2:9][C@H:10]([CH2:23][CH2:24][O:25]C(=O)[C@H](C(C)C)N)[CH2:11][N:12]1[CH:20]=[N:19][C:18]2[C:17](=[O:21])[NH:16][C:15]([NH2:22])=[N:14][C:13]1=2)=[O:7])[CH:3]([CH3:5])[CH3:4].[OH-].[Na+].FC(F)(F)C(O)=O>>[OH:25][CH2:24][CH2:23][C@@H:10]([CH2:9][O:8][C:6](=[O:7])[C@H:2]([CH:3]([CH3:4])[CH3:5])[NH2:1])[CH2:11][N:12]1[CH:20]=[N:19][C:18]2[C:17](=[O:21])[NH:16][C:15]([NH2:22])=[N:14][C:13]1=2
Reactant: CC(C)[C@H](N)C(=O)OCC[C@@H](COC(=O)[C@@H](N)C(C)C)Cn1cnc2c(=O)[nH]c(N)nc21
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](N)C(=O)OC[C@H](CCO)Cn1cnc2c(=O)[nH]c(N)nc21
Reaction time: 4 h
Yield: 13.6 %

Procedure:
(R)-9-(4-(L-valyloxy)-2-(L-valyloxymethyl)butyl)guanine from Example 23 step b) (100 mg, 0,126 mmole) was dissolved in 0.1 N NaOH aqueous solution (6.3 ml, 0.63 mmole) at room temperature. At intervals, an aliquot was taken and neutralized with 0.5 N trifluoroacetic acid. The aliquots were evaporated and analyzed by HPLC to monitor the progress of the reaction. After 4 hours, 0.5 N trifluoroacetic acid solution (1.26 ml, 0.63 mmole) was added to the solution and the reaction mixture was evaporated. The desired product was purified by HPLC, (YMC, 50×4.6 mm, gradient 0.1% TFA+0-50% 0.1% TFA in acetonitrile, in 20 minutes, UV detection at 254 nm. Yield: 13.6%
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:6][CH:5]=1)([O-])=O>C(O)C.[OH-].[Pd+2].[OH-]>[N:11]1([CH2:10][CH2:9][O:8][C:7]2[CH:17]=[CH:18][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: O=[N+]([O-])c1ccc(OCCN2CCOCC2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(OCCN2CCOCC2)cc1
Reaction time: 2 h
Yield: 63.3 %

Procedure:
To a solution of 4-[2-(4-nitro-phenoxy)-ethyl]-morpholine (2.25 g, 8.93 mmol) in ethanol (40 mL) is added palladium hydroxide (0.313 g, 0.45 mmol) and the mixture is stirred in a Parr-apparatus under hydrogen pressure (5 bars) for 2 hours. Filtration over Celite 521 and evaporation gave a red oil purified by silica gel column chromatography. Elution with DCM and a mixture 90:10 DCM:MeOH affords the title compound as a white solid (1.256 g, 63%). 1H-NMR (400 MHz, CDCl3) δ (ppm) 2.52-2.63 (4H, m), 2.71-2.80 (2H, t), 3.46 (2H, br s), 3.70-3.78 (4H, m), 4.00-4.10 (2H, m), 6.65 (2H, d), 6.77 (2H, d).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[CH:5][C:6]([F:28])=[C:7]([N:9]2[C:14]([CH3:15])=[CH:13][C:12]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])=[C:11]([Br:26])[C:10]2=[O:27])[CH:8]=1.C(N(CC)CC)C.[C:36]([O:39][CH2:40][C:41](Cl)=[O:42])(=[O:38])[CH3:37].[Cl-].[NH4+]>O1CCCC1>[C:36]([O:39][CH2:40][C:41]([NH:2][C:3]1[CH:4]=[CH:5][C:6]([F:28])=[C:7]([N:9]2[C:14]([CH3:15])=[CH:13][C:12]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])=[C:11]([Br:26])[C:10]2=[O:27])[CH:8]=1)=[O:42])(=[O:38])[CH3:37]
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1cc(N)ccc1F
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)Nc1ccc(F)c(-n2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of the compound of Example 722 (0.5 g, 1.05 mmol) in tetrahydrofuran (20 mL) was treated with triethyl amine (0.3 mL, 2.1 mmol) and acetoxy acetylchloride (0.12 mL, 1.15 mmol). After stirring at room temperature for 2 h, the reaction was complete. The reaction mixture was poured into saturated aqueous ammonium chloride. The solids were filtered off and were washed with water and diethyl ether. Title product was isolated as a white solid (0.32 g, 58%). 1H NMR (400 MHz, CD3OD) δ 7.65 (m, 3H), 7.32 (t, J=8.4 Hz, 1H), 7.04 (t, J=8.4 Hz, 2H), 6.64 (s, 1H), 5.35 (s, 2H), 4.68 (s, 2H), 2.15 (s, 3H), 2.10 (s, 3H) ppm. 19F NMR (400 MHz, CD3OD) δ −111.56 (1F), −115.99 (1F), −129.48 (1F) ppm. LC/MS, tr=5.35 minutes (5 to 95% acetonitrile/water over 8 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 540 (M+H).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:28]=[CH:27][C:7]([CH2:8][N:9]2[C:15](=[O:16])[C:14](=[N:17]O)[C:13]3[CH:19]=[CH:20][CH:21]=[CH:22][C:12]=3[C:11]3[CH:23]=[CH:24][CH:25]=[CH:26][C:10]2=3)=[CH:6][CH:5]=1>CO.[Pd]>[ClH:1].[NH2:17][CH:14]1[C:15](=[O:16])[N:9]([CH2:8][C:7]2[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:28][CH:27]=2)[C:10]2[CH:26]=[CH:25][CH:24]=[CH:23][C:11]=2[C:12]2[CH:22]=[CH:21][CH:20]=[CH:19][C:13]1=2
Reactant: COc1ccc(Cn2c(=O)c(=NO)c3ccccc3c3ccccc32)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1ccc(CN2C(=O)C(N)c3ccccc3-c3ccccc32)cc1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
Aqueous HCl 2N (20.8 mL) was added to a solution of 5-(4-methoxy-benzyl)-5H-dibenzo[b,d]azepine-6,7-dione 7-oxime (8.3 g) in methanol (83.0 mL). Pd/C (10% weight, 540 mg) was added to the reaction mixture and the system was stirred under 10 bar H2 at 50° C. for 2 days. After exchanging H2 for Ar, the reaction mixture was filtered, concentrated under reduced pressure and dried under high vacuum yielding 7-amino-5-(4-methoxy-benzyl)-5H,7H-dibenzo[b,d]azepin-6-one hydrochloride (8.7 g, quant.) as a light yellow powder. This powder was suspended in acetonitrile (43 mL) and stirred 2 hours at room temperature. The precipitate was filtered off, washed with acetonitrile and dried under reduced pressure yielding 7-amino-5-(4-methoxy-benzyl)-5H,7H-dibenzo[b,d]azepin-6-one hydrochloride (8.3 g, 96%) as an off-white powder.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][C@@:12]1([OH:28])[C:16]2([CH2:21][C:20]([CH3:23])([CH3:22])[CH2:19][C:18]([CH3:25])([CH3:24])[CH2:17]2)[C@H:15]([CH3:26])[CH2:14][C@@H:13]1[OH:27].CCN(CC)CC>C(Cl)Cl>[OH:28][C@:12]1([CH3:11])[C:16]2([CH2:21][C:20]([CH3:22])([CH3:23])[CH2:19][C:18]([CH3:25])([CH3:24])[CH2:17]2)[C@H:15]([CH3:26])[CH2:14][C:13]1=[O:27]
Reactant: C[C@@H]1C[C@H](O)[C@](C)(O)C12CC(C)(C)CC(C)(C)C2
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: C[C@@H]1CC(=O)[C@](C)(O)C12CC(C)(C)CC(C)(C)C2
Reaction time: 0.08 h
Yield: 65.4 %

Procedure:
Under N2 atmosphere with rigorous exclusion of moisture, a solution of dimethyl sulfoxide (340 mg, 4.40 mmol) in CH2Cl2 (1 mL) was injected via syringe at −70° C. within 5 min. into a stirred oxalyl chloride solution in CH2Cl2 (2 M, 1.10 ml, 2.20 mmol) diluted with CH2Cl2 (5 mL). After stirring at this temp. for 5 min., (1R*,2S*,4R*)-1,4,7,7,9,9-hexamethylspiro[4.5]decan-1,2-diol (510 mg, 2.00 mmol) dissolved in CH2Cl2 (1 mL) was injected during 5 min dropwise via syringe. Stirring was continued at −70° C. for 30 min., prior to injection of Et3N (1.01 g, 10.0 mmol). The cooling bath was removed, and the reaction mixture allowed to warm to room temp., prior to pouring into water (50 mL). The organic layer was separated, the aqueous one extracted with CH2Cl2 (2×50 mL). The combined organic extracts were washed with water (50 mL), dried (Na2SO4), and concentrated on the rotary evaporator. Purification of the resulting residue by two silica-gel FC (pentane/Et2O, 19:1, Rf=0.17) furnished (1R*,4R*)-1-hydroxy-1,4,7,7,9,9-hexamethylspiro[4.5]decan-2-one (330 mg, 65%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH:30]([CH3:32])[CH3:31])=[C:6]([CH:29]=1)[O:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][N:18]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:11][CH2:10]1.O.NN>C(O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH:30]([CH3:32])[CH3:31])=[C:6]([CH:29]=1)[O:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]1
Reactant: Cc1ccc(C(C)C)c(OCC2CCN(CCCN3C(=O)c4ccccc4C3=O)CC2)c1
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1ccc(C(C)C)c(OCC2CCN(CCCN)CC2)c1

Procedure:
17.35 g (0.04 mol) of 2-[3-[4-[[5-methyl-2-(1-methylethyl)phenoxy]methyl]piperid-1-yl]propyl]-1H-isoindole-1,3 (2H)-dione are reacted in 340 ml of ethanol with 3.9 ml (0.08 mol) of hydrazine hydrate. The mixture is heated at the reflux temperature for 3 h. The mixture is filtered, the solid being rinsed with a small amount of ethanol, the filtrate is concentrated and taken up in diethyl ether. An insoluble material is again removed by filtration and the filtrate is again concentrated. The insoluble materials are combined in a round-bottomed flask and 25 ml of concentrated hydrochloric acid and 75 ml of water are added. The mixture is brought to reflux for 2 h while stirring. It is allowed to cool, the insoluble material is removed by filtration, rinsing is carried out with water, basification is carried out with concentrated aqueous ammonia and extraction is carried out three times with diethyl ether. The organic phase is dried over sodium sulphate, filtered and concentrated under reduced pressure. A compound is obtained which is used as is in the following stage.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1.C(N(CC)CC)C.[CH2:31]([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[N:40]=[C:41]=[O:42])[CH3:32]>>[ClH:1].[N:16]12[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17]1)[C@@H:14]([NH:13][C:11]([C:9]1[S:10][C:6]3[CH:5]=[C:4]([NH:3][C:41]([NH:40][C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[O:33][CH2:31][CH3:32])=[O:42])[CH:23]=[CH:22][C:7]=3[CH:8]=1)=[O:12])[CH2:15]2
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reactant: CCOc1ccccc1N=C=O
Agent: Cl
Solvent: CCN(CC)CC
Product: CCOc1ccccc1NC(=O)Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reaction time: 18 h

Procedure:
A solution of 40 mg (0.11 mmol) of 6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride in 2 ml of THE is mixed with 29.8 μl (0.21 mmol) of triethylamine and 34.9 mg (0.21 mmol) of 2-ethoxyphenyl isocyanate. After 18 h at room temperature, the product is purified by preparative HPLC. The concentrated product fraction is dissolved in a mixture of acetonitrile and 1 N hydrochloric acid (5:1), again concentrated and dried under high vacuum. 10 mg (18.7% of theory) of the title compound are obtained.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[C:4]([C:9]2[CH:18]=[N:17][C:16]3[C:15](=O)[NH:14][C:13]([CH2:20][O:21][CH3:22])=[N:12][C:11]=3[CH:10]=2)=[N:5][CH:6]=[CH:7][CH:8]=1.N1C(C)=CC=CC=1C.P(Cl)(Cl)([Cl:35])=O>C(Cl)(Cl)Cl>[Cl:35][C:15]1[C:16]2[N:17]=[CH:18][C:9]([C:4]3[C:3]([C:2]([F:24])([F:23])[F:1])=[CH:8][CH:7]=[CH:6][N:5]=3)=[CH:10][C:11]=2[N:12]=[C:13]([CH2:20][O:21][CH3:22])[N:14]=1
Reactant: COCc1nc2cc(-c3ncccc3C(F)(F)F)cnc2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClC(Cl)Cl
Product: COCc1nc(Cl)c2ncc(-c3ncccc3C(F)(F)F)cc2n1

Procedure:
Dissolve 7-(3-trifluoromethyl-pyridin-2-yl)-2-methoxymethyl-3H-pyrido[3,2-d]pyrimidin-4-one (276 mg, 0.822 mmol) in CHCl3 (25 mL) and 2,6-lutidine (294 mg, 2.74 mmol). Add phosphorous oxycloride (0.255 mL, 2.74 mmol) dropwise and heat the resulting solution to reflux for 24 hours. Cool the solution and remove the solvent under reduced pressure. Partition the crude residue between EtOAc (50 mL) and saturated NaHCO3 (aq) (50 mL). Remove the organic phase and extract the aqueous phase with additional EtOAc (50 mL). Combine the two organic extracts, wash with brine (100 mL), and dry over Na2SO4. Remove the solvent to yield the title compound as a light brown solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1C.[CH3:12][O:13][C:14](=[O:21])[C@H:15]([CH2:17][CH2:18][S:19][CH3:20])[NH2:16].C(N(CC)CC)C>CN1CCCC1=O>[CH3:12][O:13][C:14](=[O:21])[CH:15]([NH:16][C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=1)[CH2:17][CH2:18][S:19][CH3:20]
Reactant: COC(=O)[C@@H](N)CCSC
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: COC(=O)C(CCSC)Nc1ccc([N+](=O)[O-])cc1
Temperature: 90 °C

Procedure:
1 g of 4-fluoro-3-methylnitrobenzene, 0.694 g of L-methionine methyl ester and 1.09 ml of triethylamine were added to a solution of 5 ml of N-methylpyrrolidinone. The reaction medium was heated at 90° C. for 7 hours and, after cooling to room temperature, was poured into an ice water mixture. The reaction medium was then extracted with ethyl acetate and the organic phase was dried and concentrated to dryness. After purification by chromatography on a column of silica, 4-methylsulfanyl-2-(4-nitrophenylamino)butyric acid methyl ester (28) was obtained.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1.[Cl:26][C:27]1[CH:28]=[C:29]([CH2:33]O)[CH:30]=[N:31][CH:32]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.O>[Cl:26][C:27]1[CH:28]=[C:29]([CH2:33][O:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:24][CH:25]=2)[CH:30]=[N:31][CH:32]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: OCc1cncc(Cl)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(OCc2cncc(Cl)c2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
DIAD (2.35 mmol, 0.45 mL) was added to an ice-cold solution of methyl 4-hydroxybenzoate 29a (2.35 mmol, 358 mg), (5-chloropyridin-3-yl)methanol 27a (1.57 mmol, 225 mg), and Ph3P (2.35 mmol, 616 mg) in 8 mL of THF. The mixture was stirred at 0° C. for 1 h at room temperature overnight. Water was added and the crude product was purified by flash column chromatography (silica gel, 20% EtOAc/hexanes) to afford 300 mg (68%) of 27b.
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1.[CH:19]1([C:22]2[CH:23]=[C:24]([CH3:34])[C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:26][CH:27]=2)[CH2:21][CH2:20]1>>[CH:19]1([C:22]2[CH:23]=[C:24]([CH3:34])[C:25]([N:28]3[CH2:29][CH2:30][N:31]([C:13]([C:12]4[CH:11]=[CH:10][C:9]([CH2:8][CH2:7][N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:18])=[CH:17][CH:16]=4)=[O:15])[CH2:32][CH2:33]3)=[N:26][CH:27]=2)[CH2:21][CH2:20]1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Reactant: O=C(O)c1ccc(CCN2CCCS2(=O)=O)cc1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(CCN3CCCS3(=O)=O)cc2)CC1
Yield: 70.6 %

Procedure:
Using 4-[2-(1,1-dioxo-1λ6-isothiazolidin-2-yl)ethyl]benzoic acid (162 mg) described in Preparation Example 41 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (130 mg) described in Preparation Example 83 and by the reaction and treatment in the same manner as in Example 87, the title compound (198 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>CN(C=O)C.[Cl-].[Na+].O.C(Cl)Cl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:4]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[N:3]=1
Reactant: CCOC(=O)CCBr
Reactant: Clc1nc(N2CCOCC2)c2nc[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCn1cnc2c(N3CCOCC3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79.2 %

Procedure:
A solution of 4-(2-chloro-9H-purin-6-yl)morpholine (3.0 g, 13 mmol) in DMF (39 mL) was treated with cesium carbonate (8.2 g, 25 mmol) and stirred at ambient temperature for 10 minutes. 3-bromopropanoic acid, ethyl ester (6.8 g, 38 mmol) was introduced and the reaction mixture was heated at 50° C. for 2 hr. Partial conversion prompted the addition of cesium carbonate (8.2 g, 25 mmol) and 3-bromopropanoic acid, ethyl ester (6.8 g, 38 mmol), and the reaction mixture was heated at 70° C. The reaction mixture was cooled to ambient temperature and diluted with brine and DCM and the layers separated. The aqueous phase was extracted into DCM (3×), dried over sodium sulfate, filtered, and absorbed onto celite for purification by flash chromatography to afford ethyl 3-(2-chloro-6-morpholino-9H-purin-9-yl)propanoate as a white solid (3.5 g, 83%). LC/MS (ESI+): m/z 340 (M+H)
Reaction SMILES: [F:1][C:2]1[C:3]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=2[CH3:21])=[C:4]([CH:9]=[CH:10][C:11]=1[F:12])[C:5]([NH:7][NH2:8])=[O:6].[N:22]#[C:23]Br.C(=O)(O)[O-].[Na+]>O1CCOCC1.O>[F:1][C:2]1[C:3]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=2[CH3:21])=[C:4]([C:5]2[O:6][C:23]([NH2:22])=[N:8][N:7]=2)[CH:9]=[CH:10][C:11]=1[F:12]
Reactant: Cc1cc(I)ccc1Nc1c(C(=O)NN)ccc(F)c1F
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(I)ccc1Nc1c(-c2nnc(N)o2)ccc(F)c1F
Temperature: 25 °C
Yield: 58 %

Procedure:
To a solution of 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid hydrazide (0.806 g, 2 mmol) in 5 ml of dioxane was added cyanogen bromide (0.212 g, 2 mmol) followed by a solution of sodium bicarbonate (0.17 g, 2 mmol) in 5 ml of water. The resulting mixture was stirred 18 ours at room temperature. The solution was concentrated and the residure was run column with hexanes/ethyl acetate (3/1) to give the product which was recrystallized from ethyl acetate/hexanes to provide a pale-yellow crystal. The yield: 58% m.p. 183.7-184.0° C. 1H NMR(CDCl3, 400 Hz): /ppm 8.87(1H, s, —NH—); 7.52(1H, s, Phenyl-H); 7.45-7.49(1H, m, Phenyl-H); 7.40(1H, d, J=8.3 Hz, Phenyl-H); 6.77-6.83(1H, m Phenyl-H); 6.60-6.63(1H, m, Phenyl-H); 5.02(2H, s, —NH2), 2.36(3H, s, CH3)
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:18]O>>[CH3:18][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([OH:11])=[C:2]([OH:1])[C:3]=1[CH3:12]
Reactant: Cc1c(C(=O)O)ccc(O)c1O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(O)c(O)c1C
Temperature: 25 °C
Yield: 83 %

Procedure:
To a round bottom flask equipped with magnetic stirring and a reflux condenser was added 3,4-dihydroxy-2-methylbenzoic acid (23.3 g, 139 mmol), methanol (139 mL), and concentrated sulfuric acid (0.77 mL, 13.9 mmol). This mixture was heated to reflux for 18 hours. The reaction was cooled to room temperature and the methanol evaporated. The residue was taken up in ether and washed once with saturated sodium bicarbonate solution, once with saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated to give a brown solid, methyl-3,4-dihydroxy-2-methylbenzoate, (20.9 g, 114 mmol) in 83% yield. 1H-NMR (300 MHz, CD3COCD3) δ (ppm): 2.47 (s, 3H), 3.79 (s, 3H), 6.78 (d, 1H), 7.46 (d, 1H); TLC: Rf=0.54 (1:1 ethyl acetate/hexane).