Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S1C2CCC(C([O-])=O)NC=2N=C1.[N:13]([CH2:16][CH2:17][CH2:18][C:19]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:23]([C:24](=[S:26])[NH2:25])[N:22]=[C:21]([C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=2[F:34])[S:20]1)=[N+]=[N-].Br[CH:42]1[C:47](=O)[CH2:46][CH2:45][N:44]([C:49](OC(C)(C)C)=O)[CH2:43]1.CCN(C(C)C)C(C)C>C(O)C>[F:34][C:28]1[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:27]=1[C:21]1[S:20][C:19]([CH2:18][CH2:17][CH2:16][NH2:13])([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:23]([C:24]2[S:26][C:42]3[CH2:43][N:44]([CH3:49])[CH2:45][CH2:46][C:47]=3[N:25]=2)[N:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(Br)C1
Reactant: [N-]=[N+]=NCCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(N)=S
Agent: O=C([O-])C1CCc2scnc2N1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CN1CCc2nc(N3N=C(c4cc(F)ccc4F)SC3(CCCN)c3ccccc3)sc2C1
Reaction time: 8 h
Yield: 89.9 %

Procedure:
Preparation of tert-butyl 24243-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-6,7-dihydrothiazolo[5,4-e]pyridine-5(4H)-carboxylate: To a solution of 2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carbothioamide (0.300 g, 0.717 mmol) in 10 mL of ethanol was added tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate (0.239 g, 0.860 mmol) followed by DIEA (0.25 mL, 1.43 mmol). The mixture was allowed to stir overnight at reflux then treated with tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate (100 mg) and stirred at reflux for a further 3 hrs. The cooled mixture was partitioned between saturated NaHCO3 solution (30 mL) and EtOAc (30 mL) and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic phases were washed with brine (20 mL) dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (5-10% ethyl acetate/hexanes) to afford the desired product as a bright yellow foam (0.313 g, 73%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=[O:15])[CH2:10][CH2:11][S:12][CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:17]1(O)[CH2:21][CH2:20][CH2:19][CH2:18]1.C(Cl)CCl>CN(C1C=CN=CC=1)C.ClCCl>[CH:17]1([O:15][C:14](=[O:16])[C@H:9]([CH2:10][CH2:11][S:12][CH3:13])[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: OC1CCCC1
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)OC1CCCC1
Reaction time: 16 h

Procedure:
A mixture of N-tert-butoxycarbonyl L-methionine (30 g.), cyclopentanol (31 g.), DMAP (44 g.), EDC (30 g.) and dichloromethane (200 ml.) was stirred under an inert atmosphere for 16 hours. It was then washed with 1M. aqueous citric acid (200 ml.), saturated sodium carbonate solution (100 ml.) and brine, dried and evaporated to dryness to give N-tert-butoxycarbonyl L-methionine cyclopentyl ester as a gum(36 g.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH-].[Na+].CC1C=CC(S(O[CH2:22][CH2:23][N:24]2[CH:28]=[CH:27][N:26]=[C:25]2[CH2:29][CH2:30][CH3:31])(=O)=O)=CC=1>CO>[CH2:29]([C:25]1[N:24]([CH2:23][CH2:22][S:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[CH:28]=[CH:27][N:26]=1)[CH2:30][CH3:31]
Reactant: Nc1ccc(S)cc1
Reactant: CCCc1nccn1CCOS(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1nccn1CCSc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 57.5 %

Procedure:
4-aminothiophenol (1.0 g) was dissolved in methanol (20 ml), 3N sodium hydroxide (8.0 ml) was added to the mixture, and 2-(2-propylimidazol-1-yl)ethyl 4-methylbenzene sulfonate (3.7 g) was added to the mixture. The mixture was stirred for 20 hours at room temperature, and the solvent was removed under reduced pressure. Water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/ethanol=15/1→6/1), to give 4-[[2-(2-propylimidazol-1-yl)ethyl]sulfanyl]aniline (1.2 g).
Reaction SMILES: C(OC(=O)C)(=O)C.[C:8]([O:12][C:13]([C:15]1[N:16]([CH2:24][CH:25]([OH:42])[CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:30][CH:29]=2)[C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])([CH3:11])([CH3:10])[CH3:9].C(=O)([O-])O.[Na+].[Na+].[Cl-]>CS(C)=O>[C:8]([O:12][C:13]([C:15]1[N:16]([CH2:24][C:25](=[O:42])[CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:30][CH:29]=2)[C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CCCCCCCCc1ccc(OCC(O)Cn2c(C(=O)OC(C)(C)C)cc3ccccc32)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CS(C)=O
Product: CCCCCCCCc1ccc(OCC(=O)Cn2c(C(=O)OC(C)(C)C)cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1.02 g (10.0 mmol) acetic anhydride are mixed with 10 ml absolute DMSO, stirred at room temperature for 10 min and added drop-wise to a solution of 0.120 g (0.250 mmol) tert-butyl-1-[2-hydroxy-3-(4-octylphenoxy)propyl]indole-2-carboxylate in 10 ml absolute DMSO. Having stirred for 8 hours, the solution is poured into a mixture of 5% sodium hydrogen carbonate solution and saturated NaCl solution (1:1, v/v) and hydrolyzed for 10 min. Four extractions with diethyl ether, combination of the organic phases, concentration to half the volume on the rotary evaporator, three wash steps using saturated NaCl solution, drying on sodium sulfate, filtration and reconcentration on the rotary evaporator leave as a crude product a yellow oil which is purified on silica gel by means of column chromatography (flow agent: petroleum ether/ethyl acetate 98:2) and yields the product as a yellowish oil.
Reaction SMILES: CS(O[C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:7]=1[C:16]([CH3:19])([CH3:18])[CH3:17])(=O)=O.C([O-])(=O)C.[NH4+].CO.[Mg]>[Pd].[C].O>[C:12]([C:9]1[CH:10]=[CH:11][CH:6]=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:8]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1ccc(OS(C)(=O)=O)c(C(C)(C)C)c1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Mg]
Solvent: CO
Solvent: O
Product: CC(C)(C)c1cccc(C(C)(C)C)c1
Yield: 94.9 %

Procedure:
In a nitrogen atmosphere under normal pressure, 2,4-di-tert-butylphenyl methanesulfonate (500 g, 1.76 mols), ammonium acetate (678 g, 8.79 mols) and methanol (3000 g) were mixed at 25° C., and with stirring, 10 mass % Pd/carbon (50 mass % water-containing product) (100 g) (as metal palladium; 1 mass % relative to 2,4-di-tert-butylphenyl methanesulfonate) as supported by a carbon carrier having a specific surface area of 780 m2/g (by BET method) and powdery magnesium (60 g, 2.46 mols) were put into it. With stirring, the reaction liquid was reacted at the same temperature for 9 hours. Water (1000 mL) was added to the reaction liquid and Pd-carbon was separated through filtration, then heptane (1000 g) was added to the filtrate. The organic layer obtained after extraction was concentrated under reduced pressure to give crude 1,3-di-tert-butylbenzene (318 g, yield 95% by mass). The result is shown in Table I-1.
Reaction SMILES: C([O:5][C:6](=[O:36])[C@H:7]([CH3:35])[NH:8][C@H:9]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:10][CH2:11][CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:16][CH2:15]1)(C)(C)C.C(OCC)(=O)C.[ClH:43]>>[CH2:23]([O:22][C:20]([N:17]1[CH2:18][CH2:19][CH:14]([CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]([NH:8][C@H:7]([C:6]([OH:36])=[O:5])[CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:15][CH2:16]1)=[O:21])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1.[ClH:43]
Reactant: CCOC(=O)[C@H](CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@@H](C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@@H](C)C(=O)O
Reaction time: 5 h

Procedure:
In 30 ml of 5N hydrogen chloride-ethyl acetate solution is dissolved 1.5 g of N-[(S)-5-(1-benzyloxycarbonyl-4-piperidyl)-1-ethoxycarbonylpentyl]-L-alanine tert-butyl ester, and the solution is allowed to stand at room temperature for 5 hours. The reaction solution is concentrated to dryness under reduced pressure, and the residue is rinsed with ethyl ether and dried under reduced pressure to give 1.15 g of N-[(S)-5-(1-benzyloxycarbonyl-4-piperidyl)-1-ethoxycarbonylpentyl]-L-alanine·hydrochloride as a colorless gum.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10](=[O:25])[NH:11][N:12]=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.I[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1.N>>[F:33][C:30]1[CH:31]=[CH:32][C:27]([N:11]2[C:10](=[O:25])[C:9]([CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[C:14]([C:15]3[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=3)[CH:13]=[N:12]2)=[CH:28][CH:29]=1
Reactant: CS(=O)(=O)c1ccc(-c2cn[nH]c(=O)c2Cc2ccc(F)cc2)cc1
Reactant: Fc1ccc(I)cc1
Agent: N
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)cc3)c(=O)c2Cc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to the method of Example 62, starting with 4-(4-fluorophenylmethyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and reacting with 1-iodo-4-fluorobenzene (yield: 0.0881 g, 78%). mp 175-177° C. 1H NMR (300 MHz, DMSO d6) δ 3.27-3.36 (3H, obstructed by H2O), 3.88 (bs, 2H), 6.98-7.09 (m, 4H), 7.34 (m, 2H), 7.65 (m, 2H), 7.71 (m, 2H), 8.06 (m, 3H). MS (DCI/NH3) m/z 453 (M+H)+, 470 (M+NH4)+. Anal. calc. for C24H18F2N2O3S: C, 63.71; H, 4.01; N, 6.19. Found: C, 63.61; H, 4.26; N, 6.03.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=1[C:13]1[N:14]([CH3:18])[N:15]=[CH:16][CH:17]=1.[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[N:28]=[C:29]=[O:30]>>[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[NH:28][C:29]([NH:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:19])[CH3:1])=[C:7]([C:13]2[N:14]([CH3:18])[N:15]=[CH:16][CH:17]=2)[CH:8]=1)=[O:30]
Reactant: CN(C)CCOc1ccc(N)cc1-c1ccnn1C
Reactant: O=C=Nc1ccc(F)cc1F
Product: CN(C)CCOc1ccc(NC(=O)Nc2ccc(F)cc2F)cc1-c1ccnn1C
Yield: 73.3 %

Procedure:
4-(2-Dimethylamino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (26.0 mg, 0.1 mmol) was treated with 2,4-difluorophenyl isocyanate (12.4 μL, 0.105 mmol) in a similar manner as described in Example 1.2 to afford Compound 141 as a white solid in 73.3% yield. LCMS m/z (%)=416 (M+H, 100). 1H NMR (400 MHz, DMSO-d6) δ: 8.95 (s, 1H), 8.46 (s, 1H), 8.08-8.02 (m, 1H), 7.45-7.42 (m, 2H), 7.37 (d, J=2.7 Hz, 1H), 7.33-7.27 (m, 1H), 7.12 (d, J=8.95 Hz, 1H), 7.05-6.98 (m, 1H), 6.24 (d, J=2.7 Hz, 1H), 4.03 (t, J=5.80 Hz, 2H), 3.67 (s, 3H), 2.54 (t, J=5.73 Hz, 2H), 2.12 (s, 6H).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:13])[C:6]2[CH:12]=[CH:11][S:10][C:7]=2[NH:8][CH:9]=1)(=O)[NH2:2].C1(C)C=CC=CC=1.O1CCCC1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>O1CCOCC1>[C:1]([C:4]1[C:5](=[O:13])[C:6]2[CH:12]=[CH:11][S:10][C:7]=2[NH:8][CH:9]=1)(=[S:35])[NH2:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)c1c[nH]c2sccc2c1=O
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: NC(=S)c1c[nH]c2sccc2c1=O

Procedure:
To a solution of 4,7-Dihydro-5-carbamoyl-4-oxothieno[2,3-b]pyridine derivative (vih) in an appropriate solvent, e.g. toluene, tetrahydrofuran, dioxane, an equivalent amount or a small excess amount of thioamide reagent, e.g. Lawessons reagent, is added under room temperature or ice-cooling. The mixture is stirred at a temperature of 0° C. to 80° C., and subjected to refluxing under heating if required, to give a 4,7-dihydro-5-thiocarbamoyl-4-oxothieno[2,3-b]pyridine derivative (viih).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[CH2:12][C@H:11]2[NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:6][CH:5]=1)([O-])=O.C(O)C>C(OCC)(=O)C.[Pt](=O)=O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[CH2:12][C@H:11]2[NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc([N+](=O)[O-])cc1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(N)cc1
Temperature: 25 °C
Yield: 84.6 %

Procedure:
1.39 g (5.0 mmol) of the product prepared in step 15.2 are dissolved in 25 mL of hot ethyl acetate. After cooling to room temperature, 25 mL of absolute ethanol and 0.057 g (0.25 mmol) of platinum (IV) oxide are successively added. The reaction mixture is placed under a hydrogen pressure of 2.75 bar for 2 hours, and is filtered through thin glass fibre paper. The filtrate is concentrated under vacuum and purified by chromatography on a column of silica, eluting with a cyclohexane/ethyl acetate gradient (from 70/30 to 55/45). 1.05 g of the expected product are obtained. Yield=85%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[S:18]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19]1.C(N(C(C)C)CC)(C)C.CN(C=O)C>CO>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][S:23]([C:20]4[CH:21]=[CH:22][S:18][CH:19]=4)(=[O:25])=[O:24])=[CH:3][CH:4]=3)[N:9]=[CH:10][C:11]=12
Reactant: Nc1ccc(-n2ncc3c(N)ncnc32)cc1
Reactant: O=S(=O)(Cl)c1ccsc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: Nc1ncnc2c1cnn2-c1ccc(NS(=O)(=O)c2ccsc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 17.6 %

Procedure:
Title compound 11A, 1-(4-amino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (39 mg, 1.0 eq, 0.17 mmol), 3-thiophenesulphonylchloride (31 mg, 1.0 eq, 0.17 mmol) and diisopropylethylamine (30 μl, 1.0 eq, 0.17 mmol) were added to DMF (1 ml) and the mixture was stirred for 18 hours at room temperature under an inert atmosphere. Methanol was then added (1 ml) and the solvents were removed in vacuo. The resultant residue was absorbed onto silica and purified by column chromatography using DCM/MeOH (96:4) as eluent to yield the title compound as a white solid (13 mg, 0.03 mmol, 20%). LCMS: [M+H]+=373, Rt=1.60 min, 100% purity.
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]([N:7]([CH2:18][CH3:19])[S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])(=[O:10])=[O:9])([CH3:6])[CH3:5].C1COCC1.CO.O[Li].O>O>[CH2:18]([N:7]([C:4]([CH3:5])([CH3:6])[C:3]([OH:20])=[O:2])[S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])(=[O:10])=[O:9])[CH3:19]
Reactant: CCN(C(C)(C)C(=O)OC)S(=O)(=O)c1ccccc1C
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCN(C(C)(C)C(=O)O)S(=O)(=O)c1ccccc1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.3 %

Procedure:
methyl-2-(N-ethyl-2-methylphenylsulfonamido)-2-methylpropanoate (524 mg, 1.75 mmol) was charged, and dissolved through addition of THF (5 ml), and methanol (5 ml). LiOH.H2O dissolved in H2O (5 ml) was added thereto, followed by stirring for 12 hours at room temperature. After stirring for 12 hours, the resultant solution was vacuum-evaporated, acidified with 2N—HCl to pH 2-3, and extracted with EA (×2). The organic layer was dried with MgSO4, and filtered. Through vacuum distillation, the solvent was removed so as to obtain 2-(N-ethyl-2-methylphenylsulfonamido)-2-methylpropionic acid (490 mg, 1.72 mmol, 98%).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:16](=[O:17])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[CH:29]=[CH:28][C:27]([S:30][CH2:31][CH3:32])=[CH:26][CH:25]=4)[CH:19]=3)[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.C(Cl)Cl.O.O.O.O.O.O.C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=[O:46].[Mg+2]>CO>[CH:1]1([NH:4][C:5]([C:7]2[C:16](=[O:17])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[CH:25]=[CH:26][C:27]([S:30]([CH2:31][CH3:32])=[O:46])=[CH:28][CH:29]=4)[CH:19]=3)[CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CCSc1ccc(-c2cccc(-n3cc(C(=O)NC4CC4)c(=O)c4cccnc43)c2)cc1
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CCS(=O)c1ccc(-c2cccc(-n3cc(C(=O)NC4CC4)c(=O)c4cccnc43)c2)cc1
Reaction time: 2 h

Procedure:
To a solution of N-cyclopropyl-1-[3-(4-ethylthiophenyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide from Example 18, in a 1:1 mixture of methylene chloride and methanol (9 ml/mmol), was added at 0° C. magnesium monoperoxyphthalate hexahydrate (MMPP, 0.5 molareq) and the resulting mixture was stirred in the cold for 2 hours. The mixture was quenched with saturated aqueous sodium bicarbonate and partitioned between methylene chloride and water. The crude product from the organic phase was chromatographed on silica gel eluting with a 90:9:1 mixture of methylene chloride, ethanol and 28% aqueous ammonium hydroxide to afford the title compound as a solid.
Reaction SMILES: C([O:3][C:4](=[O:25])[C@H:5]([N:11]1[CH2:15][C:14]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[CH:13][C:12]1=[O:24])[CH2:6][CH:7]([CH3:10])[CH2:8][CH3:9])C.[OH-].[Li+]>O1CCCC1>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[O:16][C:14]1[CH2:15][N:11]([C@H:5]([CH2:6][CH:7]([CH3:10])[CH2:8][CH3:9])[C:4]([OH:25])=[O:3])[C:12](=[O:24])[CH:13]=1
Reactant: CCOC(=O)[C@@H](CC(C)CC)N1CC(Oc2ccccc2Cl)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCC(C)C[C@H](C(=O)O)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 5 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
A solution of (R)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-hexanoic acid ethyl ester (1.25 g, 3.42 mmol) in tetrahydrofuran (14 mL) was treated with a 0.5N lithium hydroxide solution (4 mL) and stirred at 5° C. for 2 h. The mixture was concentrated in vacuo and the residue was dissolved in water (40 mL) and washed with diethyl ether. The organic phase was discarded and the aqueous layer acidified with 1N aqueous hydrochloric acid (10 mL) and extracted with ethyl acetate. The combined ethyl acetate layers were concentrated in vacuo which afforded (R)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-hexanoic acid (1.13 g, 98%) as a pale brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[CH:8][O:7][C:6]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=1)=[O:4].[H][H]>CO.[Pd]>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[CH:8][O:7][C:6]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=1)=[O:4]
Reactant: COC(=O)c1ccoc1-c1cccc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccoc1-c1cccc(N)c1
Yield: 85.4 %

Procedure:
A solution of 2-(3-nitrophenyl)furan-3-carboxylic acid methyl ester (1.0 g) in methanol (60 mL) containing 10% palladium on carbon (2.9 g) was stirred under 1 atmosphere of hydrogen for 1 h. The reaction mixture was then filtered through Celite. Removal of the solvent at reduced pressure gave the title compound as a yellow solid (0.75 g). C12H11NO3: M+Na+ 240
Reaction SMILES: [H-].[Na+].[NH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.[CH3:14][CH2:15][CH2:16]I.O>CS(C)=O>[NH2:3][CH2:4][CH2:5][CH2:6][N:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCI
Reactant: NCCCNc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCN(CCCN)c1ccccn1
Reaction time: 8 h
Yield: 40.5 %

Procedure:
Sodium hydride (1.14 g) was dissolved in dimethylsulphoxide (DMSO) (20 ml) at 70°-75° C. The solution was cooled and 2-(3-aminopropylamino)pyridine (6.57 g) in DMSO (20 ml) was added at room temperature. N-Propyl iodide (8.13 g) in DMSO (10 ml) was added dropwise maintaining the temperature at 20°-25° C. After allowing the mixture to stand overnight, water (250 ml) was added and this mixture was extracted with ether. The ether extracts were washed with hydrochloric acid (2N) and the aqueous layers made alkaline to pH 10.5. The aqueous layer was extracted with ether and chloroform. The pH was adjusted to pH 14 and the aqueous layer was extracted again with ether. The final ether extract was dried (K2CO3O, and the ether was evaporated to give 2-[N-(3-aminopropyl)-N-propylamino]pyridine (3.4 g) as an oil which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:11][O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[C:6]=2[N:7]=1.[CH3:24][NH2:25]>CO>[Cl:1][C:2]1[N:3]=[C:4]([NH:25][CH3:24])[C:5]2[CH2:11][O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[C:6]=2[N:7]=1
Reactant: FC(F)(F)Oc1ccc(C2COCc3c(Cl)nc(Cl)nc32)cc1
Reactant: CN
Solvent: CO
Product: CNc1nc(Cl)nc2c1COCC2c1ccc(OC(F)(F)F)cc1
Reaction time: 8 h
Yield: 87.8 %

Procedure:
To a solution of 2,4-dichloro-8-(4-(trifluoromethoxy)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine (Preparation AB) (80.7 mg, 0.221 mmol) in MeOH (2210 μL) was added methylamine (1000 μL, 2.0 mmol) (2M in THF). The reaction was allowed to stir overnight. Removed the solvent and applied to silica gel, eluting with an EtOAc/Hex gradient to afford 2-chloro-N-methyl-8-(4-(trifluoromethoxy)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine (69.8 mg, 0.194 mmol, 88% yield). LC-MS (M+H)+=360.0.
Reaction SMILES: [CH3:1][C:2]([NH:4][C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)=[O:3].C[C:13]([CH3:16])([O-])[CH3:14].[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>[CH2:5]([NH:4][C:8]1[CH:9]=[CH:10][C:5]([NH:4][C:2](=[O:3])[CH3:1])=[CH:6][CH:7]=1)[CH2:6][CH2:7][CH2:14][CH2:13][CH3:16]
Reactant: CC(C)(C)[O-]
Reactant: CC(=O)Nc1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCCCCCNc1ccc(NC(C)=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 162.2 %

Procedure:
An oven-dried resealable schlenk tube containing a stir bar was charged with Pd2(dba)3 (4.6 mg, 0.005 mmol), 2-di-cyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (11.9 mg, 0.025 mmol), 4-bromoacetanilide (107 mg, 0.5 mmol) and sodium tbutoxide (120 mg, 1.2 mmol). The tube was capped with a rubber septum, evacuated and backfilled with argon. nHexylamine (100 μL, 0.75 mmol) and tbutanol (1 mL) were added through the septum via syringe. The septum was replaced with a Teflon screw cap. The schlenk tube was sealed and put into a pre-heated oil bath at 110° C. The reaction mixture was stirred for 3 h, allowed to cool down to room temperature and quenched with water. Extraction with ethyl acetate three times followed by chromatography on silica gel column with 1:1 hexane:ethyl acetate gave 95 mg (81%) of the title compound as a white solid.