Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN1CCOCC1.[C:8]([O:12][C:13]([NH:15][CH:16]([CH3:20])[C:17]([OH:19])=O)=[O:14])([CH3:11])([CH3:10])[CH3:9].ClC(OCC(C)C)=O.S(C1C=CC(C)=CC=1)(O)(=O)=O.[NH2:40][CH:41]([C:47](=[O:49])[CH3:48])[C:42]([O:44][CH2:45][CH3:46])=[O:43]>C1COCC1>[C:8]([O:12][C:13]([NH:15][CH:16]([CH3:20])[C:17]([NH:40][CH:41]([C:47](=[O:49])[CH3:48])[C:42]([O:44][CH2:45][CH3:46])=[O:43])=[O:19])=[O:14])([CH3:9])([CH3:10])[CH3:11]
Reactant: CCOC(=O)C(N)C(C)=O
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCOC(=O)C(NC(=O)C(C)NC(=O)OC(C)(C)C)C(C)=O
Temperature: -25 °C
Reaction time: 0.5 h
Yield: 68.7 %

Procedure:
A solution of 4-methylmorpholine (900 g) in THF (15 L) was added to 2-(tert-butoxycarbonylamino)propanoic acid (1690 g, 8933.17 mmol). The mixture was cooled to −25° C. and isobutyl chloroformate (1.164 L, 8933.17 mmol) was added. After 20 minutes the second equivalent of 4-methylmorpholine (900 g) was added followed by ethyl 2-amino-3-oxobutanoate Tosylate salt (see J-P. Genet et al, Eur. J. Org. Chem., 2004, 3017-3026) (2700 g, 8507.78 mmol) suspended in THF (2.5 L). The mixture was stirred at −25° C. for 30 minutes and then left to warm to ambient temperature overnight. The reaction was quenched with water (15 L), extracted with EtOAc (3×5 L) and the combined extracts washed with 50% saturated brine (5 L). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 50 to 80% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford ethyl 2-(2-(tert-butoxycarbonylamino)propanamido)-3-oxobutanoate (1850 g, 68.7%).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:11]([O:15][C:16]([NH:18][C@H:19]1[CH2:23][C@@H:22]([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].[CH3:28][C:29]([Si:32]([O:35][CH2:36][CH2:37]I)([CH3:34])[CH3:33])([CH3:31])[CH3:30].Cl>C1COCC1>[C:11]([O:15][C:16]([NH:18][C@H:19]1[CH2:23][C@@:22]([CH2:37][CH2:36][O:35][Si:32]([C:29]([CH3:31])([CH3:30])[CH3:28])([CH3:34])[CH3:33])([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)OCCI
Reactant: COC(=O)[C@H]1C=C[C@@H](NC(=O)OC(C)(C)C)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)[C@@]1(CCO[Si](C)(C)C(C)(C)C)C=C[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: -68 °C
Reaction time: 0.75 h

Procedure:
To a −70° C. solution of LiHMDS in THF (1M, 6.97 L, 6.97 mol) was added a solution of the product of Step B (763.5 g, 3.16 mol) in THF (800 mL) over a 2 h period while keeping the temperature at or below −68° C. The resulting solution was stirred for 45 min at −68° C. A solution of the product of Step C (1.267 kg, 4.426 mol) in THF (800 mL) was added over 1 h 50 min period while maintaining a temperature of ˜−66° C. The reaction was stirred at ˜-66° C. for 45 min. The reaction was warmed to −15° C. and worked up by addition to mixture of aqueous HCl and ice. The mixture was extracted with toluene, the organic layer was washed with water, brine and dried over MgSO4. The organic layer was concentrated and purified on silica gel using a mixture of EtOAc in heptanes to provide the product of Step D as a clear oil. 1H NMR (400 MHz, CHLOROFORM-d) d=5.69-5.86 (m, 2H), 4.79-4.93 (m, 1H), 4.68-4.80 (m, 1H), 3.67 (s, 3H), 3.53-3.62 (m, 2H), 2.16-2.30 (m, 1H), 2.04-2.16 (m, 2H), 1.70-1.81 (m, 1H), 1.41 (s, 9H), 0.78-0.91 (m, 13H), 0.00 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([SH:9])[NH:8][C:4]=2[CH:3]=1.[OH-].[Na+].[CH2:14](Cl)/[CH:15]=[C:16](/[CH2:18][CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])\[CH3:17]>CO>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7]([S:9][CH2:14]/[CH:15]=[C:16](\[CH3:17])/[CH2:18][CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])=[N:8][C:4]=2[CH:3]=1
Reactant: Sc1nc2ccc(Cl)cc2[nH]1
Reactant: CC(C)=CCC/C(C)=C/CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)=CCC/C(C)=C/CSc1nc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 23.4 %

Procedure:
To a solution of the 5-chloro-2-mercaptobenzimidazole (0.665 g, 3.6 mmol) in methanol (10 mL) and 2N NaOH (7 mmol) was added geranyl chloride (0.775 g, 4.5 mmol). The reaction mixture was stirred at ambient temperature for 24 hours, evaporated in vacuo, dissolved in CH2Cl2, washed with water, and dried over Na2SO4. Evaporation and flash chromatography (Merck Kieselgel, CH2Cl2) gave an oil which was crystallized with pentane to yield a white solid of the title compound (270 mg). m.p. 102°-104° C. NMR (CDCl3)δ7.45-7.0(m,3H), 5.37(t, J=7 Hz,1H), 5.03(t,J=7Hz, 1H), 3.93(d,J=8 Hz,2H), 2.02(m,4H), 1.67(s,3H), 1.66(s,3H), 1.58(s,3H).
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][N:3]1[C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH2:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1.O1CCCC1.[OH:26][CH:27]([CH2:30][OH:31])[CH2:28][SH:29]>CO>[OH:26][CH:27]([CH2:30][OH:31])[CH2:28][S:29][S:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:2]([NH:3][C:11]1[CH:16]=[CH:15][C:14]([S:17](=[O:19])(=[O:18])[NH2:20])=[CH:13][CH:12]=1)=[O:1]
Reactant: NS(=O)(=O)c1ccc(-n2sc3ccccc3c2=O)cc1
Reactant: OCC(O)CS
Solvent: C1CCOC1
Solvent: CO
Product: NS(=O)(=O)c1ccc(NC(=O)c2ccccc2SSCC(O)CO)cc1

Procedure:
This compound was prepared according to the method of Example 132 using a suspension of 0.46 g (1.5 mmol) of 4-(3-oxo-3H-benzo[d] isothiazol-2-yl) benzenesulfonamide in a mixture of 15 mL of methanol, and 15 mL of tetrahydrofuran and 2,3-dihydroxy-1-propanethiol. The product was washed with ether and dried in vacuo to give 0.61 g of the title compound, mp >260° C.
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:3]1.[O:17]=[O+:18][O-].CC[O:22]CC>C(Cl)(Cl)(Cl)Cl>[CH3:1][CH:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:22][CH:3]1[O:17][O:18]2
Reactant: CC1C=C(c2ccccc2)c2ccccc21
Reactant: O=[O+][O-]
Reactant: CCOCC
Solvent: ClC(Cl)(Cl)Cl
Product: CC1c2ccccc2C2(c3ccccc3)OOC1O2
Yield: 70 %

Procedure:
A 1.03 g quantity (5 mmols) of 1-methyl-3-phenylindene, a known compound, was dissolved in 20 ml of carbon tetrachloride, and thereafter reacted with ozone in 1.3 times the molar quantity of the compound at 0° C. To the reaction mixture was added 50 ml of ether, and the organic layer was washed with saturated aqueous solution of sodium bicarbonate and then with saturated aqueous solution of sodium chloride. The organic layer obtained was dried over anhydrous magnesium sulfate, the solvent was thereafter distilled off in a vacuum, and the residue was subjected to silica gel column chromatography for separation and purification (eluent: benzene-hexane, 1:5), consequently giving 0.89 g (yield 70%) of a 2:1 mixture of exo- and endo-isomers of the desired compound. The two isomers were individually isolated by repeating column chromatography again and recrystallization from methanol. The physical properties of two isomeric products are shown in Table 1.
Reaction SMILES: [H-].[Na+].[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[SH:13].[CH2:14]([O:16][C:17](=[O:35])[C:18]([CH3:34])([O:31][CH2:32][CH3:33])[CH:19]([PH:23](COS(C)(=O)=O)=[O:24])[CH:20]([CH3:22])[CH3:21])[CH3:15].[CH3:36]N(C=O)C>>[CH2:14]([O:16][C:17](=[O:35])[C:18]([CH3:34])([O:31][CH2:32][CH3:33])[C:19]([CH2:36][S:13][C:4]1[CH:5]=[CH:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:3]=1)([PH2:23]=[O:24])[CH:20]([CH3:21])[CH3:22])[CH3:15]
Reactant: CN(C)C=O
Reactant: Sc1ccc2ccccc2n1
Reactant: CCOC(=O)C(C)(OCC)C(C(C)C)[PH](=O)COS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(C)(OCC)C(CSc1ccc2ccccc2n1)([PH2]=O)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
Sodium hydride (1.52 g, (60%)) and 6 g of 2-quinoline thiol were stirred together at 0° C. in 50 mL DMF. After the initial H2 evolution had subsided, the mixture was stirred at room temperature for 21/2 hours. The mixture was then cooled to 0° C. and 2-(ethoxy) (methanesulfonyloxymethyl)phosphinoyl-methyl-4-methylpentanoic acid ethyl ester (12.8 g) in 10 mL DMF was added via cannula and the resulting mixture was then stirred for 18 hours, slowly warming to room temperature. The DMP was removed by evaporation, the residue dissolved in 50 mL ethyl acetate and washed with 50 mL H2O (2×), brine (50 mL), dried with MgSO4 and evaporated to a yellow semi-solid. Purification by flash chromatography using 10% ethyl acetate/hexane to 80% ethyl acetate/hexane for the elution yielded 10 g of 2-(ethoxy) (quinolin-2-ylthiomethyl)-phosphinoyl-methyl-4-methylpentanoic acid ethyl ester (Rf 0.35 80% ethyl acetate/hexane), MS: 424 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[C:12](=O)([O-])[O-].[K+].[K+].CI.[OH-].[Na+]>CC(C)=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([O:8][CH3:12])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Solvent: CI
Product: COc1cc(F)ccc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 99.9 %

Procedure:
A solution of 5-fluoro-2-nitrophenol (10.0 g) in dry acetone (40 ml) under nitrogen was treated with potassium carbonate (8.9 g). The mixture formed a deep red coloured thick precipitate. Methyl iodide (5 ml, 11.4 g) was added slowly and the mixture stirred overnight and then at 60° C. for 3 hours. Further methyl iodide (3 ml, 6.84 g) was added and the mixture stirred at 60° C. for a further 3 hours. After this time the deep red colour had disappeared, and the mixture (now orange) was added to water (50 ml) and sodium hydroxide (2N, 40 ml), and extracted with dichloromethane (3×100 ml). The combined, dried extracts were concentrated in vacuo to give a yellow oil which upon cooling crystallised giving a pale yellow crystalline solid (4-fluoro-2-methoxy-1-nitrobenzene 10.88 g). A solution of this solid in ethanol:water (200 ml, 6:2) was added under vacuum to a prehydrogenated suspension of palladium (10% on carbon, 50% paste, 2.5 g) in ethanol:water (80 ml, 6:2). The suspension was stirred under an atmosphere of hydrogen for 2 hours, the suspension was filtered through Hyflo and the filtercake washed thoroughly with ethanol and water. The combined filtrates were concentrated in vacuo and the moist residue re-evaporated with ethanol. The purple oily residue was dissolved in dichloromethane (200 ml), dried and concentrated in vacuo to give the title compound as a dark purple liquid. (7.73 g).
Reaction SMILES: [OH:1][C@H:2]([CH3:6])[C:3](N)=O.F[B-](F)(F)F.C([O+](CC)CC)C.[NH2:19][C:20]1[C:21]([NH:29][C@@H:30]2[CH2:35][C@@H:34]([NH:36][C:37](=[O:46])[O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C@@H:33]([CH2:47][C:48]#[N:49])[CH2:32][CH2:31]2)=[C:22]2[S:28][CH:27]=[CH:26][C:23]2=[N:24][CH:25]=1>O1CCCC1.C(O)C>[C:48]([CH2:47][C@H:33]1[CH2:32][CH2:31][C@H:30]([N:29]2[C:21]3=[C:22]4[S:28][CH:27]=[CH:26][C:23]4=[N:24][CH:25]=[C:20]3[N:19]=[C:3]2[C@H:2]([OH:1])[CH3:6])[CH2:35][C@H:34]1[NH:36][C:37](=[O:46])[O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)#[N:49]
Reactant: C[C@@H](O)C(N)=O
Reactant: N#CC[C@H]1CC[C@H](Nc2c(N)cnc3ccsc23)C[C@H]1NC(=O)OCc1ccccc1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: C1CCOC1
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CC#N)[C@H](NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 61.3 %

Procedure:
A mixture of (2R)-2-hydroxypropanamide (17.1 mg, 0.192 mmol) and triethyloxonium tetrafluoroborate (34.2 mg, 0.180 mmol) in tetrahydrofuran (0.36 mL) was stirred at room temperature for 75 min and then concentrated. The residue was dissolved in ethanol (0.14 mL), and this solution was then added to a solution of benzyl [(1R,2R,5S)-5-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]-2-(cyanomethyl)cyclohexyl]carbamate (26 mg, 0.060 mmol) in ethanol (0.36 mL) in a vial. The resulting mixture was stirred at 80° C. overnight. After cooling, the mixture was concentrated and purified on silica gel, eluted with 0-10% MeOH in dichloromethane to give 18 mg of the desired product. LCMS calculated for C26H28N5O3S (M+H)+: m/z=490.2. Found: 490.0.
Reaction SMILES: [CH3:1]/[C:2](=[CH:7]\OS(C1C=CC(C)=CC=1)(=O)=O)/[C:3]([O:5][CH3:6])=[O:4].[C:19]1([SH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.COC(C)(C)C>C(Cl)(Cl)Cl>[CH3:7]/[C:2](=[CH:1]\[S:25][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)/[C:3]([O:5][CH3:6])=[O:4]
Reactant: Sc1ccccc1
Reactant: COC(=O)/C(C)=C/OS(=O)(=O)c1ccc(C)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Product: COC(=O)/C(C)=C/Sc1ccccc1
Temperature: 50 °C
Reaction time: 9 h
Yield: 76.7 %

Procedure:
11.0 g (40.7 mmol) of (E)-methyl 2-methyl-3-(p-toluenesulfonyloxy)-2-propenoate was dissolved in 100 ml of chloroform and 6.3 g (57.0 mmol) of thiophenol and 33 ml of triethylamine were added. The solution was stirred at 50° C. for 9 hours. To the reaction mixture was added tert-butyl methyl ether and washed sequentially with an aqueous 1N NaOH solution and a saturated NaCl solution, dried, and concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1) to obtain 6.5 g of (E)-methyl 2-methyl-3-(phenylthio)-2-propenoate.
Reaction SMILES: C(NC1SC(S(NC2C=CC(CC([NH:24][C:25]3[C:26](=[O:45])[N:27]([CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[F:44])[C:28](=[O:36])[N:29](CC4CC4)[C:30]=3[NH2:31])=O)=CC=2)(=O)=O)=C(C)N=1)(=O)C.Cl.CN(C)CCCN=C=NCC.[Cl:58][C:59]1[N:63]([CH3:64])[N:62]=[C:61]([CH3:65])[C:60]=1[S:66]([NH:69][C:70]1[CH:71]=[CH:72][C:73]([CH2:76][C:77]([OH:79])=O)=[N:74][CH:75]=1)(=[O:68])=[O:67].NC1C(=O)N(CC2C=CC=CC=2F)C(=O)NC=1N>CO.C(Cl)(Cl)Cl>[NH2:31][C:30]1[NH:29][C:28](=[O:36])[N:27]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[F:44])[C:26](=[O:45])[C:25]=1[NH:24][C:77](=[O:79])[CH2:76][C:73]1[CH:72]=[CH:71][C:70]([NH:69][S:66]([C:60]2[C:61]([CH3:65])=[N:62][N:63]([CH3:64])[C:59]=2[Cl:58])(=[O:67])=[O:68])=[CH:75][N:74]=1
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Nc2ccc(CC(=O)Nc3c(N)n(CC4CC4)c(=O)n(Cc4ccccc4F)c3=O)cc2)s1
Reactant: Cc1nn(C)c(Cl)c1S(=O)(=O)Nc1ccc(CC(=O)O)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1[nH]c(=O)n(Cc2ccccc2F)c(=O)c1N
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1nn(C)c(Cl)c1S(=O)(=O)Nc1ccc(CC(=O)Nc2c(N)[nH]c(=O)n(Cc3ccccc3F)c2=O)nc1
Yield: 42 %

Procedure:
Prepared as for 2-[4-(2-acetylamino-4-methyl-thiazole-5-sulfonylamino)-phenyl]-N-[6-amino-1-cyclopropylmethyl-3-(2-fluoro-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl]-acetamide (example 10, step 1) except that the coupling was performed using 1 [3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride as the coupling reagent and [5-(5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonylamino)-pyridin-2-yl]-acetic acid and 5,6-diamino-3-(2-fluoro-benzyl)-1H-pyrimidine-2,4-dione were used as the coupling partners. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 10/90 methanol/chloroform) afforded N-[6-amino-3-(2-fluoro-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl]-2-[5-(5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonylamino)-pyridin-2-yl]-acetamide (42%) as an off white solid; LRMS for C29H29ClFN7O4S (M+H)+ at m/z=577/579.
Reaction SMILES: Br[C:2]1[C:3]([S:8][CH3:9])=[N:4][CH:5]=[N:6][CH:7]=1.CCC[CH2:13][CH2:14][CH3:15].O.[O:17]1CCC[CH2:18]1>>[OH:17][CH:18]([C:2]1[C:3]([S:8][CH3:9])=[N:4][CH:5]=[N:6][CH:7]=1)[CH:14]([CH3:13])[CH3:15]
Reactant: CCCCCC
Reactant: C1CCOC1
Reactant: CSc1ncncc1Br
Solvent: O
Product: CSc1ncncc1C(O)C(C)C
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 28 %

Procedure:
10.6 g (52 mmol) of 5-bromo-4-methylthiopyrimidine was dissolved in 100 ml of tetrahydrofuran, and at −60° C., 36 ml of a n-butylithium hexane solution (1.6 mol/l) was dropwise added. After stirring at −60° C. for 30 minutes, 4.1 g (57 mmol) of isobutylaldehyde was dropwise added and further reacted for 1 hour. The reaction solution was poured into water and extracted with ethyl acetate. The obtained organic layer was washed with water and then dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent/n-hexane:ethyl acetate=3:2) to obtain 2.9 g (yield: 28%) of 5-(1-hydroxy-2-methylpropyl)-4-methylthiopyrimidine as slightly yellow crystals (melting point: 123-127° C.).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][C@@H:13]([CH3:17])[C:14]#[C:15][CH3:16])[CH:3]=1.ClC(OCC)=O.N[CH:25]1[CH:30]2[CH2:31][N:32]([CH3:34])[CH2:33][CH:26]1[CH2:27][N:28]([CH3:35])[CH2:29]2.[OH-].[Na+].C([N:40](CC)CC)C>ClCCl.O>[CH3:34][N:32]1[CH2:31][CH:30]2[CH:25]([C:3]3[C:4]([O:12][CH:13]([CH3:17])[C:14]#[C:15][CH3:16])=[C:5]([CH:9]=[C:10]([Cl:11])[C:2]=3[NH2:1])[C:6]([NH2:40])=[O:8])[CH:26]([CH2:27][N:28]([CH3:35])[CH2:29]2)[CH2:33]1
Reactant: CN1CC2CN(C)CC(C1)C2N
Reactant: CCN(CC)CC
Reactant: CC#C[C@H](C)Oc1cc(N)c(Cl)cc1C(=O)O
Agent: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC#CC(C)Oc1c(C(N)=O)cc(Cl)c(N)c1C1C2CN(C)CC1CN(C)C2
Reaction time: 0.17 h

Procedure:
A solution of 546 mg of (S)-4-amino-5-chloro-2-[(1-methyl-2-butynyl)oxy]benzoic acid and 0.9 ml of triethylamine in 10 ml of dichloromethane was cooled with ice, followed by the addition thereto of 0.225 ml of ethyl chloroformate. The obtained mixture was stirred for 10 minutes, while the temperature was brought to room temperature. 400 mg of 9-amino-3,7-dimethyl-3,7-diazabicyclo[3.3.1]nonane was added to the resulting mixture at room temperature. The obtained mixture was stirred for 30 minutes, followed by the addition thereto of 200 mg of 9-amino-3,7-dimethyl-3,7-diazabicyclo[3.3.1]nonane at room temperature. The obtained mixture was stirred for one hour, followed by the addition thereto of dichloromethane and water. The pH of the aqueous layer was adjusted to 10 or above with a 2.5N aqueous solution of sodium hydroxide. The organic phase was recovered, dried over anhydrous magnesium sulfate, and concentrated in a vacuum. The residue was purified by silica gel column chromatography (with 0 to 10 to 20% methanol/chloroform and then with chloroform/methanol/aqueous ammonia (75/25/1.5) to give 650 mg of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][S:6][C:7]1[N:12]=[C:11](Cl)[CH:10]=[C:9]([Cl:14])[N:8]=1)[CH3:2].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][S:6][C:7]1[N:8]=[C:9]([Cl:14])[CH:10]=[C:11]([NH:24][C:21]2[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[N:12]=1)[CH3:2]
Reactant: CCOC(=O)CSc1nc(Cl)cc(Cl)n1
Reactant: COc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CSc1nc(Cl)cc(Nc2ccc(OC)cc2)n1
Yield: 65.3 %

Procedure:
A stirred mixture of 5.2 g of (4,6-dichloro-2-pyrimidinylthio)acetic acid ethyl ester, 2.4 g of p-anisidine and 2.1 g of sodium carbonate in 100 ml. of ethanol was heated under reflux for 6 hr. The reaction mixture was filtered and the filtrate cooled in ice. A crystalline material was deposited which was purified by recrystallization from ethanol. There was obtained 4.5 g of product, mp. 96°-97.5°C.
Reaction SMILES: CC([N:5]([C@H:9]([C:11]1([OH:34])[CH2:14][N:13]([C:15]([C:17]2[C:22]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:25]=3[F:31])=[CH:21][C:20](=[O:32])[N:19]([CH3:33])[N:18]=2)=[O:16])[CH2:12]1)[CH3:10])C(=O)[O-])(C)C.Cl.C[OH:37]>>[C:20]([OH:32])(=[O:37])[CH3:21].[NH2:5][C@H:9]([C:11]1([OH:34])[CH2:14][N:13]([C:15]([C:17]2[C:22]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:25]=3[F:31])=[CH:21][C:20](=[O:32])[N:19]([CH3:33])[N:18]=2)=[O:16])[CH2:12]1)[CH3:10]
Reactant: C[C@H](N(C(=O)[O-])C(C)(C)C)C1(O)CN(C(=O)c2nn(C)c(=O)cc2Nc2ccc(I)cc2F)C1
Reactant: CO
Agent: Cl
Product: CC(=O)O
Product: C[C@H](N)C1(O)CN(C(=O)c2nn(C)c(=O)cc2Nc2ccc(I)cc2F)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
1,1-Dimethylethyl{(1S)-1-[1-({4-[(2-fluoro-4-iodophenyl)amino]-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl}carbonyl)-3-hydroxyazetidin-3-yl]ethyl}carbamate (55 mg, 0.09 mmol), prepared using procedures similar to those described in Example 36, was taken up in methanol (2 mL) and hydrochloric acid (4N in dioxane, 1 mL, 4 mmol) was added and the reaction was stirred at 60° C. for 2 hours. The reaction mixture was concentrated in vacuo and was purified by reverse-phase HPLC followed by lyophilization of the pure fractions to afford 6-({3-[(1S)-1-aminoethyl]-3-hydroxyazetidin-1-yl}carbonyl)-5-[(2-fluoro-4-iodophenyl)amino]-2-methylpyridazin-3(2H)-one acetate as yellow solid (40 mg, 87%). 1H NMR (400 MHz, CDCl3): 10.17 (d, 1H), 7.52-7.46 (m, 2H), 7.09 (t, 1H), 6.13-6.12 (m, 1H), 4.51-4.48 (m, 2H), 4.18-4.03 (m, 2H), 3.73 (d, 3H), 3.35-3.28 (m, 1H), 3.22-2.80 (br, 3H), 1.21-1.19 (m, 3H); MS (EI) for C17H19FIN5O3: 488 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[S:10][C:11]3[CH:17]=[C:16]([C:18]([OH:20])=O)[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.S(Cl)([Cl:23])=O>>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[S:10][C:11]3[CH:17]=[C:16]([C:18]([Cl:23])=[O:20])[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2nc3ccc(C(=O)O)cc3s2)cn1
Reactant: O=S(Cl)Cl
Product: COc1ccc(-c2nc3ccc(C(=O)Cl)cc3s2)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(6-Methoxypyridin-3-yl)-1,3-benzothiazole-6-carboxylic acid (30 mg, 0.10 mmol) was mixed with thionyl chloride (0.8 mL) and stirred at r.t. for 3 h, then heated to 50° C. for 1 h. The solvent was evaporated in vacuo to give the intermediate 2-(6-methoxypyridin-3-yl)-1,3-benzothiazole-6-carbonyl chloride as a crude product. This acid chloride was dissolved in DCM (3 mL) and added to ammonium hydroxide (conc., 2 mL). The reaction was stirred at r.t. without stopper overnight. The formed solid was collected by filtration, washed with water and dried (in vacuo over P2O5) to give the title compound (23 mg) as a yellow solid. 1H NMR δ 8.93 (d, 1H) 8.64 (s, 1H) 8.39 (dd, 1H) 7.95-8.19 (m, 3H) 7.50 (s, 1H) 7.04 (d, 1H) 3.97 (s, 3H); MS m/z (M+H) 286, (M−H) 284.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH:9][CH:10]=O)=[CH:7][CH:6]=[C:5]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:4]=1.CS(C1[N:23]=[CH:24][C:25]2[CH:31]=[CH:30][N:29]=[C:28]([NH:32][CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:26]=2[N:27]=1)(=O)=O>>[CH3:1][O:2][C:3]1[C:8]([NH:9][C:10]2[N:23]=[CH:24][C:25]3[CH:31]=[CH:30][N:29]=[C:28]([NH:32][CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:26]=3[N:27]=2)=[CH:7][CH:6]=[C:5]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:4]=1
Reactant: CC(C)(C)CNc1nccc2cnc(S(C)(=O)=O)nc12
Reactant: COc1nc(N2CCOCC2)ccc1NC=O
Product: COc1nc(N2CCOCC2)ccc1Nc1ncc2ccnc(NCC(C)(C)C)c2n1
Yield: 14 %

Procedure:
The title compound was prepared according to Example 40 using N-(2-methoxy-6-morpholinopyridin-3-yl)formamide (Preparation 71) and 2-(methylsulfonyl)-N-neopentylpyrido[3,4-d]pyrimidin-8-amine (Preparation 47). The residue was purified by silica gel column chromatography eluting with 0-5% MeOH EtOAc followed by a second chromatography eluting with 50-100% EtOAc in cyclohexane. The residue was dissolved in EtOAc and washed with HCl (0.5 M, 10 mL), dried (MgSO4) and concentrated in vacuo. The residue was further purified by passage through a SCX-2 cartridge eluting with 100% MeOH—1 M NH3 in MeOH, to afford the title compound (10 mg, 14%).