Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[NH2:5].[O-:12][C:13]#[N:14].[K+].Cl>O>[CH3:1][O:2][CH2:3][C@@H:4]([NH:5][C:13]([NH2:14])=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC[C@@H](N)c1ccccc1
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: COC[C@@H](NC(N)=O)c1ccccc1
Temperature: 100 °C

Procedure:
(S)-2-Methoxy-1-phenylethanamine (5.6 g, 37.0 mmol) and potassium cyanate (8.12 g, 100 mmol) were taken up in HCl (1 N, 40 mL, 40.0 mmol) and water (40 mL). The reaction mixture was heated to 100° C. for 3 h. Room temperature was attained, water was added, and the products extracted into EtOAc (×3) followed by 10% MeOH-DCM (×2). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was triturated in Et2O to give (S)-1-(2-methoxy-1-phenylethyl)urea. MS ESI calc'd. for C10H14N2O2 [M+1]+ 195. found 195.
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[S:13]1[C:17]2=[CH:18][N:19]=[C:20]([C:22](O)=[O:23])[CH:21]=[C:16]2[CH:15]=[CH:14]1.N>>[ClH:1].[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@@H:5]3[NH:12][C:22]([C:20]3[CH:21]=[C:16]4[CH:15]=[CH:14][S:13][C:17]4=[CH:18][N:19]=3)=[O:23])[CH2:3]1)[CH2:9]2
Reactant: NC1C2CC3CC1CN(C3)C2
Reactant: O=C(O)c1cc2ccsc2cn1
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1cc2ccsc2cn1

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and thieno[2,3-c]pyridine-5-carboxylic acid (Tetrahedron Lett. 1999, 40, 7935) according to methods A and C; yield 82 mg, 0.21 mmol (59%): 1H NMR (300 MHz, methanol-d4) δ 2.03 (d, J=14 Hz, 2H), 2.25 (s, 1H), 2.39 (d, J=14 Hz, 2H), 2.55 (s, 2H), 3.61 (s, 2H), 3.72 (s, 4H), 4.54 (s, 1H), 7.91 (d, J=5 Hz, 1H), 8.62 (d, J=5 Hz, 1H), 9.01 (s, 1H), 9.57 (s, 1H); MS (DCI/NH3) m/z 314 (M+H)+; Anal. C17H19N3OS.2HCl.1.0H2O: C, H, N.
Reaction SMILES: [NH2:1][O:2][CH2:3][CH:4]([OH:12])[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C([O-])([O-])=O.[Na+].[Na+].[CH3:19][N:20]([CH3:30])[C:21]([Cl:29])=[N:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)(Cl)Cl>[ClH:29].[CH3:19][N:20]([CH3:30])[C:21]([NH:1][O:2][CH2:3][CH:4]([OH:12])[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[N:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CN(C)C(Cl)=Nc1ccccc1
Reactant: NOCC(O)CN1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CN(C)C(=Nc1ccccc1)NOCC(O)CN1CCCCC1
Product: Cl

Procedure:
1150 mg (6.58 mmole) of 1-aminooxy-2-hydroxy-3-(1-piperidinyl)-propane (Ger. Off. 2 651 083) was dissolved in chloroform and 750 mg of Na2CO3 was added, then a solution of 1206 mg (6.58 mmole) of N,N-dimethyl-N′-phenyl-chloroformamidine (BR 888646/1959, Bayer, auth.: Kühle and Eue L.; CA 57, 136961/1962/) in 10 ml of chloroform was added dropwise. After 5 hours the solid state was filtered and the filtrate was evaporated. This residue (1800 mg oil) was dissolved in 10 ml of ethyl acetate, and the product was precipitated by addition of 10.46 ml of 0.54 N HCl/ethyl acetate. The yellow precipitate was filtered off, washed, and finally recrystallized from acetone, after ethyl acetate.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.Cl[C:22](Cl)([O:24]C(=O)OC(Cl)(Cl)Cl)Cl.[C:33]1([C:39]2([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[CH:43]3[CH2:44][NH:45][CH2:46][CH2:47][N:42]3[C:41](=[O:48])[O:40]2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O1CCCC1.O>[O:48]=[C:41]1[N:42]2[CH2:47][CH2:46][N:45]([C:22]([N:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[C:4](=[O:11])[CH2:3][CH2:2]3)=[O:24])[CH2:44][CH:43]2[C:39]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[O:40]1
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)C2CNCCN12
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: O=C1CCNc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: O=C1CCN(C(=O)N2CCN3C(=O)OC(c4ccccc4)(c4ccccc4)C3C2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 10.5 %

Procedure:
To a solution of 2,3-dihydroquinolin-4(1H)-one (75 mg, 0.51 mmol) and diisopropylethylamine (0.25 mL) in tetrahydrofuran (3 mL) was added triphosgene (0.15 g, 0.51 mmol), and the mixture was stirred at room temperature for 20 minutes. Hexahydro-1,1-diphenyl-3H-oxazolo[3,4-a]pyrazin-3-one (0.15 g, 0.51 mmol) was added thereto, and the resulting mixture was stirred at room temperature for 24 hours. The reaction solution was diluted with water and then extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solid was filtered off, and the filtrate was concentrated. The residue was purified with amino silica gel column chromatography (hexane:ethyl acetate=1:1 to ethyl acetate), and then recrystallized from diisopropyl ether to obtain the title compound (25 mg, yield 10%).
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([S:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20])[CH:12]=2)=[O:7])CCC.C1CC2N(C3C=C(C=C(C4C=CC=CC=4)C4C=CC=CC=4)C=CC=3)C3C(C2C1)=C(/C=C1/C([N:43]([CH2:47][C:48]([OH:50])=[O:49])C(S/1)=S)=O)C=CC=3>>[C:21]1([S:19]([C:13]2[CH:12]=[C:11]3[C:16]([C:17]([OH:18])=[C:8]([C:6]([NH:43][CH2:47][C:48]([OH:50])=[O:49])=[O:7])[N:9]=[CH:10]3)=[CH:15][CH:14]=2)=[O:20])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(O)CN1C(=O)/C(=C/c2cccc3c2C2CCCC2N3c2cccc(C=C(c3ccccc3)c3ccccc3)c2)SC1=S
Reactant: CCCCOC(=O)c1ncc2cc(S(=O)c3ccccc3)ccc2c1O
Product: O=C(O)CNC(=O)c1ncc2cc(S(=O)c3ccccc3)ccc2c1O

Procedure:
Prepared in analogy to Example D-1 g) from 7-benzenesulfinyl-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (Compound D-102 A). MS-(+)-ion: M+1=371.1.
Reaction SMILES: [N+](=[CH2:3])=[N-].[OH:4][CH:5]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])/[CH:6]=[CH:7]/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21]>C(Cl)Cl>[CH3:3][O:21][C:20](=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1/[CH:9]=[CH:8]/[CH:7]=[CH:6]/[CH:5]([OH:4])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCC(O)/C=C/C=C/c1ccccc1CCCCC(=O)O
Reactant: C=[N+]=[N-]
Solvent: ClCCl
Product: CCCCCCCCC(O)/C=C/C=C/c1ccccc1CCCCC(=O)OC
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
An ethereal diazomethane solution is added to a solution of 5 mg of 5-[2-[(1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl]-phenyl]-pentanoic acid (produced in example 9) in 0.5 ml of methylene chloride at 0° C. until permanent yellow dyeing and stirred for 5 minutes at 0° C. Then, it is concentrated by evaporation in a vacuum and the residue is chromatographed on silica gel. With hexane/0-80% of ether, 2.6 mg of the title compound is obtained as a colorless oil.
Reaction SMILES: [C:1]1([C:7]2[CH:34]=[CH:33][C:10]3[N:11]=[C:12]([CH2:14][C:15]4[O:19][C:18]([CH2:20][NH:21][S:22]([NH:25]C(=O)OC(C)(C)C)(=[O:24])=[O:23])=[N:17][N:16]=4)[S:13][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]1([C:7]2[CH:34]=[CH:33][C:10]3[N:11]=[C:12]([CH2:14][C:15]4[O:19][C:18]([CH2:20][NH:21][S:22](=[O:23])(=[O:24])[NH2:25])=[N:17][N:16]=4)[S:13][C:9]=3[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)NCc1nnc(Cc2nc3ccc(-c4ccccc4)cc3s2)o1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)NCc1nnc(Cc2nc3ccc(-c4ccccc4)cc3s2)o1
Reaction time: 0.5 h
Yield: 7.4 %

Procedure:
To a solution of Compound 24a (1.16 g, 2.30 mmol) in DCM (10 mL) was added TFA (5 mL) and the reaction mixture stirred for 0.5 h. The reaction mixture was concentrated under reduced pressure then azeotroped from toluene (2×). The crude residue was diluted with 1.5M K3PO4 then the aqueous layer extracted with DCM (3×). The combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified on silica gel eluting with 0-15% MeOH/DCM to give Compound 24b (68 mg, 74% yield) as a pale brown solid. LCMS=1.71 min using analytical method (B), 402.0 (M+H). 1H NMR (400 MHz, CD3OD) δ 8.24 (d, J=1.5 Hz, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.79 (dd, J=8.5, 1.8 Hz, 1H), 7.73-7.65 (m, 2H), 7.47 (t, J=7.7 Hz, 2H), 7.41-7.32 (m, 1H), 4.47 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5](I)=[CH:6][CH:7]=1.[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13].C(N(CC)CC)C>C(#N)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([C:16]#[C:15][Si:12]([CH3:14])([CH3:13])[CH3:11])=[CH:6][CH:7]=1
Reactant: C#C[Si](C)(C)C
Reactant: N#Cc1nc(I)ccc1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[Si](C)(C)C#Cc1ccc(N)c(C#N)n1

Procedure:
This compound is prepared in a manner analogous to that of Step A of Example 9, using 3.8 grams (0.015 mole) of 3-amino-2-cyano-6-iodopyridine (prepared in Step A of Example 10), 2.1 grams (0.021 mole) of trimethylsilylacetylene, 10.6 mL of triethylamine, 0.13 gram of copper iodide, and 0.29 gram of bis(triphenylphosphine)palladium(II) chloride in 50 mL of acetonitrile, yielding 3-amino-2-cyano-6-(trimethylsilylethynyl)pyridine.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[N:14]=[C:13]([N:15]([CH2:17][CH2:18][OH:19])[CH3:16])[CH:12]=[CH:11][C:8]=2C#N)=[CH:4][C:3]=1[CH:22]=[O:23].[CH3:24][C:25]([Si:28](Cl)([CH3:30])[CH3:29])([CH3:27])[CH3:26].C[CH2:33][N:34](CC)CC>C1COCC1>[Br:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:8]=[CH:11][C:12]([C:33]#[N:34])=[C:13]([N:15]([CH2:17][CH2:18][O:19][Si:28]([C:25]([CH3:27])([CH3:26])[CH3:24])([CH3:30])[CH3:29])[CH3:16])[N:14]=2)=[CH:4][C:3]=1[CH:22]=[O:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCN(CC)CC
Reactant: CN(CCO)c1ccc(C#N)c(Oc2ccc(Br)c(C=O)c2)n1
Solvent: C1CCOC1
Product: CN(CCO[Si](C)(C)C(C)(C)C)c1nc(Oc2ccc(Br)c(C=O)c2)ccc1C#N
Temperature: 25 °C
Reaction time: 48 h
Yield: 95.7 %

Procedure:
To a solution of 2-(4-bromo-3-formyl-phenoxy)-6-[(2-hydroxy-ethyl)-methyl-amino]-nicotinonitrile (9, 8 g, 21.3 mmol) in THF (anhydrous, 100 mL) were added TBDMS-Cl (3.21 g, 21.3 mmol) and Et3N (3 mL, 21.3 mmol). The solution was stirred at room temperature for 2 days. The solution was filtered and concentrated in vacuo. Purification was accomplished by silica gel chromatography, eluting with 5%-50% EtOAc/hexanes gradient, to afford 10 g (85% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[N:10]=[C:11]3[C:16]([N:17]4[CH2:22][CH:21]5[CH2:23][CH:18]4[CH2:19][NH:20]5)=[N:15][CH:14]=[N:13][C:12]=23)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[N:10]=[C:11]3[C:16]([N:17]4[CH2:22][CH:21]5[CH2:23][CH:18]4[CH2:19][N:20]5[S:39]([CH3:38])(=[O:41])=[O:40])=[N:15][CH:14]=[N:13][C:12]=23)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Clc1ccc(-c2c3ncnc(N4CC5CC4CN5)c3nn2-c2ccccc2Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CC2CC1CN2c1ncnc2c(-c3ccc(Cl)cc3)n(-c3ccccc3Cl)nc12
Yield: 101.9 %

Procedure:
A solution of Rac-(S,S)-3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-(2,5-diazabicyclo[2.2.1]hept-2-yl)-2H-pyrazolo[4,3-d]pyrimidine 4A-1 (63 mg, 0.12 mmol) in dichloromethane (2 ml) was charged with triethylamine (0.1 ml). Methanesulfonyl chloride (0.01 ml, 0.14 mmol) was added via syringe, and the resultant mixture was stirred at 23° C. for 3 days. The reaction mixture was then washed with water (2 ml) and the layers were separated. The organic solution was dried over anhydrous magnesium sulfate and concentrated. Purification of the residue by reverse-phase HPLC afforded Rac-(S, S)-3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-(5-methanesulfonyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-2H-pyrazolo[4,3-d]pyrimidine 6A-1 (63 mg, quantitative): MS: 515.0 (M+1)+; 1H NMR (400 MHz, CD3OD) δ 8.3 (s, 0,5H), 8.1 (s, 0.5H), 7.6 (m, 4H), 7.4 (m, 4H), 6.1 (s, 0.5H), 5.2 (s, 0.5H), 4.7 (m, 1H), 4.4 (m, 0.5H), 4.2 (m, 0.5H), 4.0 (m, 1H), 3.8 (m, 1H), 3.5 (m, 3H), 3.0 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:10](O)(=[O:13])[CH:11]=C.C1C2NC3C(=CC=CC=3)SC=2C=CC=1>>[F:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:8][CH2:9][CH2:11][C:10]2=[O:13]
Reactant: C=CC(=O)O
Reactant: COc1ccc(F)cc1
Agent: c1ccc2c(c1)Nc1ccccc1S2
Product: O=C1CCOc2ccc(F)cc21
Temperature: -78 °C
Reaction time: 4.5 h

Procedure:
Using the procedure established in Example 1, the reactor was charged with p-fluoroanisole (31.5 grams), acrylic acid (27 grams) and phenothiazine (0.02 grams) before being sealed, evacuated, and cooled to -78° C. The anhydrous hydrogen fluoride (110 grams) was vacuum transferred into the reactor and the mixture warmed to 40° C. for one hour then 100° C. for 4.5 hours. The excess hydrogen fluoride was then vented and the reactor cooled to 5° C. before being opened and the contents washed with D.I. water. Analysis by HPLC indicated the presence of para-fluoroanisole and 6-Fluoro-4-Chromanone. The para-fluoroanisole was removed by distillation and the desired 6-Fluoro-4-Chromanone isolated by extraction and characterized.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2].I[CH2:12][CH2:13][OH:14].C(N(C(C)C)CC)(C)C>C(#N)C>[CH:1]([N:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:12][CH2:13][OH:14])([CH3:3])[CH3:2]
Reactant: CC(C)Nc1ccccc1
Reactant: OCCI
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(CCO)c1ccccc1
Yield: 58.7 %

Procedure:
Compound 4a (617 mg, 4.6 mmol) was reacted with 2-Iodoethanol (0.54 mls, 6.9 mmol) and diisopropylethylamine (1.2 mls, 6.9 mmol) in ACN (20 mls) at 30° C. for 48 hours. The solvent was evaporated and the residue was purified by silica gel column chromatography with hexane and EtOAc to provide the intermediate 4b (483 mg, 2.7 mmol, 59% yield) as a light brown oil. HRMS (ESI, positive) m/z calcd. for C11H18N1O1 [M+H]+: 180.13829, found: 180.13829. 1H NMR (400 MHz, CDCl3) δ 7.28-7.19 (t, J=8.0 Hz, 2H), 6.92-6.85 (d, J=8.2 Hz, 2H), 6.83-6.75 (t, J=7.3 Hz, 1H), 4.03-3.88 (hept, J=6.6 Hz, 1H), 3.70-3.62 (t, J=6.2 Hz, 2H), 3.34-3.24 (m, 2H), 1.19-1.12 (d, J=6.6 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]([CH:17]([CH3:19])[CH3:18])=[C:6]([CH:16]=1)[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1.C(O)(=O)C.[O-:26][C:27]#[N:28].[Na+]>O>[NH2:14][C:11]1[N:10]=[C:9]([NH2:15])[C:8]([O:7][C:6]2[C:5]([CH:17]([CH3:19])[CH3:18])=[CH:4][C:3]([O:20][CH3:21])=[C:2]([NH:1][C:27]([NH2:28])=[O:26])[CH:16]=2)=[CH:13][N:12]=1
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1N
Reactant: N#C[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1NC(N)=O
Reaction time: 0.5 h

Procedure:
To 5-(5-amino-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (314 mg, 1.09 mmol) suspended in water (3 mL) was added acetic acid (0.25 mL, 4.34 mmol). Once all solids had dissolved, sodium cyanate (71 mg, 1.09 mmol, dissolved in 1.5 mL water) was added dropwise. After 30 minutes, the reaction was concentrated and purified with silica gel column chromatography eluting with 92/8/0.1 dichloromethane/methanol/ammonium hydroxide to yield [5-(2,4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-phenyl]-urea as an off-white solid (244 mg, 68%, M+H)+=333), which was converted to a hydrochloride salt:
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][Cl:17])[C:10]([OH:12])=O)[N:8]=1)=[O:2].P(Cl)(Cl)(Cl)=O.[NH2:23][CH:24]1[C:34](=[O:35])[N:26]2[C:27]([C:31]([OH:33])=[O:32])=[CH:28][CH2:29][S:30][C@H:25]12.C[Si](C([Si](C)(C)C)C(N)=O)(C)C>C(OCC)(=O)C.CN(C)C=O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][Cl:17])[C:10]([NH:23][CH:24]2[C:34](=[O:35])[N:26]3[C:27]([C:31]([OH:33])=[O:32])=[CH:28][CH2:29][S:30][C@H:25]23)=[O:12])[N:8]=1)=[O:2]
Reactant: NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Reactant: O=CNc1nc(C(=NOCCCl)C(=O)O)cs1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=CNc1nc(C(=NOCCCl)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Yield: 32.2 %

Procedure:
A solution of 2-(2-formamidothiazol-4-yl)-2-(2-chloroethoxyimino)acetic acid (syn isomer, 3.47 g.), N,N-dimethylformamide (1.1 g.) and phosphoryl chloride (2.3 g.) in ethyl acetate (35 ml.), and a solution of 7-amino-3-cephem-4-carboxylic acid (2.5 g.) and bis(trimethylsilyl)acetamide (12.7 g.) in ethyl acetate (25 ml.) were treated in a similar manner to that of Example 15-(1) to give 7-[2-(2-formamidothiazol-4-yl)-2-(2-chloroethoxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 1.85 g.).
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][C:7]1[C:15]2[S:14](=[O:17])(=[O:16])[N:13]=[C:12]([CH2:18][C:19]([OH:21])=O)[NH:11][C:10]=2[S:9][CH:8]=1)(=[O:4])=[O:3].F[P-](F)(F)(F)(F)F.N1([O:38][C:39](N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN1CCOCC1.C(OC(=O)[C:57]([CH2:64][NH:65][CH:66]1[CH2:69][CH2:68][CH2:67]1)([CH3:63])[CH2:58][CH2:59][CH:60]([CH3:62])[CH3:61])C.[O-]CC.[Na+].C(O)C>CN(C)C=O>[CH:66]1([N:65]2[CH2:64][C:57]([CH3:63])([CH2:58][CH2:59][CH:60]([CH3:61])[CH3:62])[C:19]([OH:21])=[C:18]([C:12]3[NH:11][C:10]4[S:9][CH:8]=[C:7]([CH2:6][NH:5][S:2]([CH3:1])(=[O:3])=[O:4])[C:15]=4[S:14](=[O:16])(=[O:17])[N:13]=3)[C:39]2=[O:38])[CH2:67][CH2:68][CH2:69]1
Reactant: CS(=O)(=O)NCc1csc2c1S(=O)(=O)N=C(CC(=O)O)N2
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCOC(=O)C(C)(CCC(C)C)CNC1CCC1
Agent: CC[O-]
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(C)CCC1(C)CN(C2CCC2)C(=O)C(C2=NS(=O)(=O)c3c(CNS(C)(=O)=O)csc3N2)=C1O
Temperature: 25 °C
Reaction time: 22 h
Yield: 23.1 %

Procedure:
[7-(Methanesulfonylamino-methyl)-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-3-yl]-acetic acid (prepared as described in Example 2c; 0.266 g, 0.753 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.314 g, 0.826 mmol) and 4-methylmorpholine (0.165 mL, 1.50 mmol) were added sequentially to a solution of rac-2-cyclobutylaminomethyl-2,5-dimethyl-hexanoic acid ethyl ester (0.192 g, 0.752 mmol) in N,N-dimethylformamide (8 mL) at 25° C. The reaction mixture was stirred at 25° C. for 22 h, and then was concentrated in vacuo. The residue was partitioned between 1.0 M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×100 mL). The organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was dissolved in ethanol (12 mL) at 25° C. A 21 wt. % solution of sodium ethoxide in ethanol (1.46 mL, 4.51 mmol) was added and the reaction mixture was heated to 70° C. for 24 h. After cooling to 25° C., the reaction mixture was partitioned between 1.0 M aqueous hydrochloric acid solution (150 mL) and ethyl acetate (2×150 mL). The organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash chromatography (Teledyne Isco RediSep column; 50-100% ethyl acetate in hexanes) to afford rac-N-{3-[1-cyclobutyl-4-hydroxy-5-methyl-5-(3-methyl-butyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-7-ylmethyl}-methanesulfonamide (0.095 g, 0.174 mmol, 23%) as an orange oil. 1H NMR (400 MHz, DMSO-d6) δ: 0.82-0.86 (6H, m), 0.94-0.99 (1H, m), 1.04 (3H, s), 1.07-1.23 (5H, m), 1.40-1.54 (2H, m), 1.65-1.70 (1H, m), 2.07 (1H, bs), 2.19-2.26 (1H, m), 2.95 (3H, s), 3.26-3.31 (1H, m), 3.46-3.51 (1H, m), 3.99-4.06 (1H, m), 4.23 (2H, d, J=6.1 Hz), 7.27 (1H, s), 7.65 (1H, t, J=6.3 Hz). LC-MS (ESI) calculated for C22H32N4O6S3 544.15. found 545.1 [M+H+].
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[C:20]3[C:19](=[O:21])[NH:18][C:17]([NH2:22])=[N:16][C:15]=3[NH:14][CH:13]=2)=[CH:6][CH:5]=1.CO.O1CCCC1.Cl>[OH-].[Na+]>[NH2:22][C:17]1[NH:18][C:19](=[O:21])[C:20]2[C:12]([CH2:11][CH2:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:23])=[O:2])=[CH:5][CH:6]=3)=[CH:13][NH:14][C:15]=2[N:16]=1
Reactant: COC(=O)c1ccc(CCc2c[nH]c3nc(N)[nH]c(=O)c23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1nc2[nH]cc(CCc3ccc(C(=O)O)cc3)c2c(=O)[nH]1
Reaction time: 4 h
Yield: 87.5 %

Procedure:
A mixture of 3.17 g (10.15 mmol) of 4-[2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid methyl ester, prepared in Example 3, in 30 ml of 1N aqueous sodium hydroxide and 5 ml methanol was stirred for 20 hours at room temperature. Tetrahydrofuran 5 ml) was added and the mixture was stirred for 4 hours then neutralized with 30 ml of 1N aqueous hydrochloric acid. The resulting precipitate was separated by filtration, washed with water (20 ml) and dried in a vacuum oven at 50° C. to obtain 2.65 g of the above product in a yield of 87 percent. 1H NMR (DMSO-d6) δ 2.45 (m, 2H), 2.91 (m, 2H), 5.99 (s, 2H), 6.27 (d, J=2.0 Hz, 1H), 7.27 (d, J=8.2 Hz, 2H), 7.79 (d, J=8.2 Hz, 2H), 10.14 (s, 1H), 10.59 (d, J=2.0 Hz, 1H), 13.2 (bs, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:18]3[C:13]([CH:14]=[C:15]([OH:19])[CH:16]=[CH:17]3)=[C:12]([C:20](=[O:26])[CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:11]=2[CH2:27][C:28]([CH3:35])([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:9])=[CH:4][CH:3]=1.Br[CH2:37][C:38]1[CH:47]=[CH:46][C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[N:39]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[N:18]3[C:13]([CH:14]=[C:15]([O:19][CH2:37][C:38]4[CH:47]=[CH:46][C:45]5[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=5)[N:39]=4)[CH:16]=[CH:17]3)=[C:12]([C:20](=[O:26])[CH2:21][C:22]([CH3:23])([CH3:24])[CH3:25])[C:11]=2[CH2:27][C:28]([CH3:34])([CH3:35])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:9])=[CH:6][CH:7]=1
Reactant: BrCc1ccc2ccccc2n1
Reactant: CCOC(=O)C(C)(C)Cc1c(C(=O)CC(C)(C)C)c2cc(O)ccn2c1C(=O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Cc1c(C(=O)CC(C)(C)C)c2cc(OCc3ccc4ccccc4n3)ccn2c1C(=O)c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 96 h
Yield: 101.7 %

Procedure:
A suspension of ethyl 3-{3-[(4-chlorophenyl)carbonyl]-1-(3,3-dimethylbutanoyl)-7-hydroxyindolizin-2-yl}-2,2-dimethylpropanoate (30 mg, 0.06 mmol), 2-(bromomethyl)quinoline (20 mg, 0.09 mmol), and potassium carbonate (17 mg, 0.12 mmol) in DMF (1.0 mL) is stirred for 96 h at 50° C. The mixture is cooled to 23° C. then filtered and concentrated in vacuo. Purification of the crude by flash chromatography (SiO2, hexanes to 1:1 hexanes:EtOAc) gives ethyl 3-{3-[(4-chlorophenyl)carbonyl]-1-(3,3-dimethylbutanoyl)-7-(quinolin-2-ylmethoxy)indolizin-2-yl}-2,2-dimethylpropanoate (39 mg, quant).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[S:6][CH:7]=1.[CH3:15][N:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17](Cl)=[O:18].P([O-])([O-])([O-])=O>>[Cl:1][CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:17](=[O:18])[N:16]([CH3:15])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:10][CH:9]=2)[S:6][CH:7]=1
Reactant: Oc1ccc(-c2nc(CCl)cs2)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Product: CN(C(=O)Oc1ccc(-c2nc(CCl)cs2)cc1)c1ccccc1

Procedure:
The title compound was prepared from 4-(4-chloromethyl-thiazol-2-yl)-phenol and N-methyl-N-phenylcarbamoyl chloride. The aqueous phase was adjusted to PH 7.0 (phosphate buffer) before extraction with ethyl acetate. The crude product was subjected to preparative HPLC (21%, white crystals). HPLC-MS m/z=359.0 (M+1), Rt: 4.60.