Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH2:1].F[C:3]1[CH:4]=[CH:5][C:6]([NH:9][NH2:10])=N[CH:8]=1.C(OC(C[CH2:19][N:20]1CCC[C@H]1C(O)=O)=O)(C)(C)C>CN(C=O)C.C(Cl)CCl>[CH:3]1[CH:4]=[CH:5][C:6]2[N:9]([OH:1])[N:10]=[N:20][C:19]=2[CH:8]=1
Reactant: O
Reactant: NNc1ccc(F)cn1
Reactant: CC(C)(C)OC(=O)CCN1CCC[C@H]1C(=O)O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: On1nnc2ccccc21
Reaction time: 8 h
Yield: 260.9 %

Procedure:
H2O (695 mg, 3.62 mmol) was added to a suspension of (5-fluoro-pyridin-2-yl)-hydrazine (418 mg, 3.29 mmol), Intermediate 84b (840 mg, 3.29 mmol), and EDC (44.0 mg, 0.33 mmol) in DMF (25.0 mL). The reaction was stirred overnight then partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, to give the title compound (1.16 g, 99%). LCMS (Method 1): Rt 2.06 mins, m/z 353.3 [MH+].
Reaction SMILES: [CH:1]1([CH2:5][O:6][C:7]2[CH:33]=[CH:32][C:10]3[N:11]=[C:12]([N:14]4[CH2:19][CH2:18][CH:17]([O:20][CH2:21][C@@H:22]([NH:24][C:25](=[O:31])OC(C)(C)C)[CH3:23])[CH2:16][CH2:15]4)[O:13][C:9]=3[CH:8]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[C:35](OCC)(=O)C>>[CH:1]1([CH2:5][O:6][C:7]2[CH:33]=[CH:32][C:10]3[N:11]=[C:12]([N:14]4[CH2:19][CH2:18][CH:17]([O:20][CH2:21][C@@H:22]([NH:24][C:25](=[O:31])[CH3:35])[CH3:23])[CH2:16][CH2:15]4)[O:13][C:9]=3[CH:8]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(C)=O
Reactant: C[C@@H](COC1CCN(c2nc3ccc(OCC4CCC4)cc3o2)CC1)NC(=O)OC(C)(C)C
Agent: Cl
Product: CC(=O)N[C@@H](C)COC1CCN(c2nc3ccc(OCC4CCC4)cc3o2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To tert-butyl [(1S)-2-({1-[6-(cyclobutylmethoxy)-1,3-benzoxazol-2-yl]piperidin-4-yl}oxy)-1-methylethyl]carbamate (130 mg) was added 4M hydrogen chloride/ethyl acetate (5 mL), and the mixture was stirred at room temperature for 15 min and concentrated. Pyridine (5 mL) and acetic anhydride (5 mL) were added to the residue, and the mixture was stirred at room temperature for 15 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate/methanol) and recrystallized from ethyl acetate/hexane to give the title compound (73 mg).
Reaction SMILES: [C:1]1(=[O:7])[O:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8](Br)[CH:9]=[CH2:10].C1(=O)OCC1.BrCCCCCCCCC=C>>[CH2:10]([CH:2]1[CH2:3][CH2:4][CH2:5][O:6][C:1]1=[O:7])[CH:9]=[CH2:8]
Reactant: C=CCBr
Reactant: O=C1CCCCO1
Agent: C=CCCCCCCCCBr
Agent: O=C1CCO1
Product: C=CCC1CCCOC1=O
Yield: 70 %

Procedure:
9.81 g of tetrahydro-3-(2-propenyl)-2H-pyrane-2-one of interest were prepared in the same manner as in Preparation Example 2Z-3 except that 10.01 g (100.0 mmol) of δ-valerolactone and 14.52 g (110.0 mmol) of allyl bromide were used instead of β-propiolactone and 10-bromo-1-decene described in Preparation Example 2Z-3, respectively.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][C:8](N)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].N([O-])=O.[Na+].[F:16][B-](F)(F)F.[Na+]>Cl>[C:1]([C:5]1[CH:11]=[CH:10][C:8]([F:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: F[B-](F)(F)F
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Product: CC(C)(C)c1ccc(F)cc1
Temperature: 140 °C
Reaction time: 0.25 h

Procedure:
4-t-Butylaniline (14.9 g, 100 mmol) was suspended in aqueous hydrochloric acid (50 ml, 6M) at 5° C. Sodium nitrite (7.6 g, 110 mmol in 10 ml water) was added at such a rate that the temperature was kept between 5°-7° C. Following the addition the resulting solution was stirred for 15 min. and sodium tetrafluoroborate (15.4 g, 140 mmol in 30 ml water) was added at 5-8° C. The mixture was stirred for 15 min. 4-t-Butylbenzenediazonium tetrafluoroborate was filtered off, dried with suction and washed with diethyl ether to yield 20.96 g. This diazonium salt was decomposed by heating to 140° C. on an oil-bath. The product was distilled off at reduced pressure. Yield 11.15 g colorless oil.
Reaction SMILES: [C:1]([C:4]1[CH:8]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:7]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:6](=[O:25])[C:5]=1O)(=O)[CH3:2].[NH:27]([C:29]1[C:30]([O:35][CH3:36])=[N:31][CH:32]=[CH:33][CH:34]=1)[NH2:28]>CCCCCC.CCOC(C)=O>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([CH:8]2[C:4]3[C:1]([CH3:2])=[N:28][N:27]([C:29]4[C:30]([O:35][CH3:36])=[N:31][CH:32]=[CH:33][CH:34]=4)[C:5]=3[C:6](=[O:25])[N:7]2[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)=[CH:10][CH:11]=1
Reactant: COc1ccc(CN2C(=O)C(O)=C(C(C)=O)C2c2ccc(Cl)cc2)cc1
Reactant: COc1ncccc1NN
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(CN2C(=O)c3c(c(C)nn3-c3cccnc3OC)C2c2ccc(Cl)cc2)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Example 57 using 4-acetyl-5-(4-chlorophenyl)-3-hydroxy-1-(4-methoxybenzyl)-1H-pyrrol-2(5H)-one (Step 71.2) and 3-hydrazinyl-2-methoxypyridine (Step 71.1). tR: 5.79 min (HPLC 1); tR: 1.29 min (LC-MS 2); ESI-MS: 475 [M+H]+ (LC-MS 2); Rf=0.60 (hexane/EtOAc 1:1).
Reaction SMILES: C[O:2][C:3](=[O:35])[C:4]([C:12](=[O:34])[C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[O:21])=[CH:15][C:14]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([NH2:11])[CH2:5][CH2:6][S:7]([CH3:10])(=[O:9])=[O:8]>C1COCC1.O>[N:24]1[CH:25]=[CH:26][CH:27]=[C:22]([C:20]([NH:19][C:16]2[CH:17]=[CH:18][C:13]([C:12]([C:4]([NH2:11])([CH2:5][CH2:6][S:7]([CH3:10])(=[O:8])=[O:9])[C:3]([OH:35])=[O:2])=[O:34])=[C:14]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:15]=2)=[O:21])[CH:23]=1
Reactant: COC(=O)C(N)(CCS(C)(=O)=O)C(=O)c1ccc(NC(=O)c2cccnc2)cc1-c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)CCC(N)(C(=O)O)C(=O)c1ccc(NC(=O)c2cccnc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
The [4-(3-pyridylcarbonylamino)-2-phenylbenzoyl]-2-amino-4-(methylsulfonyl)butanoic acid methyl ester prepared in Example 203A (43 mg, 0.081 mmol) was dissolved in 3 mL of THF and a solution of LiOH monohydrate was in 1 mL of H2O was added. The reaction mixture was stirred at 25° C. for 1 hour and then was evaporated. Formic acid (1 mL) was added to acidify to pH=3. The reaction was then evaporated once again and 1 mL of H2O was added along with 5 mL of ethyl acetate to dissolve the mixture. The ethyl acetate layer was dried over Na2SO4, filtered and evaporated and the residue was lyophilized from acetonitrile/H2O to give [4-(3-pyridylcarbonylamino)-2-phenylbenzoyl]-2-amino-4-(methylsulfonyl)butanoic acid (36 mg, 88%) as a white solid. 1H NMR (300 mHz, CD3OD) δ 9.12 (d, 1H), 8.70 (d, 1H), 8.42 (dt, 1H), 7.85-7.80 (m, 2H), 7.65-7.40 (m, 8H), 4.50 (m, 1H), 2.90 (s, 3H), 2.88-2.80 (m, 1H), 2.70-2.58 (m, 1H), 2.35-2.20 (m, 1H), 2.10-1.95 (m, 1H). HRMS calcd C24H23N3SO6 MH+ 482.1386, found 482.1373.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][N:6]=[C:5]([CH2:10][N:11]2[N:39]=[C:15]3[CH2:16][C:17](=O)[C:18]4[CH2:19][S:20][N:21]=[C:22]([N:23]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:13]([C:14]=43)=[N:12]2)[C:4]=1[CH3:40].C1(P(=[CH:60][C:61]([O:63][CH3:64])=[O:62])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[C:34]([O:33][C:31]([N:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:22]1[C:13]2[C:14]3[C:15](=[N:39][N:11]([CH2:10][C:5]4[C:4]([CH3:40])=[C:3]([O:2][CH3:1])[C:8]([CH3:9])=[CH:7][N:6]=4)[N:12]=2)[CH:16]=[C:17]([CH2:60][C:61]([O:63][CH3:64])=[O:62])[C:18]=3[CH2:19][S:20][N:21]=1)=[O:32])([CH3:35])([CH3:36])[CH3:37]
Reactant: COc1c(C)cnc(CN2N=C3CC(=O)C4=C3C(=N2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)Cc1cc2nn(Cc3ncc(C)c(OC)c3C)nc3c-2c1CSN=C3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 10 h
Yield: 33.3 %

Procedure:
A mixture composed of di-tert-butyl {2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-8-oxo-2,7,8,9-tetrahydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-4-yl}imidodicarbonate of Example 40 (752 mg), methyl triphenylphosphanylideneacetate (617 mg) and toluene (14 ml) was heated with stirring at 60° C. for 10 hours. Ethyl acetate was added to the reaction mixture, followed by washing with water. Then, the organic layer was dried over sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (ethyl acetate-chloroform) to obtain the title compound (275 mg, 33%) as an oil.
Reaction SMILES: C(O)(=O)C.Cl[C:6]1[C:26](=[O:27])[CH2:25][CH2:24][C@@:23]2([CH3:28])[C:7]=1[CH2:8][CH2:9][C@@H:10]1[C@@H:22]2[CH2:21][CH2:20][C@@:19]2([CH3:29])[C@H:11]1[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:18])[CH2:16][OH:17].[CH3:30][NH2:31]>CO>[CH3:30][NH:31][C:6]1[C:26](=[O:27])[CH2:25][CH2:24][C@@:23]2([CH3:28])[C:7]=1[CH2:8][CH2:9][C@@H:10]1[C@@H:22]2[CH2:21][CH2:20][C@@:19]2([CH3:29])[C@H:11]1[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:18])[CH2:16][OH:17]
Reactant: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC4=C(Cl)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CN
Solvent: CC(=O)O
Solvent: CO
Product: CNC1=C2CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CO)[C@@]4(C)CC[C@@H]3[C@@]2(C)CCC1=O
Reaction time: 0.5 h

Procedure:
To obtain the corresponding 4-methylamino compound, a suspension of (20S)-4-chloro-21-hydroxy-20-methylpregn-4-en-3-one acetate in methanol was mixed with 40% aqueous methylamine and refluxed for 30 minutes. Additional 40% aqueous methylamine was added and refluxing was continued for another 30 minutes. The solvent was then evaporated and the residue was purified as described above for the 4-amino compound to give (20S)-4-(methylamino)-21-hydroxy-20-methylpregn-4-en-3-one.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([OH:18])[CH3:17].CCCCCC.CCOCC>C(Cl)Cl>[CH2:1]([C:8]1[CH:9]=[C:10]([C:11](=[NH:12])[O:18][CH2:16][CH3:17])[CH:13]=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: N#Cc1cccc(Cc2ccccc2)c1
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=N)c1cccc(Cc2ccccc2)c1
Temperature: -4 °C
Reaction time: 0.25 h

Procedure:
Anhydrous hydrochloric acid was gently bubbled for 90 minutes into a solution containing 3-benzylbenzonitrile (1.0 g, 5.2 mmol) and absolute ethanol (0.45 mL, 7.8 mmol) in methylene chloride (7 mL) maintained at −4° C. After standing at 4° C. for a week, the reaction mixture was poured into 2:1 hexane/ether (500 mL), left at room temperature for 15 minutes and filtered. The residue was washed with 2:1 hexane/ether (50 mL) and dried in vacuo at room temperature. Yield 1.1 g (77 percent). mp 121-122° C.; 1H NMR (CDCl3) δ 12.58 (br, 1H), 8.29-8.25 (m, 2H), 7.49-7.44 (m, 2H), 7.32-7.27(m, 2H), 7.22-7.18(m, 3H), 4.93 (q, J=6.9 Hz, 2H), 4.09 (s, 2H), 1.60 (t, J=6.9 Hz, 3H); EI/MS 240 m/e (M+1);
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[C:11]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([NH:39][C:40](=[O:48])[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[NH2:47])=[N:37][CH:38]=1>>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH:47][C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[C:40]([NH:39][C:36]2[CH:35]=[CH:34][C:33]([Cl:32])=[CH:38][N:37]=2)=[O:48])=[O:14])=[C:11]([O:18][CH:19]2[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:24]2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(OCc3ccccc3)ccc2C(=O)O)CC1
Reactant: Nc1ccccc1C(=O)Nc1ccc(Cl)cn1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(OCc3ccccc3)ccc2C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1

Procedure:
Using methods substantially equivalent to those described in Example 1-F, 4-benzyloxy-2-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzoic acid (529 mg, 1.27 mmol) and N-(5-chloropyridin-2-yl)-2-aminobenzamide (297 mg, 1.20 mmol) afforded, after purification by chromatography (SiO2: EtOAc in hexanes), 493 mg (63%) of the title compound.
Reaction SMILES: [ClH:1].Cl.Cl.[NH2:4][C@@H:5]1[C:23](=[O:24])[N:7]2[C:8]([C:20]([O-:22])=[O:21])=[C:9]([CH2:12][N+:13]3[N:14]([CH3:19])[C:15]([NH2:18])=[CH:16][CH:17]=3)[CH2:10][S:11][C@H:6]12.C[Si](C)(C)NC(=O)C.Cl.[NH2:34][C:35]1[S:39][N:38]=[C:37](/[C:40](=[N:44]/[O:45][C:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])([CH3:48])[CH3:47])/[C:41]([Cl:43])=[O:42])[N:36]=1.C(OCC)C>O1CCCC1>[ClH:43].[ClH:1].[ClH:43].[NH2:34][C:35]1[S:39][N:38]=[C:37]([C:40](=[N:44][O:45][C:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])([CH3:47])[CH3:48])[C:41]([NH:4][C@@H:5]2[C:23](=[O:24])[N:7]3[C:8]([C:20]([O-:22])=[O:21])=[C:9]([CH2:12][N+:13]4[N:14]([CH3:19])[C:15]([NH2:18])=[CH:16][CH:17]=4)[CH2:10][S:11][C@H:6]23)=[O:42])[N:36]=1
Reactant: Cn1c(N)cc[n+]1CC1=C(C(=O)[O-])N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)Cl)c1nsc(N)n1
Agent: CC(=O)N[Si](C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cn1c(N)cc[n+]1CC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)C(=NOC(C)(C)C(=O)OC(C)(C)C)c3nsc(N)n3)[C@H]2SC1
Reaction time: 1 h
Yield: 194.8 %

Procedure:
To a solution of 7β-amino-3-(3-amino-2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate trihydrochloride (2 g) and N-(trimethylsilyl)acetamide (6.28 g) in tetrahydrofuran (40 ml) was added (Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)acetyl chloride hydrochloride (1.84 g) under ice-cooling. After being stirred for 1 hour, the reaction mixture was added dropwise to ethyl ether (300 ml), and the resulting precipitate was collected by filtration to give 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)-acetamido]-3-(3-amino-2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate trihydrochloride (syn isomer) (3.4 g).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:21])[CH:6]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14].I[CH2:23][CH2:24][CH2:25][CH:26]([O:32][C:33](=[O:35])[CH3:34])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>CN(C)C=O>[CH3:3][O:4][C:5]([C:6]([S:17]([CH3:20])(=[O:19])=[O:18])([CH2:23][CH2:24][CH2:25][CH:26]([O:32][C:33](=[O:35])[CH3:34])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[O:21]
Reactant: CCCCCC(CCCI)OC(C)=O
Reactant: COC(=O)CCCCCCC(C(=O)OC)S(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCC(CCCC(CCCCCCC(=O)OC)(C(=O)OC)S(C)(=O)=O)OC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
A suspension of 57% sodium hydride/mineral oil (3.84 g., 0.091 mole) is washed by decantation with petroleum ether to remove the mineral oil. The residual solid is suspended in dry dimethylformamide (100 ml.) and treated with a solution of dimethyl-2-methylsulfonylazelate (23.5 g., 0.08 mole) in dry dimethylformamide (60 ml.) added dropwise at ambient temperature under a nitrogen atmosphere. The resulting solution is stirred for 1 hour at room temperature, cooled to ~10° C., and treated with 1-iodo-4-acetoxynonane (30 g., 0.096 mole) added at such a rate as to maintain an internal temperature less than 35° C. After 19 hours at ambient temperature, the reaction mixture is filtered. Collected sodium iodide (17.1 g.) is washed with ether. The combined filtrate and washings are concentrated in vacuo at ~100° C. yielding a residual oil which is partitioned between ether and dilute hydrochloric acid. The organic extract is washed with water and saturated brine, dried over magnesium sulfate and evaporated in vacuo leaving the title compound as a viscous oil (37.7 g., 98%), pmr (CDCl3)δ2.0 (s, 3H), 3.0 (s, 3H), 3.65 (s, 3H), 3.81 (s, 3H) and 4.9 (b, H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[NH:11][C:12]1[CH:17]=[C:16]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:15]=[C:14]([S:24][CH3:25])[N:13]=1.O.NN>C(O)C.[Fe](Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH:11][C:12]1[CH:17]=[C:16]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:15]=[C:14]([S:24][CH3:25])[N:13]=1
Reactant: CSc1nc(Nc2c(C)cccc2[N+](=O)[O-])cc(N2CCOCC2)n1
Agent: Cl[Fe]Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: CSc1nc(Nc2c(C)cccc2N)cc(N2CCOCC2)n1
Temperature: 80 °C
Yield: 79.1 %

Procedure:
N-(2-Methyl-6-nitrophenyl)-2-(methylsulfanyl)-6-(morpholin-4-yl)pyrimidin-4-amine (750 mg) was dissolved in ethanol (22.5 mL), and iron chloride (III) hexahydrate (56 mg) and activated carbon (75 mg) were added thereto, followed by stirring at 80° C. Hydrazine monohydrate (0.3 mL) was added dropwise thereto, followed by heating and refluxing overnight. The reaction mixture was cooled to room temperature and filtered through celite. The mother liquid was concentrated and the residue was purified using silica gel column chromatography (hexane:ethyl acetate) to obtain 3-methyl-N2-[2-(methylsulfanyl)-6-(morpholin-4-yl)pyrimidin-4-yl]benzene-1,2-diamine (544 mg) as a pale yellow powder.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([CH2:8]O)[CH:3]=1.[CH3:10][N:11]([CH:13]=O)[CH3:12].O=P(Cl)(Cl)[Cl:17].CCN(CC)CC>C(Cl)Cl>[Cl:17][CH2:8][C:4]1[N:5]=[CH:6][N:7]=[C:2]([N:1]=[CH:10][N:11]([CH3:13])[CH3:12])[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1cc(CO)ncn1
Reactant: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C=Nc1cc(CCl)ncn1
Reaction time: 2 h

Procedure:
To a suspension of (6-aminopyrimidin-4-yl)methanol (52 mg, 0.42 mmole) in CH2Cl2 (2 mL) was added DMF (0.03 mL, 0.42 mmole) then POCl3 (0.04 mL, 0.42 mmole) at room temperature. After 2 hours, Et3N (0.3 mL) was added and stirring continued. After 18 hours, the mixture was concentrated. The residue was taken up in saturated NaHCO3 and extracted with CH2Cl2 (4×). The combined organic layers were dried (MgSO4), filtered, and concentrated to give the title compound as its DMF amidine. 1H-NMR (300 MHz, d6-DMSO) δ 8.78 (s, 1H), 8.65 (s, 1H), 6.90 (s, 1H), 4.60 (s, 2H), 3.18 (s, 3H), 3.05 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:14])[N:12]=2)[C:7](=[O:15])[C:6]([C:16]([OH:18])=[O:17])=[CH:5]1.S(OC)(O[CH3:23])(=O)=O>C(O)C.[OH-].[Na+]>[CH3:23][O:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:14])[N:12]=2)[C:7](=[O:15])[C:6]([C:16]([OH:18])=[O:17])=[CH:5]1
Reactant: Cc1ccc2c(=O)c(C(=O)O)cn(CCO)c2n1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCCn1cc(C(=O)O)c(=O)c2ccc(C)nc21

Procedure:
1,4-Dihydro-1-(2-hydroxyethyl)-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid (1 g) in ethanol (30 ml) and aqueous sodium hydroxide (10 ml, 40%) was treated alternatively with dimethyl sulphate (5 ml) and aqueous sodium hydroxide (10 ml, 40 %) until dimethylsulphate (25 ml) had been added. The mixture was refluxed for 1.5 hours and concentrated to a volume of 20 ml. Concentrated hydrochloric acid was added and the solid was collected and washed with water and dried. The product had m.p. 244°-245° (d).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[O:17]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][O:17]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(Cl)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(c1ccc(Cl)cc1)c1ccc(OC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
4-Chloro-4′-hydroxybenzophenone (50 g, 0.215 mol) is dissolved in dichloromethane (400 ml). 3,4-Dihydro-2H-pyran (21.7 g, 0.257 mol) and a catalytic amount of p-toluenesulfonic acid are added to the solution. The solution is stirred for 6 hours at room temperature and then allowed to stand over night, 1 N aqueous sodium hydroxide solution (100 ml) is added to the reaction mixture and stirred for 15 minutes. Organic layer is separated and washed twice with 1 N aqueous sodium hydroxide solution and once with water. Dichloromethane solution is dried and evaporated to dryness. Yield 68.6 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29]C)=[O:28])=[CH:22][CH:21]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.CO.[OH-].[Li+].Cl>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:9][CH2:10][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][C:27]([OH:29])=[O:28])=[CH:24][CH:25]=3)[CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(OCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)Cc1ccc(OCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl [4-(2-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethoxy)phenyl]acetate (20 mg, 0.047 mmol) in 3 ml THF was added 1 ml methanol and 1 ml water. Lithium hydroxide (5.6 mg, 0.23 mmol) was added to the mixture, and the mixture was stirred at RT overnight. 1 M hydrochloric acid was added to adjust the pH to 4. The volatiles were removed under vacuum, and the remaining aqueous layer was extracted with dichloromethane (3×10 ml). The organics were combined, dried over magnesium sulphate, filtered, and the filtrate concentrated under reduced pressure to afford the title compound. LC/MS (m/z) 416.3 (M+H)+.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([C:14](=[NH:18])OCC)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N[CH2:38][C:39](O)=[O:40])C1C=CC=CC=1.[F:42][C:43]([F:48])([F:47])[CH2:44][NH:45][NH2:46]>C(Cl)Cl.C(O)C>[CH2:1]([C:8]1[CH:9]=[C:10]([C:14]2[NH:18][CH2:38][C:39](=[O:40])[N:45]([CH2:44][C:43]([F:48])([F:47])[F:42])[N:46]=2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CNCc1ccccc1
Reactant: CCOC(=N)c1cccc(Cc2ccccc2)c1
Reactant: NNCC(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCO
Product: O=C1CNC(c2cccc(Cc3ccccc3)c2)=NN1CC(F)(F)F
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A suspension of ethyl 3-benzylbenzenecarboximidoate (0.5 g, 1.8 mmol) in methylene chloride (100 mL) was washed with saturated aqueous sodium bicarbonate (2×80 mL) brine (50 mL), dried over magnesium sulfate and concentrated to 6 mL. To this was added benzylglycinate p-toluenesulfonate (0.615 g, 1.8 mmol) in portions over 10 minutes, stirred at room temperature under nitrogen for 14 hours, and concentrated under reduced pressure to leave a pink gum which was dissolved in absolute ethanol (6 mL). Following dropwise addition of a solution of 1,1,1-trifluoroethylhydrazine in ethanol (70 percent, 0.19 mL, 1.8 mmol), the reaction mixture was stirred at room temperature under nitrogen for 14 hours, adsorbed onto silica and chromatographed on silica, eluting with a ethyl acetate/hexane mobile phase. The major fraction was concentrated under reduced pressure to leave a fluffy, yellowish solid. Yield 0.345 g (63 percent). mp 104-106° C.; 1H NMR (CDCl3) δ 7.50-7.46 (m, 2H), 7.37-7.16(m, 7H), 4.9 (br, 1H), 4.40 (q, J=8.7 Hz, 2H), 4.12 (s, 2H), 4.02 (s, 2H); ES/MS 347 m/e (M+).
Reaction SMILES: [CH2:1]([O:3][C:4]([PH:9](=[O:13])OCC)([O:6][CH2:7][CH3:8])[CH3:5])[CH3:2].[CH3:14][Mg]Cl.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:14][PH:9](=[O:13])[C:4]([O:6][CH2:7][CH3:8])([O:3][CH2:1][CH3:2])[CH3:5]
Reactant: C[Mg]Cl
Reactant: CCO[PH](=O)C(C)(OCC)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(C)(OCC)[PH](C)=O

Procedure:
By a procedure analogous to that of Example 1, but using ethyl 1,1-diethoxyethylphosphinate (10.5 g) and 33.5 ml of the methylmagnesium chloride solution and adding 14.1 g of potassium carbonate in 30 ml of water to precipitate inorganic salts, methyl (1,1-diethoxyethyl)phosphine oxide is obtained as a colourless oil.