Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]=[N+]=[N-])[CH:6]=[CH:7][CH:8]=1.[FH:12]>CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[F:12])[NH2:9]
Reactant: COc1cccc(N=[N+]=[N-])c1
Reactant: F
Solvent: CCCCCC
Product: COc1cc(N)ccc1F
Reaction time: 10 h

Procedure:
A solution of 10.73g. (0.07 mole) of 3-methoxyphenylazide in 100 ml. of hexane was added to 20 ml. of concentrated hydrofluoric acid and the reaction mixture, contained in a bomb, was aged for 10 hours at room temperature with agitation. The reaction mixture was then cooled, vented, and poured from the bomb. The bomb was then rinsed with 50 ml. of water, followed by 20 ml. of dichloromethane. The reaction mixture poured from the bomb was blown down under nitrogen, and then combined with the bomb rinsings, and this mixture was cooled and brought to a pH of about 12 with KOH pellets. The mixture was extracted three times with 50 ml. of dichloromethane per extraction, and the combined extracts were dried over MgSO4 and concentrated to 7.31g. (53%) of a dark oil. An aliquot of this product was distilled under reduced pressure to obtain a pale yellow oil with a b.p. of 150°-152° C. at 50 mm. Hg. Structure of the final product as 3-methoxy-4-fluoroaniline was confirmed by mass spectroscopy.
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CCN(C(C)C)C(C)C.[OH:24][C:25]([C:27]([F:30])([F:29])[F:28])=[O:26].[F:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[CH:39]([F:60])[CH:40]1[CH2:45][CH2:44][N:43]([C:46]2[N:51]=[C:50]3[CH2:52][NH:53][CH2:54][CH2:55][C:49]3=[N:48][C:47]=2[NH:56][CH:57]([CH3:59])[CH3:58])[CH2:42][CH2:41]1.C=O>CO>[F:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[CH:39]([F:60])[CH:40]1[CH2:45][CH2:44][N:43]([C:46]2[N:51]=[C:50]3[CH2:52][N:53]([CH3:1])[CH2:54][CH2:55][C:49]3=[N:48][C:47]=2[NH:56][CH:57]([CH3:58])[CH3:59])[CH2:42][CH2:41]1.[C:25]([OH:26])([C:27]([F:30])([F:29])[F:28])=[O:24]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)Nc1nc2c(nc1N1CCC(C(F)c3ccc(F)cc3F)CC1)CNCC2
Agent: C=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC(C)Nc1nc2c(nc1N1CCC(C(F)c3ccc(F)cc3F)CC1)CN(C)CC2
Reaction time: 0.5 h

Procedure:
Sodium triacetoxyborohydride (15.3 mg, 0.072 mmol) was added to a mixture of DIPEA (9.4 mg, 0.072 mmol), 3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (19.3 mg, 0.036 mmol) and formaldehyde (3 μL, 0.036 mmol) in MeOH (360 μL) at rt. After 30 min, the mixture was purified by HPLC Method A to give the title compound as a TFA salt (19.3 mg, 97%) as a yellow film. 1H NMR (400 MHz, methanol-d4) δ ppm 1.24 (dd, J=6.4, 2.2 Hz, 6H), 1.40-1.48 (m, 1H), 1.53-1.74 (m, 2H), 1.96-2.14 (m, 2H), 2.60-2.73 (m, 2H), 2.93-3.06 (br m, 2H), 3.06 (s, 3H), 3.39-3.54 (m, 3H), 3.69-3.81 (m, 1H), 4.18 (dt, J=13.1, 6.4 Hz, 2H), 4.16-4.36 (br m, 1H), 5.52 (dd, J=46.2, 7.6 Hz, 1H), 6.97-7.08 (m, 2H), 7.47-7.54 (m, 1H); ESI-MS m/z [M+H]+ 434.4.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C@@H:9]([O:31][C:32]([N:34]2[CH2:39][CH2:38][CH:37]([N:40]3[CH2:46][CH2:45][C:44]4[CH:47]=[CH:48][CH:49]=[CH:50][C:43]=4[NH:42][C:41]3=[O:51])[CH2:36][CH2:35]2)=[O:33])[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)=[O:11])=[CH:4][C:3]=1[CH3:52].C([O-])([O-])=O.[K+].[K+]>Cl.CN(C=O)C>[O:51]=[C:41]1[N:40]([CH:37]2[CH2:36][CH2:35][N:34]([C:32]([O:31][C@H:9]([CH2:8][C:5]3[CH:6]=[N:7][C:2]([NH2:1])=[C:3]([CH3:52])[CH:4]=3)[C:10](=[O:11])[N:12]3[CH2:17][CH2:16][CH:15]([N:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)[CH2:14][CH2:13]3)=[O:33])[CH2:39][CH2:38]2)[CH2:46][CH2:45][C:44]2[CH:47]=[CH:48][CH:49]=[CH:50][C:43]=2[NH:42]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCN(C(=O)OC(C)(C)C)CC3)CC2)cnc1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCNCC3)CC2)cnc1N

Procedure:
A solution of 75 mg (0.10 mmol) of tert-butyl 4-(1-{(R)-3-(6-amino-5-methyl-pyridin-3-yl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyloxy]-propionyl}-piperidin-4-yl)-piperazine-1-carboxylate (Example 114) in 5 mL 2 M HCl was stirred for 20 h at RT. After lyophilisation of the reaction mixture the residue was dissolved in 1 mL DMF, made alkaline with 0.6 mL saturated K2CO3 solution and purified by HPLC. The fractions containing the product were combined and again lyophilised.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[N:7]1([CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3([CH2:28][NH:29][C:30](=O)[CH3:31])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1.O.[OH-].[Na+]>O1CCCC1>[N:7]1([CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3([CH2:28][NH:29][CH2:30][CH3:31])[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)=[CH:18][CH:17]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CC(=O)NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCNCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Temperature: 25 °C
Yield: 77.7 %

Procedure:
LiAlH4 (1.0M in diethylether, 4.72 mL, 4.72 mmol) was added dropwise at 0° C. to a solution of (N-{4-[4-(3-pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-ylmethyl}-acetamide (848 mg, 2.36 mmol) in tetrahydrofuran (2 mL) under an atmosphere of nitrogen. The reaction mixture was allowed to warm to ambient temperature for 2 hours then heated to 50° C. for 10 hours. The reaction mixture was cooled to 0° C., water (3 mL) was added dropwise followed by sodium hydroxide (2.0M, 6 mL) and water (3 mL). The resulting solid was filtered over a small pad of celite, washed with Et2O/DCM (1:1 6×50 mL) and concentrated in vacuo to give the title compound as a pale yellow solid (635 mg, 78%). 1H NMR (400 MHz, CDCl3) δ 7.20 (d, 2H), 6.88 (d, 2H), 4.02 (t, 2H), 3.80-3.68 (m, 2H), 3.55 (dt, 2H), 2.68 (s, 2H), 2.60 (t, 2H), 2.58-2.42 (m, 6H), 2.18-2.08 (m, 2H), 2.00 (pentet, 2H) 1.94-1.86 (m, 2H), 1.84-1.76 (m, 4H), 1.92 (t, 3H). HRMS (ESI+) 347.2693 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:11][C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]([OH:16])=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:8]=1
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1cc(CBr)cc(C(C)(C)C)c1O

Procedure:
A mixture of 2,6-di-tert-butyl-4-methylphenol (2.34 g), N-bromosuccinimide (1.88 g) and carbon tetrachloride (25 ml) was refluxed for 2 hrs. The mixture was filtered to remove the insoluble precipitate to give a solution of 4-bromomethyl-2,6-di-tert-butylphenol. To the solution was added 3-amino-4-(2-chlorophenyl)-6,8-dimethylquinoline (2.0 g), and the whole was stirred for 5 hrs. at room temperature. The mixture was diluted with chloroform, washed with water, dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was purified by a column chromatography on silica gel and recrystallized from a mixture of acetone and isopropyl ether to give 4-(2-chlorophenyl)-3-(2,6-di-tert-butyl-4-hydroxyphenyl)amino-6,8-dimethylquinoline as colorless prisms (1.59 g, 44.9%). m.p. 183°-185° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:10](=N)[O:11][CH3:12])=[N:6][C:7]=1[O:8][CH3:9].C[OH:15]>Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]([O:11][CH3:12])=[O:15])=[N:6][C:7]=1[O:8][CH3:9]
Reactant: COC(=N)c1ccc(Br)c(OC)n1
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc(Br)c(OC)n1

Procedure:
A stirred solution of methyl 5-bromo-6-methoxypyridine-2-carboximidoate (C29) (9.42 g, 38.4 mmol) in methanol (66 mL) and concentrated hydrochloric acid (6.6 mL) was heated under reflux for 18 hours. The reaction was concentrated to dryness under reduced pressure. The resulting solid was dissolved in dichloromethane (500 mL) and washed with saturated aqueous sodium bicarbonate solution (250 mL). The aqueous phase was extracted with dichloromethane (200 mL), and the combined organics were washed with water (250 mL), with saturated aqueous sodium chloride solution (250 mL), dried over magnesium sulfate and concentrated under reduced pressure to provide the title compound. The reaction was repeated on additional material (1.65 g, 6.73 mmol), worked up in a similar manner, combined with the first reaction, and purified by silica gel chromatography (Eluant: 10% ethyl acetate in heptane) to provide the title compound as a yellow solid. Yield: 4.48 g, 18.2 mmol, 40%. LCMS m/z 246.1 (M+1). 1H NMR (400 MHz, CDCl3) δ 3.97 (s, 3H), 4.11 (s, 3H), 7.59 (d, J=7.8 Hz, 1H), 7.93 (d, J=7.8 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([O:11][CH2:12][CH2:13][CH2:14][C:15]#[C:16][CH2:17][OH:18])[CH:5]=[CH:4][C:3]=1[C:19](=[O:21])[CH3:20]>C(Cl)Cl.[O-2].[Mn+2]>[C:19]([C:3]1[CH:4]=[CH:5][C:6]([O:11][CH2:12][CH2:13][CH2:14][C:15]#[C:16][CH:17]=[O:18])=[C:7]([CH2:8][CH2:9][CH3:10])[C:2]=1[OH:1])(=[O:21])[CH3:20]
Reactant: CCCc1c(OCCCC#CCO)ccc(C(C)=O)c1O
Agent: [Mn+2]
Agent: [O-2]
Solvent: ClCCl
Product: CCCc1c(OCCCC#CC=O)ccc(C(C)=O)c1O
Reaction time: 2 h
Yield: 73 %

Procedure:
To 2.07 g of 1-[2-hydroxy-4-[(6-hydroxy-4-hexynyl)oxy]-3-propylphenyl]ethanone in 150 ml of methylene chloride at 25° was added 20.7 g of activated manganese oxide and the mixture was stirred for 2 hours. After filtration, the filtrate was concentrated in vacuo to yield 1.50 g (73% yield) of the titled compound.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([CH3:14])=[CH:8]2)([CH3:3])[CH3:2].[CH2:15]([O:17]C1C=C2C(=CC=1)NC(C)=C2C=O)C>>[CH:1]([O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([CH3:14])=[C:8]2[CH:15]=[O:17])([CH3:3])[CH3:2]
Reactant: Cc1cc2cc(OC(C)C)ccc2[nH]1
Reactant: CCOc1ccc2[nH]c(C)c(C=O)c2c1
Product: Cc1[nH]c2ccc(OC(C)C)cc2c1C=O
Reaction time: 1.5 h

Procedure:
This compound was prepared from 408c (347 mg, 1.83 mmol) in a manner similar to that for 409a except for after the drop-wise addition of substituted indole, the solution was stirred for 90 min A cream-colored powder was obtained (313 mg, 78%): mp 179-181° C. TLC Rf 0.43 (75% EtOAc/hexanes). 1H NMR (600 MHz, d6-DMSO) δ 11.84 (s, 1H), 10.00 (s, 1H), 7.56 (d, 1H, J=2.4 Hz), 7.26-7.25 (d, 1H, J=8.64 Hz), 6.77-6.76 (dd, 1H, J1=8.7 Hz, J2=2.46 Hz), 4.56-4.50 (sep, 1H, J=6 Hz), 2.64 (s, 3H), 1.27-1.26 (d, 6H, J=6 Hz). 13C NMR (150 MHz, d6-DMSO) δ 184.0, 153.4, 148.6, 130.1, 126.4, 113.58, 113.56, 112.0, 105.5, 69.9, 22.0, 11.5. Elemental analysis calculated for C13H15NO2: C, 71.87; H, 6.96; N, 6.45. Found: C, 71.70; H, 6.83; N, 6.60.
Reaction SMILES: CC1N=C(N2CCN(C3C=CC=CC=3)C2=O)SC=1C(OCC)=O.[CH:24]1([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:37][C:38]([C:42]([O:44]CC)=[O:43])=[C:39]([CH3:41])[N:40]=3)[C:32]2=[O:47])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:37][C:38]([C:42]([OH:44])=[O:43])=[C:39]([CH3:41])[N:40]=3)[C:32]2=[O:47])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: CCOC(=O)c1sc(N2CCN(CC3CCCCC3)C2=O)nc1C
Agent: CCOC(=O)c1sc(N2CCN(c3ccccc3)C2=O)nc1C
Product: Cc1nc(N2CCN(CC3CCCCC3)C2=O)sc1C(=O)O
Yield: 86 %

Procedure:
Following the procedure as described in Example 6, making variations as required to replace ethyl 4-methyl-2-(2-oxo-3-phenylimidazolidin-1-yl)thiazole-5-carboxylate with ethyl 2-(3-(cyclohexylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate, the title compound was obtained in 86% yield: 1H NMR (300 MHZ, DMSO-d6) δ 4.06-3.82 (m, 2H), 3.52-3.42 (m, 2H), 2.98 (d, J=6.9 Hz, 2H), 2.52 (s, 3H), 1.73-1.52 (m, 6H), 1.27-1.08 (m, 3H), 0.90-0.72 (m, 2H): MS (ES+) 324.2 (M+1).
Reaction SMILES: FC(F)(F)S(OC)(=O)=O.[CH3:10][C:11]1[S:20][C:19]2[NH:18][C:17]3[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=3[NH:15][C:14](=S)[C:13]=2[CH:12]=1.[S:26]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C@H:33]2[CH2:38][NH:37][CH2:36][CH2:35][NH:34]2)=[CH:27]1.S1C=CC=C1CC[C@H]1CNCCN1>ClCCl.CO.ClCCl.N1C=CC=CC=1>[CH3:10][C:11]1[S:20][C:19]2[NH:18][C:17]3[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=3[N:15]=[C:14]([N:37]3[CH2:36][CH2:35][NH:34][C@@H:33]([CH2:32][CH2:31][C:28]4[CH:29]=[CH:30][S:26][CH:27]=4)[CH2:38]3)[C:13]=2[CH:12]=1
Reactant: Cc1cc2c(s1)Nc1ccccc1NC2=S
Reactant: c1cc(CC[C@H]2CNCCN2)cs1
Agent: COS(=O)(=O)C(F)(F)F
Agent: c1csc(CC[C@H]2CNCCN2)c1
Solvent: CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCc2ccsc2)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Add methyl trifluoromethanesulfonate (241 μL, 2.13 mmol) to a 0° C. slurry of 2-methyl-4,9-dihydro-3-thia-4,9-diaza-benzo[f]azulene-10-thione (437 mg, 1.77 mmol) in dichloromethane (5 mL). Stir 2 h at 0° C. then warm to ambient temperature and stir 16 h. Concentrate the reaction to an orange powder. Add a 6:1 mixture of (S)-2-(2-thiophen-3-yl-ethyl)-piperazine and (S)-2-(2-thiophen-2-yl-ethyl)-piperazine (346 mg, 1.76 mmol) and pyridine (5 mL). Heat to reflux for 7.5 h and stir at ambient temperature for 18 h. Concentrate the reaction, dissolve the residue in methanol-dichloromethane, apply to a SCX column. Wash the column with methanol-dichloromethane to remove impurities then elute the product with 2N ammonia in methanol-methanol (10%). Concentrate and purify by silica gel chromatography using 2N ammonia in methanol-methylene chloride (1%–4%) as the eluent to give 333 mg of a brown foam. Purify by radial silica gel chromatography using a 4 mm plate and 1% isopropylamine in tetrahydrofuran-hexanes (10%–20%) as the eluent to give 218 mg (30%) of the title compound: mass spectrum (ion spray): m/z=409 (M+1), 407 (M −1). HR-MS calculated for C22H25N4S2: 409.1521. Found 409.1540. 1H NMR (DMSO-d6): δ 7.56 (s, 1H), 7.43 (dd, 1H), 7.13 (s, 1H), 6.99 (d, 1H), 6.87–6.74 (m, 3H), 6.67 (d, 1H), 6.31 (s, 1H), 3.88 (br d, 1H), 3.76 (br d, 1H), 2.88 (br d, 1H), 2.80–2.53 (m, 5H), 2.45–2.38 (m, 1H), 2.27 (s, 3H), 1.61 (dd, 2H).
Reaction SMILES: NC(C(O)=O)CCSC.C[O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[N:20][O:21][CH:22]=2)=[CH:14][CH:13]=1.CS(O)(=O)=O>>[O:21]1[CH:22]=[C:18]([C:15]2[CH:14]=[CH:13][C:12]([OH:11])=[CH:17][CH:16]=2)[CH:19]=[N:20]1
Reactant: COc1ccc(-c2cnoc2)cc1
Agent: CS(=O)(=O)O
Agent: CSCCC(N)C(=O)O
Product: Oc1ccc(-c2cnoc2)cc1
Temperature: 70 °C
Yield: 68.2 %

Procedure:
To a round-bottomed flask was added D,L-methionine (1.30 g, 8.73 mmol), 4-(4-methoxy-phenyl)-isoxazole (1.02 g, 5.82 mmol), and methanesulfonic acid (24 ml). The resulting solution was heated to about 70° C. for about eighteen hours, and was then allowed to cool to room temperature and poured onto ice water. The mixture was adjusted to about pH 4, and the heterogenous mixture was filtered. The solid was washed with water and then dried to yield the title compound as an off-white solid (640 mg, 68% yield). LRMS ([M−H]−)=160.0.
Reaction SMILES: [CH2:1]([C:3]([N:7]=[C:8]=[N:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)([CH3:6])[CH2:4][CH3:5])[CH3:2].C([N:20]=[C:21]=[N:22]C1C=NC=CC=1)(C)(C)C>>[C:21]([N:22]=[C:8]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[NH:7][C:3]([CH2:4][CH3:5])([CH3:6])[CH2:1][CH3:2])#[N:20]
Reactant: CC(C)(C)N=C=Nc1cccnc1
Reactant: CCC(C)(CC)N=C=Nc1cccnc1
Product: CCC(C)(CC)NC(=NC#N)Nc1cccnc1

Procedure:
By following the procedure of Example 1, but substituting N-(1-ethyl-1-methylpropyl)-N'-3-pyridylcarbodiimide for the N-tert-butyl-N'-3-pyridylcarbodiimide, the N"-cyano-N-(1-ethyl-1-methylpropyl)-N'-3-pyridylguanidine was obtained with a melting point of 184.5°-186.0° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:5][CH:4]=1.[NH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[NH2:17].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH2:10][CH2:11][C:12](=[O:14])[N:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[N:17]=2)=[CH:7][CH:8]=1
Reactant: NNc1ccccn1
Reactant: COc1ccc(C(=O)CCC(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: COc1ccc(C2=NN(c3ccccn3)C(=O)CC2)cc1
Temperature: 25 °C

Procedure:
In a 1 neck round bottom flask equipped with a Dean-Stark trap and condenser, 4-(4-methoxyphenyl)-4-oxo-butyric acid (5.0 g, 20 mmol), 2-hydrazinopyridine (3.9 g, 36 mmol) and p-toluene sulfonic acid (0.3 g) in 100 mL benzene were heated to reflux for 2 h while water was removed. The reaction was cooled to rt, an equal volume of Et2O was added and the product collected; Mp>300° C. This solid was dissolved in HOAc (50 mL) and heated at 100° C. for 6 h. The reaction was concentrated, dissolved in EtOAc and washed with saturated NaHCO3 solution, water, NaCl solution and dried (MgSO4). The solvent was concentrated to a thick oil; MS m/z 282 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][C:7]([CH2:15][OH:16])([C:11]([O:13]C)=[O:12])[C:6]=2[CH:17]=1.[OH-].[Na+]>C(Cl)Cl.CCOCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][C:7]([CH2:15][OH:16])([C:11]([OH:13])=[O:12])[C:6]=2[CH:17]=1
Reactant: COC(=O)C1(CO)CCOc2ccc(F)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(O)C1(CO)CCOc2ccc(F)cc21
Temperature: 25 °C
Yield: 41.2 %

Procedure:
To a solution of 7 g (0.029 mole) Methyl 6-fluoro-3,4-dihydro-4-(hydroxymethyl)-2H-benzopyran-4-carboxylate in 200 mL of McOH was added 7.2 mL of 5N NaOH. The reaction was heated on a steam bath overnight then cooled to room temperature. The MeOH was evaporated and the residue dissolved in water then acidified to pH 4.0 with concentrated HCl. The aqueous was extracted with EtOAc and the EtOAc layer was dried over Na2SO4, filtered and evaporated to give 6 g of crude product. Chromatography on 160 g of silica gel eluting with CH2Cl2 /ether gave 2.7 g of product, m.p. 134°-135° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([S:7]([C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](O)=[O:13])(=[O:9])=[O:8])[CH2:3][CH2:2]1.S(Cl)([Cl:21])=O.C[O-].[Na+]>ClCCl.CO>[O:1]1[CH2:6][CH2:5][N:4]([S:7]([C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([Cl:21])=[O:13])(=[O:9])=[O:8])[CH2:3][CH2:2]1
Reactant: O=C(O)c1ccccc1S(=O)(=O)N1CCOCC1
Reactant: O=S(Cl)Cl
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=C(Cl)c1ccccc1S(=O)(=O)N1CCOCC1
Temperature: 60 °C
Yield: 113.2 %

Procedure:
To a slurry of 2-(morpholinosulfonyl)benzoic acid (327 mg, 1.21 mmol) in dichloromethane (11 mL) was added thionyl chloride (0.220 mL, 3.01 mmol). The reaction was heated at 60° C. for 1 hour, after which LCMS analysis (sodium methoxide solution, 25% in methanol) revealed reaction completion. The reaction was concentrated to afford 2-(morpholinosulfonyl)benzoyl chloride (0.397 g, 1.37 mmol) as a viscous yellow residue and this was used in the next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([O:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:10]=[CH:9]2.[NH2:28][C:29]1[C:30]([C:37]([NH:39][C:40](SC)=[NH:41])=[O:38])=[N:31][C:32]([Cl:36])=[C:33]([NH2:35])[N:34]=1.CCN(C(C)C)C(C)C>CCO>[NH2:28][C:29]1[C:30]([C:37]([NH:39][C:40](=[NH:41])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[CH:12]=[C:11]([O:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])[CH:10]=[CH:9]3)=[O:38])=[N:31][C:32]([Cl:36])=[C:33]([NH2:35])[N:34]=1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: CC(C)(C)OC(=O)NCCCOc1ccc2cc(CCCCN)ccc2c1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCCOc1ccc2cc(CCCCNC(=N)NC(=O)c3nc(Cl)c(N)nc3N)ccc2c1
Temperature: 70 °C
Yield: 84.2 %

Procedure:
To a solution of carbamate 88 (500 mg, 1.34 mmol) and methyl 3,5-diamino-6-chloropyrazine-2-carbonylcarbamimidothioate (10, 790 mg, 2.01 mmol) in EtOH (30 mL) was added DIPEA (1.75 mL, 9.39 mmol) at room temperature. The reaction mixture was heated at 70° C. in a sealed tube for 2 h, then cooled to room temperature, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 90:9:1 CHCl3/CH3OH/NH4OH) to afford carbamate 89 (660 mg, 84%) as a yellow solid: 1H NMR (300 MHz, CD3OD) δ 7.65 (d, J=7.5 Hz, 2H), 7.56 (s, 1H), 7.31 (dd, J=8.4, 1.5 Hz, 1H), 7.16 (d, J=2.4 Hz, 1H), 7.08 (dd, J=8.7, 2.4 Hz, 1H), 4.10 (t, J=6.3 Hz, 2H), 2.81 (t, J=6.6 Hz, 2H), 2.01-1.97 (m, 2H), 1.83-1.60 (m, 4H), 1.43 (s, 9H).
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[SH:19][C:20]1[O:24][C:23]([C:25]([NH2:27])=[O:26])=[N:22][N:21]=1.C(=O)(O)[O-].[Na+].Cl>CC(C)=O>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:19][C:20]3[O:24][C:23]([C:25](=[O:26])[NH2:27])=[N:22][N:21]=3)[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: NC(=O)c1nnc(S)o1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: NC(=O)c1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)o1

Procedure:
7-Aminocephalosporanic acid (10.88 g, 40 mmole) and 5-mercapto-1,3,4-oxadiazol-2-ylcarboxamide (6.40 g, 44 mmole) in 50% aqueous acetone (500 ml) were treated with solid sodium bicarbonate to pH 7 then heated at 60° for 5 hours. The solution was acidified to pH 4.0 with 5 N hydrochloric acid, cooled in an ice bath for one hour and the precipitated solid collected, washed with water (100 ml) ethanol (200 ml) and ether (200 ml) and dried in vacuo, 5.87 g (41.1%), δ(CF3CO2H) 3.5-4.1 (2H,m, C2 methylene), 4.4-4.9 (2H,m, --CH2S--), 5.42 (2H,s, β-lactam protons), 7.89 (2H, d, J 28 Hz, --CONH2).
Reaction SMILES: CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.[CH2:17]([O:19][C:20]1[CH:21]=[CH:22][C:23]([F:38])=[C:24]([C:26]2[C:31]([CH3:32])=[C:30]([CH3:33])[N:29]=[C:28]([C:34](OC)=[O:35])[CH:27]=2)[CH:25]=1)[CH3:18].CCO>C1COCC1>[CH2:17]([O:19][C:20]1[CH:21]=[CH:22][C:23]([F:38])=[C:24]([C:26]2[C:31]([CH3:32])=[C:30]([CH3:33])[N:29]=[C:28]([CH:34]=[O:35])[CH:27]=2)[CH:25]=1)[CH3:18]
Reactant: CCOc1ccc(F)c(-c2cc(C(=O)OC)nc(C)c2C)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1ccc(F)c(-c2cc(C=O)nc(C)c2C)c1
Reaction time: 2.5 h
Yield: 98.4 %

Procedure:
1M DIBAL in toluene (8.7 mL, 8.7 mmol) was added dropwise over 12 minutes to a stirred solution of methyl 4-(5-ethoxy-2-fluoro-phenyl)-5,6-dimethyl-pyridine-2-carboxylate (which may be prepared as described in Description 52) (1.32 g, 4.35 mmol) in dry THF (25 mL) at −75° C. The reaction was stirred at this temp for 2.5 h then EtOH (0.2 ml) was added to quench. After 1 minute the reaction was poured into saturated Rochelle salt solution (200 ml). The mixture was extracted with EtOAc (100 ml) then DCM (2×100 ml). The combined organic extracts were dried (Na2SO4), filtered and evaporated to a white solid, which was dried at RT under vacuum for 16 h to afford 4-(5-ethoxy-2-fluoro-phenyl)-5,6-dimethyl-pyridine-2-carbaldehyde (D53) (1.17 g);