Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)[C:4](=[O:25])[CH:5]([CH2:22][C:23]#[CH:24])[C:6]([NH:8][S:9]([C:12]1C=C[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)(=[O:11])=[O:10])=[O:7])C.C(/S(N)(=O)=O)=C\C1C=CC=CC=1.[F:40][C:41]1[CH:50]=[CH:49][C:44]([NH:45][CH:46]([CH3:48])[CH3:47])=[CH:43][CH:42]=1>>[F:40][C:41]1[CH:50]=[CH:49][C:44]([N:45]([CH:46]([CH3:48])[CH3:47])[C:4](=[O:25])[CH:5]([CH2:22][C:23]#[CH:24])[C:6]([NH:8][S:9](/[CH:12]=[CH:13]/[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:11])=[O:10])=[O:7])=[CH:43][CH:42]=1
Reactant: CC(C)Nc1ccc(F)cc1
Reactant: C#CCC(C(=O)NS(=O)(=O)c1ccc2ccccc2c1)C(=O)N(CC)CC
Agent: NS(=O)(=O)/C=C/c1ccccc1
Product: C#CCC(C(=O)NS(=O)(=O)/C=C/c1ccccc1)C(=O)N(c1ccc(F)cc1)C(C)C
Yield: 36.4 %

Procedure:
In the same manner as in Example 152 (3), the object compound was obtained using the compound (3.00 g) obtained in Example 152 (2) and trans-β-styrenesulfonamide (3.23 g). This was subjected to hydrolysis in the same manner as in Example 1 (3), and condensed with 4-fluoro-N-isopropylaniline (1.29 g) in the same manner as in Example 1 (4) to give a crude product. This was purified by silica gel column chromatography to give the title compound (1.25 g) as a white powder.
Reaction SMILES: [C:1](Cl)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[O:15]=[C:16]([CH2:18][N:19]([C:21](=[NH:23])[NH2:22])[CH3:20])[OH:17].N1C=CC=CC=1.C(=O)=O>ClCCl.CC(C)=O>[C:1]([NH:23][C:21](=[NH:22])[N:19]([CH2:18][C:16]([OH:17])=[O:15])[CH3:20])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: CN(CC(=O)O)C(=N)N
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: CCCCCCCCCCCC(=O)NC(=N)N(C)CC(=O)O
Temperature: 25 °C

Procedure:
In a dry 3-necked, round bottomed flask, equipped with a magnetic stirrer, a thermometer, a nitrogen inlet tube and the dropping funnel containing the dodecanoyl chloride solution, 7.34 g (56 mmol) of creatine is suspended, with stirring, in 50 ml of dry dichloromethane. To this suspension a catalytic amount (0.1 mmol) of pyridine is also added. The suspension is stirred in a dry ice and acetone bath to a temperature of between about −15° C. and 0° C. When the target temperature is reached the drop wise addition of dodecanoyl chloride is commenced. Addition of dodecanoyl chloride continues, with cooling and stirring, until all of the dodecanoyl chloride is added, after which the reaction is allowed to warm to room temperature with constant stirring. The solution is then filtered to remove any remaining creatine, and the volatile dichloromethane and pyridine are removed under reduced pressure yielding 2-(3-dodecanoyl-1-methylguanidino)acetic acid.
Reaction SMILES: [CH2:1]([S:4](Cl)(=[O:6])=[O:5])[CH2:2][CH3:3].[NH2:8][C:9]1[CH:35]=[CH:34][C:12]([C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[C:17]([C:24]3[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=3)[C:27]([O:29][CH3:30])=[O:28])[N:16]=2)=[O:14])=[CH:11][C:10]=1[O:36][CH3:37]>N1C=CC=CC=1.ClCCl>[CH3:37][O:36][C:10]1[CH:11]=[C:12]([CH:34]=[CH:35][C:9]=1[NH:8][S:4]([CH2:1][CH2:2][CH3:3])(=[O:6])=[O:5])[C:13]([C:15]1[N:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]2=[C:17]([C:24]2[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=2)[C:27]([O:29][CH3:30])=[O:28])[N:16]=1)=[O:14]
Reactant: CCCS(=O)(=O)Cl
Reactant: COC(=O)c1cccc(-c2nc(C(=O)c3ccc(N)c(OC)c3)n3ccccc23)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCS(=O)(=O)Nc1ccc(C(=O)c2nc(-c3cccc(C(=O)OC)c3)c3ccccn23)cc1OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
0.17 ml (1.5 mmol) of 1-propanesulfonyl chloride is added to 0.5 g (1.24 mmol) of methyl 3-[3-(4-amino-3-methoxybenzoyl)imidazo[1,5-a]pyridin-1-yl]benzoate obtained in example 111 in 6 ml of pyridine. The reaction medium is stirred at ambient temperature for 18 h and then concentrated under reduced pressure. The residue obtained is taken up in dichloromethane. The organic phase obtained is washed with water, dried over sodium sulfate and concentrated under reduced pressure. The residue obtained is purified by column chromatography on silica gel, elution being carried out with dichloromethane. 0.34 g of a yellow oil is collected. MS+: 508; 1H NMR (d6-DMSO): 0.96-1.01 (3H, t), 1.74-1.81 (2H, m), 3.16-3.19 (2H, m), 3.92 (3H, s), 4.00 (3H, s), 7.33-7.73 (2H, m), 7.38-7.51 (1H, m), 7.53-7.96 (2H, m), 8.03-8.30 (2H, m), 8.33-9.85 (2H, m), 8.38 (1H, s), 8.63 (1H, s), 9.25 (1H, m)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]#[N:12])=[CH:2]1.[CH:13]([N-]C(C)C)(C)[CH3:14].[Li+].BrCCCl>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2([C:11]#[N:12])[CH2:14][CH2:13]2)=[CH:2]1
Reactant: N#CCc1c[nH]c2ccccc12
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCBr
Product: N#CC1(c2c[nH]c3ccccc23)CC1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
1H-indole-3-ylacetonitrile (18.7 g) was dissolved in tetrahydrofuran (240 mL) and, after cooling to −30° C., lithium diisopropylamide (2.0M heptane/tetrahydrofuran/ethylbenzene solution, 240 mL) was added dropwise, followed by stirring at −5° C. for 30 minutes. The reaction mixture was cooled to −30° C. and 1-bromo-2-chloroethane (11.0 mL) was added dropwise, followed by stirring for 2 hours while heating to 0° C. The reaction mixture was poured into ice/hydrochloric acid (2N, 360 mL) and extracted with ethyl acetate. The organic layer was washed in turn with water, an aqueous saturated sodium hydrogen carbonate solution and saturated saline, dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain a compound and the compound was recrystallized from (hexane:ethyl acetate=1:1) to obtain the titled compound having the following physical properties (8.67 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:20][C:21]4[NH:27][C:26](=[O:28])[CH2:25][CH2:24][NH:23][C:22]=4[N:29]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[F:39][CH2:40][CH2:41]I.O>CN(C=O)C>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[CH:20][C:21]4[N:27]([CH2:41][CH2:40][F:39])[C:26](=[O:28])[CH2:25][CH2:24][NH:23][C:22]=4[N:29]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CCN4)cc2)CCC1
Reactant: FCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(CCF)C(=O)CCN4)cc2)CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.7 %

Procedure:
To a solution of tert-butyl(1-(4-(2-oxo-8-phenyl-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-7-yl)phenyl)cyclobutyl)carbamate (101 mg, 0.21 mmol) in dry DMF (1 ml) was added sodium hydride (12 mg, 0.32 mmol) and 1-fluoro-2-iodoethane (27 μl, 0.32 mmol) under nitrogen. The resulting mixture was stirred for 1 hour at room temperature. Water was added and the mixture was extracted with EtOAc (3×10 ml). The combined organic phases were dried over Na2SO4 and concentrated to dryness under reduced pressure. The resulting residue was purified by Biotage silica gel chromatography (gradient 0 to 100% EtOAc in cyclohexane) to give the title compound (52 mg, 47%). 1H NMR (500 MHz, CDCl3): 7.62 (1H, s), 7.31-7.22 (7H, m), 7.16-7.14 (2H, m), 5.01 (1H, s), 4.75 (1H, br s), 4.74 (2H, dt), 4.07 (2H, dt), 3.92-3.88 (2H, m), 2.73 (2H, t), 2.55-2.25 (4H, m), 2.10-2.03 (1H, m), 1.86-1.78 (1H, m), 1.44-1.15 (9H, br).
Reaction SMILES: [CH2:1]([O:4][NH:5][C@@H:6]1[C:11]([C:12]([N:14]([CH3:16])[CH3:15])=[O:13])=[CH:10][C@@H:9]([CH2:17][O:18][CH3:19])[NH:8][CH2:7]1)[CH:2]=[CH2:3].CCN(C(C)C)C(C)C.Cl[C:30](Cl)([O:32]C(=O)OC(Cl)(Cl)Cl)Cl>C(#N)C>[CH2:1]([O:4][N:5]1[C:30](=[O:32])[N:8]2[CH2:7][C@H:6]1[C:11]([C:12]([N:14]([CH3:16])[CH3:15])=[O:13])=[CH:10][C@H:9]2[CH2:17][O:18][CH3:19])[CH:2]=[CH2:3]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C=CCON[C@H]1CN[C@H](COC)C=C1C(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C=CCON1C(=O)N2C[C@H]1C(C(=O)N(C)C)=C[C@H]2COC
Temperature: 25 °C
Reaction time: 8 h
Yield: 206.3 %

Procedure:
A solution of (3R,6S)-3-(allyloxyamino)-6-(methoxymethyl)-N,N-dimethyl-1,2,3,6-tetrahydropyridine-4-carboxamide (Intermediate 142, 725 mg, 2.69 mmol) and Hunig's Base (1.880 mL, 10.77 mmol) in acetonitrile (350 mL) was cooled to below 0° C. in an ice-salt bath and then a solution of triphosgene (320 mg, 1.08 mmol) in ACN (22 mL) was added at a rate of 0.1 mL/min. The reaction was stirred overnight at rt. Upon completion of the reaction, the solvents were removed and the crude mixture was redissolved in EtOAc, washed with sat. NaHCO3 and brine, dried over MgSO4, filtered and concentrated to obtain the desired product (658 mg, 83%) as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[BH3-]C#N.[Na+].[NH:28]1[CH:32]=[CH:31][N:30]=[C:29]1[CH:33]=O>CO>[NH:28]1[CH:32]=[CH:31][N:30]=[C:29]1[CH2:33][N:13]1[CH2:14][CH2:15][CH:10]([N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:8][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH2:11][CH2:12]1
Reactant: O=Cc1ncc[nH]1
Reactant: Cc1cccnc1CN(Cc1ncccc1C)C1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cc1cccnc1CN(Cc1ncccc1C)C1CCN(Cc2ncc[nH]2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 32.7 %

Procedure:
To a solution of COMPOUND 249 (0.1182 g, 0.38 mmol) in MeOH (8 mL) was added NaBH3CN (0.0477, 0.76 mmol) and 2-imidazole carboxaldehyde (0.0438 g, 0.46 mmol), and stirred at room temperature for 24 hours then concentrated. Saturated NaHCO3 (15 mL) was added and extracted with CH2Cl2 (2×40 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated. Purification of the crude material by column chromatography on silica gel (20:1:1 CH2Cl2-MeOH—NH4OH) provided 0.0486 g (31%) of COMPOUND 336 as a white solid. 1H NMR (CDCl3) δ 1.67-1.87 (m, 4H), 1.99 (t, 2H, J=11.3 Hz), 2.08 (s, 6H), 2.47-2.55 (m, 1H), 2.87 (d, 2H, J=11.1 Hz), 3.58 (s, 2H), 3.82 (s, 4H), 6.98 (s, 2H), 7.02-7.09 (m, 2H), 7.35 (d, 2H, J=7.2 Hz), 8.33 (d, 2H, J=3.9 Hz). 13C NMR (CDCl3) δ 18.39, 27.23, 54.15, 55.31, 56.25, 57.94, 121.88, 122.77, 127.09, 133.81, 138.42, 146.20, 157.67. ES-MS m/z 377 (M+Na+). Anal. Calcd. for C23H30N6.0.6CH4O: C, 69.18; H, 7.97; N, 20.51. Found: C, 69.05; H, 7.78; N, 20.39.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[S:21][C:20]([C:22](O)=[O:23])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[C@H:10]([CH3:25])[CH2:9]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.C(Cl)(C(Cl)=O)=O.[CH3:36][N:37](C=O)[CH3:38]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[S:21][C:20]([C:22]([N:37]([CH3:38])[CH3:36])=[O:23])=[CH:19][CH:18]=3)(=[O:15])=[O:16])[C@H:10]([CH3:25])[CH2:9]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1
Reactant: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1ccc(C(=O)O)s1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1ccc(C(=O)N(C)C)s1
Reaction time: 6 h

Procedure:
To a solution of 5-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}sulfonyl)thiophene-2-carboxylic acid (260 mg, 0.575 mmol) in DCM (5 mL) was added (COCl)2 (150.5 μL, 1.726 mmol) and DMF (1 small drop). The resultant mixture was stirred for 3 h. The solvent was evaporated and the crude residue was redissolved in dioxane (5 mL). To this was added 2N NH3 in EtOH (2 mL). The reaction mixture was stirred for 6 h then concentrated. The crude product was purified on SiO2 column eluted with hexanes/EtOAc to give the titled compound (less polar fraction, a side product) as a light yellow solid (48 mg, 17%). HRMS: calcd for C19H21F4N3O3S2+H+, 480.10332. found (ESI-FTMS, [M+H]1+), 480.1042.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[CH2:43]([NH:45][CH2:46][C:47]([CH2:53][NH:54][C:55]1[CH:63]=[CH:62][CH:61]=[C:60]2[C:56]=1[CH:57]=[N:58][N:59]2[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)([OH:52])[C:48]([F:51])([F:50])[F:49])[CH3:44]>CN(C=O)C.CS(C)=O>[CH2:43]([N:45]([CH2:46][C:47]([OH:52])([CH2:53][NH:54][C:55]1[CH:63]=[CH:62][CH:61]=[C:60]2[C:56]=1[CH:57]=[N:58][N:59]2[C:64]1[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=1)[C:48]([F:51])([F:50])[F:49])[C:1](=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH3:44]
Reactant: O=C(O)c1ccccc1
Reactant: CCNCC(O)(CNc1cccc2c1cnn2-c1ccccc1)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCN(CC(O)(CNc1cccc2c1cnn2-c1ccccc1)C(F)(F)F)C(=O)c1ccccc1
Reaction time: 0.02 h
Yield: 61.3 %

Procedure:
To benzoic acid (11 mg, 0.09 mmol) was added a solution of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (34 mg, 0.09 mmol) in DMF (0.2 ml) followed by N,N-diisopropylethylamine (32 μL, 0.182 mmol). The mixture was shaken for 1 minute and then a solution of 3-(ethylamino)-1,1,1-trifluoro-2-{[(1-phenyl-1H-indazol-4-yl)amino]methyl}-2-propanol (26 mg, 0.07 mmol) in DMF (0.2 ml) was added. The mixture was again shaken for 1 minute and then left to stand at room temperature for 18 hours. The crude reaction was diluted with dimethyl sulfoxide (0.1 ml) and purified by mass-directed autopreparation (system A) to give the title compound (20.7 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8](=[NH:34])[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]([C@H:19]2[N:23]3[C:24](=[O:33])[C:25]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:26][N:27]=[C:22]3[CH2:21][CH2:20]2)=[O:18])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(OC(=O)NC([C:45]1[CH:50]=[CH:49][C:48](CNC([C@H]2N3C(=O)C(N(CC)CC)=CN=C3CC2)=O)=[CH:47][CH:46]=1)=N)(C)(C)C.C1(CS(Cl)(=O)=O)C=CC=CC=1>>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8](=[NH:34])[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]([C@H:19]2[N:23]3[C:24](=[O:33])[C:25]([NH:28][S:29]([CH2:32][C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)(=[O:31])=[O:30])=[CH:26][N:27]=[C:22]3[CH2:21][CH2:20]2)=[O:18])=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2CCc3ncc(NS(C)(=O)=O)c(=O)n32)cc1
Reactant: CCN(CC)c1cnc2n(c1=O)[C@H](C(=O)NCc1ccc(C(=N)NC(=O)OC(C)(C)C)cc1)CC2
Agent: O=S(=O)(Cl)Cc1ccccc1
Product: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2CCc3ncc(NS(=O)(=O)Cc4ccccc4)c(=O)n32)cc1
Yield: 44 %

Procedure:
Following a procedure similar to that for the preparation of 16a, intermediate 3a (50 mg, 0.117 mmol) and alpha-toluene sulfonyl chloride (26.7 mg, 0.14 mmol) yielded 35.6 mg (44%) of 36a. MS (ESI) 581.1 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=[O:12])#[N:2].C(N(CC)CC)C.[SH2:20]>N1C=CC=CC=1>[C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=[O:12])(=[S:20])[NH2:2]
Reactant: N#Cc1cccc2c1CCC2=O
Reactant: S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: NC(=S)c1cccc2c1CCC2=O
Reaction time: 16 h

Procedure:
A solution of 12.1 g (77 mmol) of 4-cyano-2,3-dihydro-1H-inden-1-one [see Coll. Czechoslov. Chem. Commun. 4, 3227 (1978)] in 220 ml of pyridine and 10.6 ml (77 mmol) of triethylamine is saturated with hydrogen sulfide for 3 hours at 40° and is then stirred at the same temperature for 16 hours. The reaction mixture is cooled and then concentrated to dryness by evaporation, and 300 ml of water are added to the residue. The yellow product that has crystallized out is filtered off with suction, washed with water, dried and recrystallized from ethyl acetate. In that manner there is obtained the title compound, m.p. 197° (decomp.).
Reaction SMILES: [N:1]1[CH:6]=CC=[CH:3][CH:2]=1.[CH:7]1([C:13]([Cl:15])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.C(OCC)(=[O:18])C>>[ClH:15].[CH:7]1([C:13]([O:14][CH2:3][CH2:2][NH:1][CH3:6])=[O:18])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CCOC(C)=O
Reactant: O=C(Cl)C1CCCCC1
Reactant: c1ccncc1
Product: CNCCOC(=O)C1CCCCC1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
After stirring at room temperature for 2 hrs., pyridine (0.65 mL) and cyclohexanecarbonyl chloride (0.58 mL) were added, and the mixture was stirred overnight at room temperature. Ethyl acetate (50 mL) was added to the reaction mixture, and the mixture was washed with water (50 mL), a 5% aqueous citric acid solution (50 mL) and saturated brine (50 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, a 4N hydrogen chloride-ethyl acetate solution (10 mL) was added to the residue. After stirring at room temperature for 2 hrs., diethyl ether (10 mL) was added, and the precipitated solid was collected by filtration. The solid was dried under reduced pressure to give the title compound (1.88 g) as a white solid.
Reaction SMILES: [O:1]=[C:2]([C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)[CH2:3][CH2:4][C:5]([NH:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:16]=1[NH:15][C:14]([C:17]1[S:18][CH:19]=[CH:20][N:21]=1)=[CH:13]2)=[O:6].O1CCCC1.[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[OH:1][CH:2]([C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)[CH2:3][CH2:4][C:5]([NH:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:16]=1[NH:15][C:14]([C:17]1[S:18][CH:19]=[CH:20][N:21]=1)=[CH:13]2)=[O:6]
Reactant: O=C(CCC(=O)c1cccs1)Nc1cccc2cc(-c3nccs3)[nH]c12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(CCC(O)c1cccs1)Nc1cccc2cc(-c3nccs3)[nH]c12
Reaction time: 1 h
Yield: 84.2 %

Procedure:
To a mixture of 4-oxo-N-[2-(1,3-thiazol-2-yl)-1H-indol-7-yl]-4-(2-thienyl)butanamide (1.43 g), tetrahydrofuran (10 ml) and methanol (10 ml) was added sodium borohydride (0.16 g) at 0° C., and the mixture was stirred at the same temperature for 1 hr. To the reaction mixture was added 10% aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography and the title compound (1.21 g, yield 84%) was obtained as colorless crystals from a fraction eluted with ethyl acetate. melting point 155-157° C.
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][C:13]([Cl:16])([Cl:15])[Cl:14])=[O:10])[N:6]2[C:17](=[O:20])[CH:18]([NH2:19])[C@H:5]2[S:4]1.C[Si](CC(N)=O)(C)C.C(Cl)Cl.[O:32]=[C:33]([CH2:38][Br:39])[CH2:34][C:35](Br)=[O:36]>C(Cl)(Cl)(Cl)Cl.O>[CH3:2][CH:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][C:13]([Cl:16])([Cl:14])[Cl:15])=[O:10])[N:6]2[C:17](=[O:20])[CH:18]([NH:19][C:35](=[O:36])[CH2:34][C:33](=[O:32])[CH2:38][Br:39])[C@H:5]2[S:4]1
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(N)[C@H]2S1
Reactant: O=C(Br)CC(=O)CBr
Agent: C[Si](C)(C)CC(N)=O
Agent: Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)CC(=O)CBr)[C@H]2S1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2,2,2-trichloroethyl 2-methyl-7-amino-3-cephem-4-carboxylate hydrochloride (0.38 g.), trimethylsilylacetamide (1.1 g.) and methylene chloride (10 ml.) was stirred for 30 minutes at room temperature, and thus obtained solution was cooled to -15° C. To the solution was added dropwise 3-oxo-4-bromobutyryl bromide (1.0 m mole) in carbon tetrachloride (13 ml.) under cooling to -15° C., and the mixture was stirred for 1.5 hours at the same temperature and for 30 minutes without external cooling. The mixture was poured into cold water, and then the organic layer was separated therefrom. The organic layer was washed with 2N hydrochloric acid (8 ml ×3) and water (10 ml ×2) in turn, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was pulverized in diisopropyl ether, collected by filtration and then dried to give pale brown powder of 2,2,2-trichloroethyl 2-methyl-7-(3-oxo-4-bromobutyramido)-3-cephem-4-carboxylate (0.31 g.), mp 78° to 83° C. (dec.).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]2[CH:6]=[N:7][CH:8]=[C:2]12.[CH2:9]([O:12][C:13]([N:15]1[C@H:19]([CH:20]=[O:21])[CH2:18][C@@H:17]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:16]1)=[O:14])[CH:10]=[CH2:11].O>C1COCC1>[CH2:9]([O:12][C:13]([N:15]1[C@H:19]([CH:20]([OH:21])[C:5]2[S:1][C:2]3=[CH:8][N:7]=[CH:6][N:3]3[CH:4]=2)[CH2:18][C@@H:17]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:24])[CH3:25])[CH2:16]1)=[O:14])[CH:10]=[CH2:11].[CH2:9]([O:12][C:13]([N:15]1[C@H:19]([CH:20]([OH:21])[C:4]2[N:3]3[CH:6]=[N:7][CH:8]=[C:2]3[S:1][CH:5]=2)[CH2:18][C@@H:17]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:24])[CH3:25])[CH2:16]1)=[O:14])[CH:10]=[CH2:11]
Reactant: c1cn2cncc2s1
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O
Solvent: C1CCOC1
Solvent: O
Product: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(O)c1cn2cncc2s1
Product: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(O)c1csc2cncn12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 1.69 M n-butyllithium-hexane solution (7.2 ml) is added dropwise to a solution of 2.09 g of imidazo[5,1-b]thiazole in 40 ml of dry THF over a period of 10 min while maintaining the temperature at −70° C. or below, and the mixture is stirred at that temperature for 2 hr. A solution of 5.32 g of (3R,5S)-1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5-formylpyrrolidine in 20 ml of THF is gradually added dropwise to the mixed solution, and the mixture is stirred at −70° C. for 1.5 hr. The temperature is raised to 0° C. over a period of one hr, and the mixture is stirred at 0° C. for one hr and further at room temperature for 1.5 hr. Water is added to the reaction solution, and the mixture is extracted three times with ethyl acetate. The organic layer is washed twice with saturated saline, dried over anhydrous magnesium sulfate, and filtered, and the solvent is removed by evaporation under reduced pressure. The resultant crude product is successively purified by column chromatography on Sephadex LH-20 (dichloromethane:methanol=1:1) and on silica gel (hexane:ethyl acetate=1:1) to give 0.92 g of (3R,5S)-1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5-[1-hydroxy-1-(imidazo[5,1-b]thiazol-2-yl)methyl]pyrrolidine (a diastereomer mixture) and 1.85 g of (3R,5S)-1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5-[1-hydroxy-1-(imidazo[5,1-b]thiazol-3-yl)methyl]pyrrolidine (a diastereomer mixture) as a yellow amorphous material.
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH:9](C)[CH2:10][CH2:11][CH2:12][C:13]#N)=[C:6]([CH2:18][CH2:19][CH3:20])[C:5]=1[OH:21])(=[O:3])[CH3:2].[N-:22]=[N+:23]=[N-:24].[Na+].[Cl-].[NH4+].[CH3:28][N:29](C)C=O>>[OH:21][C:5]1[C:6]([CH2:18][CH2:19][CH3:20])=[C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:28]2[NH:29][N:24]=[N:23][N:22]=2)[CH:16]=[CH:17][C:4]=1[C:1](=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CN(C)C=O
Reactant: CCCc1c(OC(C)CCCC#N)ccc(C(C)=O)c1O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: CCCc1c(OCCCCCc2nnn[nH]2)ccc(C(C)=O)c1O

Procedure:
A mixture of 13.70 g 5-(4-acetyl-3-hydroxy-2-propylphenoxy)hexane-nitrile, 9.30 g sodium azide, 7.65 g ammonium chloride in 275 mL anhydrous dimethylformamide was stirred and heated at 120° for 90 hr. An additional 3.10 g of sodium azide and 2.57 g of ammonium chloride were added after 54 hr. The solvent was removed in vacuo and the residual solid was treated with 350 mL of water and acidified with 7 mL of 6N hydrochloric acid. The product was extracted with ethyl acetate and the dried (magnesium sulfate) extract was concentrated in vacuo to give an oil which was purified by high pressure liquid chromatography. Elution with toluene (70):ethyl acetate (25):acetic acid (10) gave a solid which was recrystallized from acetone-hexane. Filtration gave 8.55 g, mp 98°-100°, of 1-[2-hydroxy-3-propyl-4-[5-1H-tetrazol-5-yl)pentyloxy]phenyl ethanone. A second crop of 1.80 g, mp 94°-97°, was obtained.