Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[NH:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]([CH2:18][NH:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13]1.C(N(CC)CC)C.[C:35](S(O)(=O)=O)([NH2:37])=[NH:36]>CN(C=O)C>[OH:1][C@H:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[NH2:37][C:35](=[NH:36])[N:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]([CH2:18][NH:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13]1
Reactant: N=C(N)S(=O)(=O)O
Reactant: O=C(NC[C@@H]1CCCNC1)c1ccccc1
Agent: O=C(O)[C@H](O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N=C(N)N1CCC[C@@H](CNC(=O)c2ccccc2)C1
Temperature: 25 °C
Yield: 62.4 %

Procedure:
Bc) 19.3 g of the mandelic acid salt obtained under Bb) are suspended in 193 ml of DMF, treated with 21.7 ml of triethylamine and 7.75 g of formamidinesulfonic acid and stirred at room temperature. The reaction mixture is evaporated and the residue is chromatographed on RP-18 silica gel with a water-acetonitrile gradient. There are isolated 13.4 g of (S)-N-[1-(amino-imino- methyl)-piperidin-3-ylmethyl]-benzamide (R)-hydroxy-phenylacetate (1:1), MS (FAB): 218 M-(H2N--CN).
Reaction SMILES: CO[C:3]1[CH2:8][N:7]([CH3:9])[C:6](=[O:10])[CH2:5][N:4]=1.[Cl-:11].[NH4+:12]>C(O)C>[ClH:11].[NH2:12][C:3]1[CH2:8][N:7]([CH3:9])[C:6](=[O:10])[CH2:5][N:4]=1
Reactant: [Cl-]
Reactant: COC1=NCC(=O)N(C)C1
Reactant: [NH4+]
Solvent: CCO
Product: CN1CC(N)=NCC1=O
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 5-methoxy-1-methyl-3,6-dihydro-1H-pyrazin-2-one (2.3 g) and ammonium chloride (936 mg) in dry ethanol (32 mL) was stirred at room temperature for 1 h and then refluxed for 2 h. The reaction mixture was cooled to room temperature and evaporated under reduced pressure. The residue was triturated with chloroform at room temperature for 30 min. The precipitate was filtered off and dried in vacuo. The 5-amino-1-methyl-3,6-dihydro-1H-pyrazin-2-one hydrochloride was obtained as a pale brown powder (1.7 g, 66%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[N:9]=1.C(Cl)(Cl)Cl>CO>[NH3:1].[CH3:15][O:14][C:10]1[N:9]=[C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH:13]=[CH:12][CH:11]=1
Reactant: C1CNCCN1
Reactant: COc1cccc(Cl)n1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cccc(N2CCNCC2)n1
Product: N
Yield: 62.1 %
Yield: 28 %

Procedure:
In a sealed tube, 8.6 g of piperazine and 2.9 g (0.02 mole) of 2-chloro-6-methoxypyridine were reacted at 150° C. for 4 hours. After the reaction, the reaction mixture was applied to silica gel column chromatography (the eluent used was a mixture of chloroform: methanol : 28% aqueous ammonia = 40 : 9 : 1) to obtain 2.4 g of 1-(6-methoxy-2-pyridyl)piperazine as pale yellow liquid.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:16]C(=O)C)=[CH:9][C:10]=2[O:12][C:13](=O)C)[O:5][C:4](=[O:20])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].CI>C(COC)OC>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:16])=[CH:9][C:10]=2[O:12][CH3:13])[O:5][C:4](=[O:20])[CH:3]=1
Reactant: CC(=O)Oc1cc(OC(C)=O)c2c(C)cc(=O)oc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CI
Product: COc1cc(O)cc2oc(=O)cc(C)c12

Procedure:
The 4-methyl-5,7-diacetoxycoumarin (XXXIV) was dissolved in dimethoxyethane (80 ml) and a solution of dry K2CO3 (6.6 g) and methyl iodide (3 ml) was added. The mixture was refluxed for 6 h, the solvent was evaporated and the residue, after addition of water:methanol (50:50; 80 ml), was heated to reflux 20 min. By evaporation of the MeOH under reduced pressure and by cooling a precipitate was formed, which by crystallization of first from MeOH and then from Me2CO gave 4-methyl-5-methoxy-7-hydroxycoumarin (XXXV; 1.52 g; m.p. 261°-3° C.). ##STR38##
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[CH2:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH:10]1[NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21].Cl.C(OC(C)C)(=O)C>CCCCCCC>[C:1]([C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH:10]([NH:18][C:19](=[O:24])[C:20]([F:21])([F:23])[F:22])[CH2:9]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: O=C(NC1Cc2ccccc2C1)C(F)(F)F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCCC
Solvent: CC(=O)OC(C)C
Product: CC(=O)c1ccc2c(c1)CC(NC(=O)C(F)(F)F)C2
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 89.7 %

Procedure:
A 1 L, 3-necked, round-bottomed flask, equipped with a mechanical stirrer, digital thermometer, cooling bath, and nitrogen inlet-outlet, was charged with acetyl chloride (205.5 g, 2.62 mole) and cooled to 0-5° C. Aluminum chloride was added in portions (4×36.4 g [145.5 g, 1.09 mole]) at 0-5° C., while maintaining the internal temperature below 15° C. The slurry was cooled to 0-5° C. and stirred for 15 minutes. N-(2,3-dihydro-1H-inden-2-yl)-2,2,2-trifluoroacetamide (5×20 g, 0.436 mole) was added in portions over 40 minutes at 10-minute intervals, while maintaining temperature at 0-10° C. The resulting tan solution was stirred at 0-5° C. for 1 hour. To the solution was added 400 mL of heptane, while maintaining the temperature at 0-5° C. The resulting bi-phasic mixture was added to a 0° C. to −5° C. mixture of 1 N HCl (650 mL) and isopropyl acetate (125 mL) in a 5 L, 3-necked, round-bottomed flask, equipped with a mechanical stirrer, digital thermometer, and a cooling bath, while maintaining the internal temperature at 0-25° C. over a period of 20 minutes. The 5 L, round-bottomed flask was rinsed with acetyl chloride (20 mL), followed by heptane (110 mL) and added to the batch. The reaction mixture was warmed to 22-24° C. over a period of 30 minutes and then heated to 40-45° C. and stirred at 40-45° C. for 1 hour. The slurry was cooled to 21-25° C. and stirred for 1 hour. The solids were collected by filtration using a Büchner funnel with suction over a polypropylene filter paper. The filter cake was washed with heptane (2×200 mL) followed by 1 N HCl (350 mL), and deionized water (2×200 mL). The solids were dried at 60-65° C. under vacuum (10-30 torr) with nitrogen bleeding to obtain 106.1 g (yield 90%) of N-(5-acetyl-2,3-dihydro-1H-inden-2-yl)-2,2,2-trifluoroacetamide (m.p. 113-115° C.).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[CH2:18][C:19](=[O:35])[NH:20][C:21]4[CH:27]=[C:26]([C:28]5[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=5)[CH:25]=[CH:24][C:22]=4[N:23]=3)[CH:12]=2)[S:9][CH:10]=1)=O)C.COCCO[AlH2-]OCCOC.[Na+].C1(C)C=CC=CC=1>C1COCC1>[F:34][C:31]1[CH:30]=[CH:29][C:28]([C:26]2[CH:25]=[CH:24][C:22]3[N:23]=[C:17]([C:13]4[CH:14]=[CH:15][CH:16]=[C:11]([C:8]5[S:9][CH:10]=[C:6]([CH2:4][OH:3])[N:7]=5)[CH:12]=4)[CH2:18][C:19](=[O:35])[NH:20][C:21]=3[CH:27]=2)=[CH:33][CH:32]=1
Reactant: CCOC(=O)c1csc(-c2cccc(C3=Nc4ccc(-c5ccc(F)cc5)cc4NC(=O)C3)c2)n1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C1CC(c2cccc(-c3nc(CO)cs3)c2)=Nc2ccc(-c3ccc(F)cc3)cc2N1
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 47.1 %

Procedure:
To a solution of 2-{3-[7-(4-fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-phenyl}-thiazole-4-carboxylic acid ethyl ester (Example 153) (110 mg, 0.23 mmol) in THF (7 mL) was added a 3.5 M solution of sodium dihydrido-bis(2-methoxyethoxy)aluminate in toluene (0.66 mL, 2.3 mmol). The raction mixture was stirred at 23° C. for 15 min. and then poured into ice-cold 10% aq. acetic acid. The mixture was extracted with ethyl acetate and the organic layer was washed successively with H2O, sat. Na2CO3-sol. and brine, dried over Na2SO4 and evaporated in vacuum. The residue was triturated with ethyl acetate to give the title compound as light yellow solid (48 mg).
Reaction SMILES: [H-].[CH3:2][CH2:3][CH2:4][CH2:5][CH2:6][C@H:7]([OH:26])/[CH:8]=[CH:9]/[C@@H:10]1[C@@H:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])[C:13](=[O:14])[CH2:12][C@H:11]1[OH:25].[CH3:27][CH2:28][CH2:29][CH2:30][CH2:31][C@H:32]([OH:51])/[CH:33]=[CH:34]/[C@@H:35]1[C@@H:40]([CH2:41]/[CH:42]=[CH:43]\[CH2:44][CH2:45][CH2:46][C:47]([OH:49])=[O:48])[C:38](=[O:39])[CH2:37][C@H:36]1[OH:50]>>[CH3:2][CH2:3][CH2:4][CH2:5][CH2:6][C@H:7]([OH:26])/[CH:8]=[CH:9]/[C@@H:10]1[C@@H:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])[C@@H:13]([OH:14])[CH2:12][C@H:11]1[OH:25].[CH3:27][CH2:28][CH2:29][CH2:30][CH2:31][C@H:32]([OH:51])/[CH:33]=[CH:34]/[C@@H:35]1[C@@H:40]([CH2:41]/[CH:42]=[CH:43]\[CH2:44][CH2:45][CH2:46][C:47]([OH:49])=[O:48])[C@@H:38]([OH:39])[CH2:37][C@H:36]1[OH:50]
Reactant: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)O
Reactant: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1C/C=C\CCCC(=O)O
Agent: [H-]
Product: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](O)C[C@H]1O
Product: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](CCCCCCC(=O)O)[C@@H](O)C[C@H]1O

Procedure:
Hydride reduction of the PGE1, PGE2, 11-desoxy-PGE1, and 11-desoxy-PGE2 analogues described in Sections B, C, and D, above, yield the corresponding PGF1, PGF2, 11-desoxy-PGF1 and 11-desoxy-PGF2 analogues, respectively:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[C:16]([C:17]#[N:18])=[CH:15][N:14]=[C:13](S(C)(=O)=O)[N:12]=3)=[CH:9][N:8]([S:23]([C:26]3[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:5]2=[N:6][CH:7]=1.[NH2:33][CH:34]([CH:37]([CH3:39])[CH3:38])[CH2:35][OH:36].C(N(C(C)C)CC)(C)C>C1COCC1>[OH:36][CH2:35][C@H:34]([NH:33][C:13]1[N:12]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([CH3:1])[CH:3]=3)[N:8]([S:23]([C:26]3[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH:9]=2)[C:16]([C:17]#[N:18])=[CH:15][N:14]=1)[CH:37]([CH3:39])[CH3:38]
Reactant: CC(C)C(N)CO
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(S(C)(=O)=O)ncc3C#N)c3cc(C)cnc32)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nc(N[C@@H](CO)C(C)C)ncc3C#N)c3cc(C)cnc32)cc1
Yield: 76.9 %

Procedure:
A mixture of 4-(5-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(methylsulfonyl)pyrimidine-5-carbonitrile (120 mg, 0.257 mmol), (R)-(+2-amino-3-methyl-1-butanol (57 l, 0.515 mmol) and diisopropylethylamine (90 l, 0.515 mmol) in THF (4 mL) was heated at reflux for 1 hour. The reaction mixture was concentrated in vacuo and the residue was purified on silica gel by flash column chromatography to give the title compound as a colourless glassy solid (97 mg, 77% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:21]=[C:20]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]([NH:22]C(=O)OC(C)(C)C)=[CH:17][C:18]=3[NH:19]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:21]=[C:20]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]([NH2:22])=[CH:17][C:18]=3[NH:19]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)[nH]c1cc(OCc3ccccc3)ccc12
Agent: Cl
Solvent: C1COCCO1
Product: Nc1ccc2c(c1)[nH]c1cc(OCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 102 %

Procedure:
To tert-butyl 7-(benzyloxy)-9H-carbazol-2-ylcarbamate (200 mg, 0.51 mmol) was added 10 mL of a 4 M HCl in dioxane solution. The mixture was stirred at rt for 4 h and concentrated under reduced pressure. The residue was washed with ether (15 mL) and suspended in EtOAc (50 mL). To this suspension was added 10 mL of a NaHCO3 (sat.) and the mixture was stirred for 5 min. The organic layer was dried over MgSO4 and concentrated to afford 7-(benzyloxy)-9H-carbazol-2-amine as a brown solid (150 mg, 100%). 1H NMR (400 MHz, DMSO-d6) δ 11.33 (s, 1H), 7.99 (d, J=8.4 Hz, 1H), 7.92 (d, J=8.8 Hz, 1H), 7.42 (d, J=6.8 Hz, 2H), 7.34-7.21 (m, 3H), 7.27-7.23 (m, 1H), 7.00-6.97 (m, 2H), 6.81 (dd, J=8.8, 2.4 Hz, 1H), 5.12 (s, 2H); MS (ESI) m/z 289 (M+H+).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:18])=[C:13]([CH:17]=1)[C:14](O)=[O:15])=[O:7].[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1>C1COCC1>[Cl:18][C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:19]=[CH:20][CH:21]=[C:3]([C:2]([F:23])([F:22])[F:1])[CH:4]=2)=[CH:17][C:13]=1[CH2:14][OH:15]
Reactant: O=C(Nc1ccc(Cl)c(C(=O)O)c1)c1cccc(C(F)(F)F)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)c(CO)c1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.8 %

Procedure:
To a solution of intermediate 1 (Example 2) (1.4 g, 4.1 mmol) in anhydrous THF (20 mL) at room temperature under argon, 1.5 M diisobutylaluminum hydride in toluene (DIBAL-H, 9 mL, 13.5 mmol) was added. After the reaction mixture was stirred at room temperature for 1 h, the solution was refluxed under argon for overnight. The solution was quenched by minimum amount of methanol and water. The organic solvent was removed by reduced pressure. The crude was suspended in water (50 mL) and extracted by ethyl acetate (2×50 mL). The organic layers were combined, washed with brine, dried over Na2SO4 and filtered. The organic solvent was removed and the crude product was purified by silica gel column with CHCl3 as an eluent to give the final product as a white solid (700 mg, 52%).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C@@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C@@:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:44][CH2:43][C:42](=[O:45])[NH:41][CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:38]3[CH2:44][CH2:43][C:42](=[O:45])[NH:41][CH2:40][CH2:39]3)=[O:36])[C@@:16]([C:28]3[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=3)([CH3:27])[C@@:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: O=C1CCNCCN1
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCNC(=O)CC1

Procedure:
In a manner analogous to the method described in example 3, (4S,5R)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with [1,4]-diazepan-5-one (Oakwood Products) to give the title compound. HR-MS (ES, m/z) calculated for C33H39N6O3Cl2 [(M+H)+] 637.2455, observed 637.2452.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5](=[CH:11]OCC)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[I:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[I:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][CH:11]=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:15])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:19][CH:18]=1
Reactant: Nc1ccc(I)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CNc1ccc(I)cc1)C(=O)OCC
Yield: 77.1 %

Procedure:
A mixture of ethoxymethylene malonic acid diethyl ester (20.1 mL, 0.10 mol) and 4-iodoaniline (22 g, 0.10 mole) in toluene (300 ml) was heated to reflux for 1 h. After this period of time, solvents were removed under vacuum, and the crude material was precipitated in methyl tert-butyl ether and the resulting white solid was filtered, and dried under vacuum to give 30 g product.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)([CH3:15])[CH3:14]>>[CH:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:24])=[O:23])=[CH:18][CH:17]=1)([CH3:15])[CH3:14]
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc(C(C)C)cc2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 4-isopropylbenzenesulfonyl chloride according to METHOD A, giving 0.57 g (78%) of a pink powder: MS (electrospray, [M−H]−) m/z 367.2.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13][CH3:14])(=[O:12])[CH:10]=[CH2:11].N12CCN(CC1)CC2.C(O)(=O)C>C(OCC)C>[CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:8][CH:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10](=[CH2:11])[C:9]([O:13][CH3:14])=[O:12]
Reactant: C=CC(=O)OC
Agent: C1CN2CCN1CC2
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: O=Cc1ccccc1
Product: C=C(C(=O)OC)C(O)c1ccccc1
Temperature: 35 °C
Reaction time: 60 h
Yield: 90 %

Procedure:
A mixture of benzaldehyde (82.1 mL, 0.81 mol) , methyl acrylate (109.1 mL, 1.211 mol) , 1,4-diazabicyclo(2,2,2)octane (13.6 g, 0.12 mol), and acetic acid (1.4 mL, 0.024 mol) was allowed to stir at 35° C. for 60 h, at which point the reaction was determined to have proceeded to 70% completion by 1H NMR. Methyl acrylate (20.9 mL, 0.23 mol) was then added and the solution was allowed to react at 35° C. for an additional 48 h. The mixture was diluted with diethyl ether (1.0 L) and was washed with 2×200 mL portions of a pH 7 phosphate buffer. After concentration in vacuo, the remaining mixture was distilled at reduced pressure (12 mm) to afford 6.5 g of unreacted benzaldehyde and 130.0 g (90%) of the desired product as a colorless oil: b.p. 130° C. (12 mm); IR (film) 1718, 1440 cm-1 ; 1H NMR (CDCl3) δ 3.67 (s, 3H) , 5.52 (br s, 1H) , 5.83-5.85 (m, 1H) , 6.29-6.31 (m, 1H) , 7.23-7.39 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 51.8, 72.9, 125.8, 126.5, 127.7, 128.3, 141.2, 141.9, 166.6.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:15][C:16]([OH:18])=O)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([F:14])[CH:9]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:26]=[CH:27][C:28]([NH2:31])=[N:29][CH:30]=2)[N:20]=1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:15][C:16]([NH:31][C:28]2[CH:27]=[CH:26][C:25]([C:21]3[N:20]=[N:19][CH:24]=[CH:23][CH:22]=3)=[CH:30][N:29]=2)=[O:18])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([F:14])[CH:9]=1
Reactant: O=C(O)Cc1ccc(-c2ccnc(F)c2)c(F)c1
Reactant: Nc1ccc(-c2cccnn2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(-c2ccnc(F)c2)c(F)c1)Nc1ccc(-c2cccnn2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(3-fluoro-4-(2-fluoropyridin-4-yl)phenyl)acetic acid 207-6 (37 mg, 0.15 mmol), was dissolved in DMF (2 mL), 5-(pyridazin-3-yl)pyridin-2-amine (31 mg, 0.18 mmol) and DIEA (131 uL, 0.75 mmol) were added to the solution before O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (86 mg, 0.23 mmol). The mixture was stirred at room temperature overnight. The solvent was removed by rotary evaporation. The crude product was purified by reverse phase HPLC to give 2-(3-fluoro-4-(2-fluoropyridin-4-yl)phenyl)-N-(5-(pyridazin-3-yl)pyridin-2-yl)acetamide 213. MS m/z 404.2 (M+1)); 1H NMR 400 MHz (DMSO-d6) δ 11.11 (s, 1H), 9.22 (dd, 1H), 9.13 (dd, 1H), 8.55 (dd, 1H), 8.34 (d, 1H), 8.29 (dd, 1H), 8.23 (d, 1H), 8.02 (d, 1H), 7.83-7.78 (m, 1H), 7.71-7.65 (m, 1H), 7.60-7.57 (m, 1H), 7.44-7.35 (m, 3H), 3.90 (s, 2H).
Reaction SMILES: CN([S+](N(C)C)N(C)C)C.C[Si-](F)(F)(C)C.[Si]([O:34][CH2:35][CH2:36][N:37]([CH2:102][CH3:103])[CH2:38][CH2:39][C@@H:40]([NH:49][C:50]1[CH:55]=[CH:54][C:53]([S:56]([NH:59][C:60](=[O:94])[C:61]2[CH:66]=[CH:65][C:64]([N:67]3[CH2:72][CH2:71][CH:70]([C@H:73]([C:81]4[CH:86]=[CH:85][CH:84]=[CH:83][C:82]=4[C:87]4[CH:92]=[CH:91][C:90]([Cl:93])=[CH:89][CH:88]=4)[NH:74][S@:75]([C:77]([CH3:80])([CH3:79])[CH3:78])=[O:76])[CH2:69][CH2:68]3)=[CH:63][CH:62]=2)(=[O:58])=[O:57])=[CH:52][C:51]=1[S:95]([C:98]([F:101])([F:100])[F:99])(=[O:97])=[O:96])[CH2:41][S:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>CN(C=O)C>[Cl:93][C:90]1[CH:91]=[CH:92][C:87]([C:82]2[CH:83]=[CH:84][CH:85]=[CH:86][C:81]=2[C@H:73]([NH:74][S@:75]([C:77]([CH3:78])([CH3:80])[CH3:79])=[O:76])[CH:70]2[CH2:71][CH2:72][N:67]([C:64]3[CH:65]=[CH:66][C:61]([C:60]([NH:59][S:56]([C:53]4[CH:54]=[CH:55][C:50]([NH:49][C@H:40]([CH2:39][CH2:38][N:37]([CH2:102][CH3:103])[CH2:36][CH2:35][OH:34])[CH2:41][S:42][C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=5)=[C:51]([S:95]([C:98]([F:101])([F:100])[F:99])(=[O:96])=[O:97])[CH:52]=4)(=[O:58])=[O:57])=[O:94])=[CH:62][CH:63]=3)[CH2:68][CH2:69]2)=[CH:88][CH:89]=1
Reactant: CCN(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CC[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)c2ccc(N3CCC([C@@H](N[S@@](=O)C(C)(C)C)c4ccccc4-c4ccc(Cl)cc4)CC3)cc2)cc1S(=O)(=O)C(F)(F)F
Agent: CN(C)[S+](N(C)C)N(C)C
Agent: C[Si-](C)(C)(F)F
Solvent: CN(C)C=O
Product: CCN(CCO)CC[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)c2ccc(N3CCC([C@@H](N[S@@](=O)C(C)(C)C)c4ccccc4-c4ccc(Cl)cc4)CC3)cc2)cc1S(=O)(=O)C(F)(F)F
Reaction time: 1 h
Yield: 114.6 %

Procedure:
A solution of TASF (0.46 ml. 0.46 mmol, 1 M in DMF) was added to a solution of N-(4-((R)-4-((2-(tert-butyldiphenylsilyloxy)ethyl)(ethyl)amino)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)phenylsulfonyl)-4-(4-((R)-(4′-chlorobiphenyl-2-yl)((S)-1,1-dimethylethylsulfinamido)methyl)piperidin-1-yl)benzamide (EXAMPLE 12, STEP 1, 0.30 g, 0.23 mmol) in DMF (1.9 ml) and the reaction mixture was stirred at r.t for 1 hour. The reaction mixture was concentrated under reduced pressure, diluted with DCM and washed with H2O. The organic layer was dried (Na2SO4), concentrated under reduced pressure and dried under vacuum to give 4-(4-((R)-(4′-chlorobiphenyl-2-yl)((S)-1,1-dimethylethylsulfinamido)methyl)piperidin-1-yl)-N-(4-((R)-4-(ethyl(2-hydroxyethyl)amino)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)phenylsulfonyl)benzamide (EXAMPLE 12, STEP 2, 0.28 g) which was used in the preparation of EXAMPLE 12, STEP 3, without further purification.
Reaction SMILES: [C:1]([CH:5]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([OH:12])=O)[CH:6]=[CH2:7])([O:3][CH3:4])=[O:2].O1CCCC1.ClC(OC)=O.[NH2:29][CH:30]1[C:56](=[O:57])[N:32]2[CH:33]([C:40]([O:42][CH:43]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:41])[C:34]([C:37](=[O:39])[CH3:38])=[CH:35][S:36][C@H:31]12>CN(CC1C=CC=CC=1)C.C(OCC)(=O)C>[C:1]([CH:5]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([NH:29][CH:30]1[C:56](=[O:57])[N:32]2[CH:33]([C:40]([O:42][CH:43]([C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:41])[C:34]([C:37](=[O:39])[CH3:38])=[CH:35][S:36][C@H:31]12)=[O:12])[CH:6]=[CH2:7])([O:3][CH3:4])=[O:2]
Reactant: CC(=O)C1=CS[C@@H]2C(N)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Reactant: C=CC(NC(C(=O)O)c1ccccc1)C(=O)OC
Agent: CN(C)Cc1ccccc1
Agent: COC(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CC(NC(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(C(C)=O)=CS[C@H]12)c1ccccc1)C(=O)OC
Temperature: -15 °C
Yield: 68 %

Procedure:
To a cooled (-15° C.), stirred slurry of 0.381 g. of 2-(1-carbomethoxy-2-propenylamino)-2-phenylacetic acid and 25 ml. of tetrahydrofuran was added three drops of N,N-dimethylbenzylamine and 0.109 ml. of methyl chloroformate. The reaction mixture was allowed to stir with cooling under an argon atmosphere for 10 minutes. The reaction mixture was then cooled to -20° C. and a solution of 0.521 g. of benzhydryl 7-amino-3-acetyl-2-cephem-4-carboxylate in 5 ml. of tetrahydrofuran was added dropwise. The resulting mixture was allowed to stir under argon with cooling for approximately one hour, after which time the mixture was transferred to a separatory funnel with the aid of cold ethyl acetate. The organic solution was washed with cold 1N.HCl, and brine, and then dried over anhydrous sodium sulfate. Evaporation in vacuo to dryness gave a product which was chromatographed on silica gel using a toluene-ethyl acetate gradient to give 0.556 g. (68 percent) of the title product as a tan froth: