Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:9][C:10]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])=[CH:11][CH2:12]O)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[C:23]([O:31]CC)([O:28][CH2:29][CH3:30])(OCC)[CH3:24].C(O)(=O)CC>C(O)C>[O:15]([CH2:14][C:10]([CH2:9][O:1][Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3])([CH:11]=[CH2:12])[CH2:24][C:23]([O:28][CH2:29][CH3:30])=[O:31])[Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)OCC(=CCO)CO[Si](C)(C)C(C)(C)C
Reactant: CCOC(C)(OCC)OCC
Solvent: CCC(=O)O
Solvent: CCO
Product: C=CC(CO[Si](C)(C)C(C)(C)C)(CO[Si](C)(C)C(C)(C)C)CC(=O)OCC
Yield: 77.9 %

Procedure:
A mixture of 6a (9.36 g, 27 mmol), triethyl orthoacetate (34.75 mL, 189 mmol) and propionic acid (0.2 mL, 2.7 mmol) was heated at 138° C. for 20 h with removal of ethanol. The reaction mixture was cooled and concentrated under vacuum, and the residue was purified by flash column chromatography over silica gel with hexane:EtOAc (19:1) as eluant to give 7a (8.77 g, 78%) as an oil; IR (neat) 1737, 1471 cm-1 ; 1H NMR (CDCl3) δ 0.01 (br s, 12 H, SiCH3), 0.85 (br s, 18 H, C(CH3)3), 1.21 (t, 3 H, CH3CH2), 2.42 (s, 2 H, CH2COEt), 3.61 (AB q, J=9.3 Hz, 4 H), 4.06 (q, 2 H, CH2CH3), 5.06 (m, 2 H, CH=CH2), 5.84 (dd, J=19.9, 11.3, 1 H, CH=CH2); 13C NMR (CDCl3) δ -5.58, 14.24, 18.23, 25.84, 36.81, 45.97, 59.84, 64.63, 114.47, 139.73, 171.87. Anal. Calcd for C21H44O4Si2 : C, 60.52; H, 10.64. Found: C, 60.46; H, 10.62.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]2[C:14](=[O:15])[N:13]([C:16]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[CH:29]=[C:28]([NH:30][C:31]5[CH:36]=[CH:35][C:34]([C:37]([N:39]6[CH2:44][CH2:43][O:42][CH2:41][CH2:40]6)=[O:38])=[CH:33][N:32]=5)[C:27](=[O:45])[N:26]([CH3:46])[CH:25]=4)[C:17]=3[CH:18]=[O:19])[CH2:12][CH2:11][NH:10][C:9]=2[CH:47]=1)([CH3:4])([CH3:3])[CH3:2].C(O)C.[BH4-].[Na+]>C1COCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]2[C:14](=[O:15])[N:13]([C:16]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[CH:29]=[C:28]([NH:30][C:31]5[CH:36]=[CH:35][C:34]([C:37]([N:39]6[CH2:44][CH2:43][O:42][CH2:41][CH2:40]6)=[O:38])=[CH:33][N:32]=5)[C:27](=[O:45])[N:26]([CH3:46])[CH:25]=4)[C:17]=3[CH2:18][OH:19])[CH2:12][CH2:11][NH:10][C:9]=2[CH:47]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1cc(-c2cccc(N3CCNc4cc(C(C)(C)C)ccc4C3=O)c2C=O)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: Cn1cc(-c2cccc(N3CCNc4cc(C(C)(C)C)ccc4C3=O)c2CO)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Reaction time: 0.33 h

Procedure:
The 60:40 mixture from the previous step, with the major component being 2-(8-tert-Butyl-5-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-6-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-benzaldehyde, 76 mg, was dissolved in 3 mL THF, and 3 mL absolute ethanol was added. Sodium borohydride (5 mg, 1 eq), was added, and the reaction stirred for 20 minutes, during which time the reaction changed from purple color to colorless. The reaction as quenched with water, and then 1 drop glacial acetic acid was added. The mixture was extracted with ethyl acetate 3×, the organic layers combined and washed with aqueous saturated sodium bicarbonate solution and brine, dried over MgSO4, filtered, and the organic solvent removed under vacuum. The residue was chromatographed over silica gel, eluting first with methylene chloride, and then 3% methanol in methylene chloride, to give the title compound as a white solid, 33 mg, (M+H)+=637.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][CH:14]1[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:23].C(C(C(C)C)([NH-])C)(C)C.[Li+].C([C:36]([O:38][CH3:39])=[O:37])#N>O1CCCC1>[CH3:13][C:14]1([C:36]([O:38][CH3:39])=[O:37])[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:23]
Reactant: COC(=O)C#N
Reactant: CC1Cc2ccccc2C1=O
Agent: CC(C)C(C)([NH-])C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C1(C)Cc2ccccc2C1=O
Reaction time: 0.5 h

Procedure:
To a flask cooled at 0 degrees Centigrade containing diisopropylamine (2.06 mL, 14.58 mmol) in tetrahydrofuran (14 mL) was added dropwise over 15 minutes a solution of n-butyl lithium (5.55 mL of 2.5 M in hexanes, 14.58 mmol). This mixture was stirred for 30 min. A second flask containing the 2-methyl-1-indanone (2.03 g, 13.89 mmol) in tetrahydrofuran (10 mL) was cooled to −78 degrees Centigrade under N2. The freshly prepared lithium diisopropylethylamide was cooled to −78 degrees centigrade and added drop wise via cannula. The orangish mixture became somewhat heterogeneous over 30 minutes and then neat methyl cyanoformate (1.32 mL, 16.66 mmol) was added and the reaction mixture stirred an additional 40 minutes while allowing the reaction to warm to −20 degrees centigrade. The reaction was quenched with saturated aqueous NH4Cl solution and the organics extracted 2×25 mL diethyl ether, washed one time in brine, then dried (Na2SO4), filtered and concentrated to give methyl 2-methyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate. No further purification was necessary.
Reaction SMILES: C(O[C:5]1[C:6](=[O:14])[C:7](=[O:13])[C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])(C)C.[CH2:15]([NH:17][CH2:18][CH3:19])[CH3:16]>CCO>[CH2:15]([N:17]([CH2:18][CH3:19])[C:5]1[C:6](=[O:14])[C:7](=[O:13])[C:8]=1[O:9][CH:10]([CH3:11])[CH3:12])[CH3:16]
Reactant: CCNCC
Reactant: CC(C)Oc1c(OC(C)C)c(=O)c1=O
Solvent: CCO
Product: CCN(CC)c1c(OC(C)C)c(=O)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
A mixture of 3,4-diisopropoxy-3-cyclobutene-1,2-dione (1.0 g, 5.05 mmol) and diethylamine (549 μl, 5.30 mmol) in EtOH (25 ml) was stirred overnight at room temperature. The solvent was removed in vacuo to give the title compound as a yellow oil (1.0 g). δH (DMSO-d6, 390 K) 5.33-5.27 (1H, m), 3.58 (4H, q, J 7.1 Hz), 1.42 (6H, d, J 6.1 Hz), 1.23 (6H, t, J 7.2 Hz); m/z (ES+, 70 V) 212 (MH+).
Reaction SMILES: [CH2:1]([NH2:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C([O:21][C:22]1[C:31]2[C:26](=[C:27]([NH:32]C(C)=O)[CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[S:36](Cl)(=[O:38])=[O:37])(=O)C>CC(C)=O>[NH2:32][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:26]=1[CH:25]=[CH:24][C:23]([S:36](=[O:38])(=[O:37])[NH:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[C:22]2[OH:21]
Reactant: CC(=O)Nc1cccc2c(OC(C)=O)c(S(=O)(=O)Cl)ccc12
Reactant: CCCCCCCCCCCCCCCCN
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCNS(=O)(=O)c1ccc2c(N)cccc2c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.6 %

Procedure:
30 g of hexadecylamine was dissolved in 250 liters of acetone. To this solution was added gradually a solution of 40 g of 1-acetoxy-5-acetamino-naphthalene-2-sulfonyl chloride synthesized above in 150 ml of acetone while stirring, and, after completion of the addition, stirring was continued for about one hour at about 40° C. Then, the reaction solution was ice-cooled, and the precipitated crystals were collected by filtration and well washed with 1 liter of methanol. The crystals were refluxed for 8 hours together with 200 ml of ethanol, 30 g of NaOH, and 100 ml of water. After being allowed to cool to room temperature, the solution was neutralized with acetic acid, and the crystals thus precipitated were collected by filtration and recrystallized from an ethanol-water mixture solvent to obtain 22 g (54% yield) of product.
Reaction SMILES: [N:1]1([S:10]([C:13]2[CH:22]=[C:21]3[C:16]([CH2:17][CH2:18][N:19](C(=O)C)[CH2:20]3)=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[ClH:26]>C(O)CCC>[ClH:26].[N:1]1([S:10]([C:13]2[CH:22]=[C:21]3[C:16]([CH2:17][CH2:18][NH:19][CH2:20]3)=[CH:15][CH:14]=2)(=[O:11])=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CC(=O)N1CCc2ccc(S(=O)(=O)n3ccc4ccccc43)cc2C1
Agent: Cl
Solvent: CCCCO
Product: O=S(=O)(c1ccc2c(c1)CNCC2)n1ccc2ccccc21
Yield: 72 %

Procedure:
A mixture of 1-[7-(indole-1-sulfonyl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethanone (D1) (12 g, 34 mmol) in 3M hydrochloric acid (200 ml) and n-butanol (100 ml) was refluxed for 7 h. The reaction mixture was evaporated in vacuo to dryness and the residue was recrystallized from 2-propanol/diethyl ether to give the title compound (E1) (8.5 g, 72%), NMR (D6-DMSO) 3.03 (2H, t, J=6.0 Hz), 3.29 (2H, t, J=6.0 Hz), 4.29 (2H, s), 6.85 (1H, d, J=3.7 Hz), 7.22-7.43 (3H, m), 7.60 (1H, d, J=7.6 Hz), 7.79-7.85 (2H, m), 7.94-8.01 (2H, m); MS: m/z (MH+) 313.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:16]=[C:15]([CH:17]([CH3:19])[CH3:18])[NH:14][N:13]=2)[C:5]2[CH2:10][CH2:9][CH2:8][C:6]=2[N:7]=1.[NH:20]1[CH2:27][CH2:26][CH2:25][C@H:21]1[C:22]([OH:24])=[O:23].[OH-].[Na+].C(N(CC)C(C)C)(C)C>O1CCOCC1>[CH:17]([C:15]1[NH:14][N:13]=[C:12]([NH:11][C:4]2[C:5]3[CH2:10][CH2:9][CH2:8][C:6]=3[N:7]=[C:2]([N:20]3[CH2:27][CH2:26][CH2:25][CH:21]3[C:22]([OH:24])=[O:23])[N:3]=2)[CH:16]=1)([CH3:19])[CH3:18]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CC(C)c1cc(Nc2nc(Cl)nc3c2CCC3)n[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1cc(Nc2nc(N3CCCC3C(=O)O)nc3c2CCC3)n[nH]1
Temperature: 100 °C
Reaction time: 16 h
Yield: 78 %

Procedure:
To a suspension of 2-chloro-N-(5-isopropyl-1H-pyrazol-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine, Compound (iii) (5 g, 18 mmol) in dioxane (60 mL) was added L-proline (3.11 g, 27 mmol) followed by 5N NaOH (5.4 mL, 27 mmol) and N,N-diisopropylethyl amine (2.32 g, 18 mmol). The reaction mixture was allowed to stir at 100° C. for 16 h. The solvent was removed under reduced pressure and the residue was acidified with 1 N HCl solution to pH 4. The product was suspended in water (10 mL), filtered, washed with ether and dried to afford 1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxylic acid (5 g, 78% yield).
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[CH:7]=1)([CH3:5])[C:3]#[N:4]>CO.[Pd]>[NH2:12][C:8]1[CH:7]=[C:6]([C:2]([CH3:5])([CH3:1])[C:3]#[N:4])[CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C#N)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C#N)c1cccc(N)c1
Yield: 83.1 %

Procedure:
2-Methyl-2-(3-nitrophenyl)-propionitrile (0.5 g) was hydrogenated over 10% Pd—C in methanol (10 ml) at atmospheric pressure until no further gas uptake was observed. The reaction mixture was then filtered over celite and concentrated to oil. Column chromatography over silica gel by eluting with ethyl acetate/pet ether (1:9) gave 2-(3-amino-phenyl)-2-methyl-propionitrile (0.35 g, 83%) as an oil.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([B:18]([OH:20])[OH:19])=[CH:14][C:13]=1[C:21]([F:24])([F:23])[F:22].Cl>>[OH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([B:18]([OH:19])[OH:20])=[CH:14][C:13]=1[C:21]([F:24])([F:22])[F:23]
Reactant: OB(O)c1ccc(OCCCOC2CCCCO2)c(C(F)(F)F)c1
Agent: Cl
Product: OCCCOc1ccc(B(O)O)cc1C(F)(F)F
Temperature: 50 °C

Procedure:
4-(3-(Tetrahydro-2H-pyran-2-yloxy)propoxy)-3-(trifluoromethyl)phenylboronic acid (30.6 g) was added to hydrochloric acid (1M in MeOH) and the mixture was heated at 50° C. for 40 minutes. Solvent and HCl were then removed under reduced pressure and residue (20.3 g) was used for next step without further purification. Proton NMR indicates 2 sets of product peaks assumed to be monomer and dimer or trimer. 1H NMR (CDCl3 (0.7 ml)+CD3OD (0.2 ml)) δ: 7.7-8.0 (2×d and 2×s, 2H), 7.0 (2×d, 1H), 4.22 (t, 2H), 3.86 (t, 2H), 3.48 (tt, 2H).
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][C@H:11]2[N:21]3[C:22]4[N:13]([C:14](=[O:24])[CH:15]=[CH:16][C:17]=4[CH:18]=[CH:19][C:20]3=[O:23])[CH2:12]2)[CH2:6][CH2:5]1.C(N(CC)CC)C.[O:32]1[C:41]2[C:36](=[CH:37][CH:38]=[C:39]([CH:42]=O)[CH:40]=2)[CH2:35][CH2:34][CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.CO>[ClH:1].[O:32]1[C:41]2[C:36](=[CH:37][CH:38]=[C:39]([CH2:42][NH:3][CH:4]3[CH2:5][CH2:6][N:7]([CH2:10][C@H:11]4[N:21]5[C:22]6[N:13]([C:14](=[O:24])[CH:15]=[CH:16][C:17]=6[CH:18]=[CH:19][C:20]5=[O:23])[CH2:12]4)[CH2:8][CH2:9]3)[CH:40]=2)[CH2:35][CH2:34][CH2:33]1
Reactant: O=Cc1ccc2c(c1)OCCC2
Reactant: NC1CCN(C[C@@H]2Cn3c(=O)ccc4ccc(=O)n2c43)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=c1ccc2ccc(=O)n3c2n1C[C@H]3CN1CCC(NCc2ccc3c(c2)OCCC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 26 %

Procedure:
A solution of (1R)-1-[(4-amino-1-piperidinyl)methyl]-1,2-dihydro-4H,9H-imidazo[1,2,3-ij]-1,8-naphthyridine-4,9-dione dihydrochloride (for a preparation see example 5A(j)) (188 mg, 0.503 mmol) and triethylamine (0.175 ml, 1.256 mmol) in chloroform (4.5 ml) and methanol (0.5 ml) at rt was stirred at rt for 15 min then 3,4-dihydro-2H-chromene-7-carbaldehyde (for a synthesis see WO2007067511 Example 19 (chromane-7-carbaldehyde)) (68 mg, 0.419 mmol) in chloroform (2 ml) was added dropwise at rt. The reaction mixture was stirred at rt for 1 h then sodium triacetoxyborohydride (444 mg, 2.096 mmol) was added in one portion and the reaction mixture was stirred at rt overnight. LCMS showed a mixture of product, some residual aldehyde. Additional sodium triacetoxyborohydride (267 mg, 1.258 mmol) was added and the reaction stirred at rt for 6 h. The reaction was quenched with NaHCO3 (aq) (20 ml) and extracted with 20% MeOH/DCM (3×30 ml). The combined organic layers were dried over MgSO4, filtered, evaporated and chromatographed (0-50% MeOH/DCM) to deliver the free base of the title compound as a pale yellow clear oil (49 mg, 0.11 mmol, 26%).
Reaction SMILES: C(N(CC)CC)C.Br[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([CH:16]=1)[C:14]#[N:15].[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=1)#[CH:18]>C(OCC)(=O)C.[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:27][C:26]([F:28])([F:29])[O:25][C:21]1[CH:20]=[C:19]([C:17]#[C:18][C:9]2[CH:10]=[N:11][CH:12]=[C:13]([CH:16]=2)[C:14]#[N:15])[CH:24]=[CH:23][CH:22]=1
Reactant: C#Cc1cccc(OC(F)(F)F)c1
Reactant: N#Cc1cncc(Br)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: N#Cc1cncc(C#Cc2cccc(OC(F)(F)F)c2)c1
Temperature: 50 °C
Reaction time: 18 h
Yield: 14.7 %

Procedure:
Add triethylamine (1.73 mL, 12.28 mmol), copper (I) iodide (34.0 mg, 0.180 mmol) and bis(triphenylphosphine)palladium (II) dichloride (107.7 mg, 0.150 mmol) to a solution of 5-bromonicotinonitrile (562.2 mg, 3.07 mmol) and 1-ethynyl -3-trifluoromethoxybenzene, (prepared as described in PREPARATION 28), (571.4 mg, 3.07 mmol) in ethyl acetate (3 mL). Stir in a sealed tube at 50° C. for 18 h, concentrate and purify the residue by silica gel chromatography, eluting with 100:0 to 100:50 hexanes:ethyl acetate, to give the title compound (130 mg, 15%).
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[O:9][C:8]2([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[O:7][C@@H:6]([CH2:15][C:16]([OH:18])=[O:17])[CH2:5]1)#[N:2].[C:19](O)([CH3:22])([CH3:21])[CH3:20].C1(N=C=NC2CCCCC2)CCCCC1.C(OCC)C>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([CH2:3][C@H:4]1[O:9][C:8]2([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[O:7][C@@H:6]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:5]1)#[N:2]
Reactant: CC(C)(C)O
Reactant: N#CC[C@@H]1C[C@H](CC(=O)O)OC2(CCCCC2)O1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CC#N)OC2(CCCCC2)O1
Temperature: 0 °C

Procedure:
(±)-cis-4-(cyanomethyl)-1,5-dioxaspiro[5.5]-undecane-2-acetic acid 3.32 g (13.12 mmol), is dissolved in 15 mL of dichloromethane, cooled to 0° C. and 0.1 g of 4-dimethylaminopyridine (DMAP) added, followed by t-butyl alcohol, and followed by 3.25 g of dicyclohexylcarbodiimide (DCC). This solution is stirred and allowed to slowly warm to room temperature over a 16.5-hour period. TLC shows mainly product, and some slightly lower Rf by-product. The mixture is stirred one hour and 50 mL of dichloromethane is added and stirring continued four hours. One hundred mL of diethyl ether is added and then filtered. The filtrate is concentrated at reduced pressure. This crude concentrate is chromatographed on silica gel and eluted with 4:1 hexane:ethyl acetate to yield (±)-cis-1,1-dimethylethyl 4-(cyanomethyl)-1,5-dioxaspiro[5.5]undecane-2-acetate.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][C:21]([NH2:23])=[NH:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN([CH:27]=[C:28]1[C:33](=[O:34])[CH2:32][CH2:31][CH2:30][C:29]1=O)C>CCO>[Si:1]([O:18][CH2:19][CH2:20][C:21]1[N:23]=[CH:27][C:28]2[C:33](=[O:34])[CH2:32][CH2:31][CH2:30][C:29]=2[N:22]=1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=C1C(=O)CCCC1=O
Reactant: CC(C)(C)[Si](OCCC(=N)N)(c1ccccc1)c1ccccc1
Solvent: CCO
Product: CC(C)(C)[Si](OCCc1ncc2c(n1)CCCC2=O)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 3-(tert-butyldiphenylsilyloxy)propanamidine (25 g, 77 mmol) and 2-((dimethylamino)methylene)cyclohexane-1,3-dione (12.8 g, 77 mmol) in dry EtOH (400 mL) was heated at 80° C. for 3 h. After cooling to room temperature, the solvent was evaporated. Flash chomatography (SiO2, EtOAc/hexane=1:1) gave the title compound as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH2:14][N:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)=[N:12][N:11]=[N:10]2)=[CH:5][C:4]=1[C:28]([F:31])([F:30])[F:29])#[N:2].Cl.O1CCOCC1>CO>[N:15]1([CH2:14][C:13]2[N:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([C:28]([F:31])([F:29])[F:30])[CH:5]=3)[N:10]=[N:11][N:12]=2)[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2nnnn2-c2ccc(C#N)c(C(F)(F)F)c2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: N#Cc1ccc(-n2nnnc2CN2CCNCC2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
To a solution of 1,1-dimethylethyl 4-({1-[4-cyano-3-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)-1-piperazinecarboxylate (Intermediate 25, 532 mg, 1.22 mmol) in methanol (8 mL) was added hydrochloric acid in dioxane (5 mL, 20.0 mmol). The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated, the white solid was dissolved in methanol and poured onto a 5 g SCX cartridge, washed with methanol (2 CV) and eluted with 10% ammonia) in methanol (2 CV). The ammonia in methanol fraction was concentrated under vacuum to leave a white solid, 4-[5-(1-piperazinylmethyl)-1H-tetrazol-1-yl]-2-(trifluoromethyl)benzonitrile (402 mg).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34](O)=[O:35])=[CH:26][CH:25]=1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:34]([C:27]3[C:28]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:24]=[CH:25][CH:26]=3)=[O:35])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Reactant: O=C(O)c1ccnc2ccccc12
Product: Nc1nc(C(=O)N2[C@H](CNC(=O)c3ccnc4ccccc34)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with quinoline-4-carboxylic acid. LC-MS (basic): tR=0.77 min; [M+H]+=488.1.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][CH2:13][CH2:14][F:15])/[C:8]([OH:10])=O)[N:6]=1.[NH2:16][C@@H:17]1[C:35](=[O:36])[N:19]2[C:20]([C:32]([OH:34])=[O:33])=[C:21]([CH2:24][O:25][C:26](=[O:31])[CH2:27][C:28](=[O:30])[CH3:29])[CH2:22][S:23][C@H:18]12>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][CH2:13][CH2:14][F:15])/[C:8]([NH:16][C@@H:17]2[C:35](=[O:36])[N:19]3[C:20]([C:32]([OH:34])=[O:33])=[C:21]([CH2:24][O:25][C:26](=[O:31])[CH2:27][C:28](=[O:30])[CH3:29])[CH2:22][S:23][C@H:18]23)=[O:10])[N:6]=1
Reactant: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Nc1nc(/C(=N/OCCF)C(=O)O)cs1
Product: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)/C(=N\OCCF)c3csc(N)n3)[C@H]2SC1

Procedure:
Starting from 2-(2-aminothiazol-4-yl)-2(Z)-(2-fluoroethoxyimino)acetic acid and 7β-amino-3-(3-oxobutyryloxymethyl)-3-cephem-4-carboxylic acid, the above-identified compound is obtained by the procedure of Reference Example 3.
Reaction SMILES: [C:1]([O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1)(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].O[C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][C:36]([C:39](=[O:48])[CH:40]([CH3:47])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[CH:35][CH:34]=2)=[CH:29][CH:28]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1)(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH3:47][CH:40]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C:39]([C:36]1[CH:37]=[CH:38][C:33]([C:30]2[CH:31]=[CH:32][CH:27]=[CH:28][CH:29]=2)=[CH:34][CH:35]=1)=[O:48]
Reactant: CCCCCCC(C)C(=O)c1ccc(-c2ccc(O)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCCCCCCCCCCCCC(=O)Oc1ccc(C(=O)O)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCC(C)C(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Into a flask were charged 96.2 mg (0.28 mmol) of 4-tetradecanoyloxy benzoic acid, 78.0 mg (0.25 mmol) of 4-hydroxy-4'-(2-methyloctanoyl) biphenyl, 63.5 mg (0.31 mmol) of dicyclohexylcarbodiimide, 3.5 mg (0.03 mmol) of 4-dimethylamino pyridine and 5 ml of dried dichloromethane, which was heated under reflux for 7 hours. After the cooling, the resulting solid was filtered off and washed with dichloromethane. The organic phase was washed with 0.1 normal hydrochloric acid and further with water, dried on anhydrous magnesium sulfate, and the solvent was distilled off. This product was recrystallized with ethanol to obtain 63.5 mg (yield 40%) of white 4-tetradecanoyloxy benzoic acid-4-(2-methyloctanoyl) biphenyl.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH3:18])[CH:16]=3)[NH:11][C:10]=2[CH3:19])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH3:18])[CH:16]=3)[N:11]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:10]=2[CH3:19])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: Cc1ccc2[nH]c(C)c(Sc3ccc(Cl)cc3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(C)c(Sc2ccc(Cl)cc2)c2cc(C)ccc21
Reaction time: 24 h

Procedure:
A stirred solution of 3-[(4-chlorophenyl)thio]-2,5-dimethyl-1H-indole (300 mg) in dry N,N-dimethylformamide (15 ml) was treated with sodium hydride (42 mg of a 60% dispersion in mineral oil). After 10 minutes the reaction was treated with ethyl bromoacetate (116 μl) and stirring continued for 24 hours. The reaction was poured into distilled water (200 ml) and extracted with diethyl ether (3×100 ml). The extracts were dried (MgSO4), evaporated in vacuo and the residue purified by flash column chromatography eluting with 10% ethyl acetate in iso-hexane. The subtitle compound was obtained as a yellow solid (yield 130 mg).