Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[C:11]1[CH:12]=[C:13]2[C:17]3=[C:18]([CH2:20][S:21][CH2:22][CH2:23][N:16]3[C@H:15]3[CH2:24][CH2:25][N:26](C(OC(C)(C)C)=O)[CH2:27][C@@H:14]23)[CH:19]=1>>[C:3]1([C@@H:2]([NH:9][C:11]2[CH:12]=[C:13]3[C:17]4=[C:18]([CH2:20][S:21][CH2:22][CH2:23][N:16]4[C@H:15]4[CH2:24][CH2:25][NH:26][CH2:27][C@@H:14]34)[CH:19]=2)[CH3:1])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CCSC3
Product: C[C@H](Nc1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCSC2)c1ccccc1

Procedure:
Using (S)-(−)-α-methylbenzylamine and following the procedures described in EXAMPLE 168, tert-butyl (7bR,11aS)-6-bromo-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate from EXAMPLE 7, Part A was converted into the title compound of EXAMPLE 169. 1H NMR(CDCl3) δ 7.40-7.20 (m, 5H), 6.22 (d, 1H, J=2.2 Hz), 6.14 (d, 1H, J=2.2 Hz), 4.39 (q, 1H, J=6.6 Hz), 3.62 (ABq, 2H, JAB=15.5 Hz), 3.55-3.43 (m, 1H), 3.32-3.20 (m, 2H), 3.05-2.81 (m, 4H), 2.77-2.60 (m, 1H), 2.50 (dd, 1H, J=12.8, 9.7 Hz), 2.00-1.85 (m, 2H), 1.49 (d, 3H, J=6.6 Hz). LRMS (ES)+: 366.4 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[S:12]([NH:15][C:16]1[CH:20]=[CH:19][S:18][C:17]=1[C:21]([O:23]C)=[O:22])(=[O:14])=[O:13].[OH-].[Li+]>O1CCCC1.CO>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:9])[F:11])[CH:5]=[CH:4][C:3]=1[S:12]([NH:15][C:16]1[CH:20]=[CH:19][S:18][C:17]=1[C:21]([OH:23])=[O:22])(=[O:14])=[O:13]
Reactant: COC(=O)c1sccc1NS(=O)(=O)c1ccc(C(F)(F)F)cc1Br
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1sccc1NS(=O)(=O)c1ccc(C(F)(F)F)cc1Br
Temperature: 77.5 °C
Yield: 34.6 %

Procedure:
To a solution of 97 (330.0 mg; 0.74 mmol) in tetrahydrofuran (8 mL) and methanol (2 mL) was added aqueous lithium hydroxide (4 mL; 2M). The reaction mixture was heated at 75-80° C. for 6 hours, allowed to cool to room temperature and then concentrated under reduced pressure. The resulting residue was dissolved in chloroform (15 mL) and washed with aqueous hydrochloric acid (2×10 mL; 2N). The organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by preparative HPLC to afford the title compound as a white solid (110 mg).
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[OH:19].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>C1(C)C=CC=CC=1.O.CC#N.CC#N.CC#N.CC#N.F[P-](F)(F)(F)(F)F.[Cu+]>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[O:19][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Oc1cc(Cl)ccc1Cl
Reactant: O=C(O)c1ccccc1I
Agent: [Cu+]
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)c1ccccc1Oc1cc(Cl)ccc1Cl

Procedure:
To a solution of 2-iodo-benzoic acid (3.0 g, 12.10 mmol, 1.0 equiv; [CAS RN 88-67-5]) and 2,5-dichloro-phenol (1.97 g, 12.10 mmol, 1.0 equiv; [CAS RN 583-78-8]) in toluene (50 mL) was added caesium carbonate (7.88 g, 24.20 mmol, 2.0 equiv; [CAS RN 534-17-8]) and tetrakis(acetonitrile)copper(I) hexafluorophosphate (1.13 g, 3.02 mmol, 0.25 equiv; [CAS RN 64443-05-6]). The reaction mixture was heated to reflux over night. The solvent was evaporated under reduced pressure and the crude reaction product taken up in water (100 mL), acidified to pH 1 by addition of a solution of 1 M HCl and extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO4 and the product purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane (+1% acetic acid)/ethyl acetate affording 2.78 g (81%) of the title compound as a white solid. MS (ISN): 281.1 [M−H]−.
Reaction SMILES: [N:1]([C:4]1[CH:17]=[C:16]2[C:7]([O:8][C:9]3[C:10]([F:26])=[CH:11][C:12]([O:24][CH3:25])=[CH:13][C:14]=3[C@@:15]32[CH2:22][CH2:21][O:20][C:19]([NH2:23])=[N:18]3)=[CH:6][CH:5]=1)=[N+]=[N-].CP(C)C>C1COCC1>[F:26][C:10]1[C:9]2[O:8][C:7]3[C:16](=[CH:17][C:4]([NH2:1])=[CH:5][CH:6]=3)[C@@:15]3([CH2:22][CH2:21][O:20][C:19]([NH2:23])=[N:18]3)[C:14]=2[CH:13]=[C:12]([O:24][CH3:25])[CH:11]=1
Reactant: COc1cc(F)c2c(c1)[C@]1(CCOC(N)=N1)c1cc(N=[N+]=[N-])ccc1O2
Agent: CP(C)C
Solvent: C1CCOC1
Product: COc1cc(F)c2c(c1)[C@]1(CCOC(N)=N1)c1cc(N)ccc1O2
Reaction time: 5 h

Procedure:
The crude (S)-7′-azido-4′-fluoro-2′-methoxy-5,6-dihydrospiro[[1,3]oxazine-4,9′-xanthen]-2-amine (1.29 g, 3.63 mmol) was dissolved in THF (27 mL). A THF solution of trimethylphosphine (3.63 mL, 3.63 mmol) was added. After 5 h, the mixture was quenched with 35 mL of 1M aqueous HCl, and the mixture was stiffed overnight. The mixture was then neutralized with saturated NaHCO3 (70 mL) and the aqueous layer mixture was extracted with EtOAc (500 mL). The organic layer was washed with saturated brine (35 mL), dried over MgSO4 and concentrated to afford crude (S)-4′-fluoro-2′-methoxy-5,6-dihydrospiro[[1,3]oxazine-4,9′-xanthene]-2,7′-diamine, which was used without purification in the next step. MS m/z=330 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10]([Si:14](Cl)([CH3:16])[CH3:15])([CH3:13])([CH3:12])[CH3:11].N1C=CN=C1>ClCCl>[C:10]([Si:14]([CH3:16])([CH3:15])[O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=Cc1ccc(O)cc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.4 %

Procedure:
4-Hydroxybenzaldehyde (5.14 g, 42.1 mmol) was added to a suspension of tert-butyl-dimethyl-silyl chloride (6.7 g, 44.4 mmol) and imidazole (3.03 g, 44.5 mmol) in dichloromethane (100 ml) under an atmosphere of nitrogen at room temperature. The reaction mixture was stirred at room temperature for 18 hours, and then washed sequentially with 1 M hydrochloric acid (2-fold 50 ml) followed by a saturated aqueous solution of sodium hydrogen carbonate (50 ml). The organic phase was separated, dried over anhydrous magnesium sulphate and the solvent removed in vacuo. The residual yellow oil was passed through a plug of silica gel eluting with 1:1, by volume, dichloromethane:pentane giving 4-(tert-butyl-dimethyl-silanyloxy)-benzaldehyde (7.5 g) as a golden yellow oil.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([O:11][CH3:12])[CH:5]=1)=[O:3].[Br:13][C:14]1[CH:15]=[C:16]([Li])[CH:17]=[CH:18][CH:19]=1>>[Br:13][C:14]1[CH:15]=[C:16]([C:2]([C:4]2[CH:9]=[CH:8][C:7]([F:10])=[C:6]([O:11][CH3:12])[CH:5]=2)([OH:3])[CH3:1])[CH:17]=[CH:18][CH:19]=1
Reactant: COc1cc(C(C)=O)ccc1F
Reactant: [Li]c1cccc(Br)c1
Product: COc1cc(C(C)(O)c2cccc(Br)c2)ccc1F

Procedure:
In an analogous reaction sequence to that described for Building Block C, the reaction of 4-fluoro-3-methoxyacetophenone with 3-bromophenyllithium yielded the (RS)-1-(3-bromo-phenyl)-1-(4-fluoro-3-methoxy-phenyl)-ethanol which was used as crude material in the following elimination reaction with a catalytic amount of p-toluenesulfonic acid to yield the title compound (yield: 91% of theory) as a light yellow oil. TLC: Rf: 0.69 (silica gel; heptane:ethyl acetate=4:1, UV, 254 nm).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]#[N:10])=[N:6][CH:7]=1.Br[CH2:12][CH2:13][CH2:14][CH2:15]Br>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:9]#[N:10])[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:6][CH:7]=1
Reactant: BrCCCCBr
Reactant: N#CCc1ccc(Br)cn1
Product: N#CC1(c2ccc(Br)cn2)CCCC1
Yield: 78 %

Procedure:
The title compound was prepared from (5-bromo-pyridin-2-yl)-acetonitrile and 1,4-dibromobutane following a procedure analogous to that described in Step 3 for Intermediate 4. Yield: 78% of theory; Mass spectrum (ESI+): m/z=251/253 (Br) [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=2)=[CH:5][CH:4]=1)=O.[CH:23]1([CH2:28][CH2:29][NH2:30])[CH2:27][CH2:26][CH2:25][CH2:24]1.[BH4-].[Na+].O>CO>[CH:23]1([CH2:28][CH2:29][NH:30][CH2:1][C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]([O:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=3)=[CH:5][CH:4]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)c3ccccc23)nc1
Reactant: NCCC1CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc(CNCCC3CCCC3)c3ccccc23)nc1
Reaction time: 16 h

Procedure:
To a solution of 6-(4-formylnaphthalen-1-yloxy)nicotinamide (Preparation 2) (200 mg, 0.7 mmol) in MeOH (10 mL) was added 2-cyclopentyl ethylamine (116 mg, 1.0 mmol) and 4 Å molecular sieves (200 mg). The mixture was stirred for 16 h before adding NaBH4 (130 mg, 3.4 mmol). After 1.5 h water (1 mL) was added and the mixture filtered. Solvent was removed in vacuo and the residue purified by column chromatography (0.5% NH3: 2% MeOH:DCM) to give the title compound: RT=2.68 min; m/z (ES+)=390.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([NH2:7])=[N:4][CH:3]=1.[C:8]12([C:18](Cl)=[O:19])[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2.C(N(CC)CC)C>O1CCCC1>[Br:1][C:2]1[S:6][C:5]([NH:7][C:18]([C:8]23[CH2:17][CH:12]4[CH2:11][CH:10]([CH2:16][CH:14]([CH2:13]4)[CH2:15]2)[CH2:9]3)=[O:19])=[N:4][CH:3]=1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: Nc1ncc(Br)s1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ncc(Br)s1)C12CC3CC(CC(C3)C1)C2
Temperature: 80 °C

Procedure:
A mixture of 5-bromothiazol-2-amine (3.0 g, 11.5 mmol), adamantane-1-carbonyl chloride (2.74 g, 13.8 mmol), triethylamine (3.2 mL, 23 mmol) and 4-di(methylamino)pyridine (1.1 g) in tetrahydrofuran (100 mL) was heated at 80° C. for 48 hours. The mixture was cooled to ambient temperature, concentrated, diluted with water and extracted with ethyl acetate. The organic extract was dried (Na2SO4), filtered and concentrated. Purification by flash chromatography (silica gel, 25% ethyl acetate/hexanes) afforded the title compound, MS (ESI) m/z 342 (M+H)+
Reaction SMILES: [O:1]=[S:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[NH:14][C:15](=O)[C:16]3[S:21][C:20]([CH3:22])=[CH:19][C:17]=3[N:18]=2)[CH2:4][CH2:3]1.[F:24][CH:25]([CH2:28][NH2:29])[CH2:26][NH2:27]>>[F:24][CH:25]([CH2:28][NH2:29])[CH2:26][NH:27][C:15]1[C:16]2[S:21][C:20]([CH3:22])=[CH:19][C:17]=2[N:18]=[C:13]([N:5]2[CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[S:2](=[O:1])[CH2:3][CH2:4]2)[N:14]=1
Reactant: NCC(F)CN
Reactant: Cc1cc2nc(N3CCS(=O)c4ccccc4C3)[nH]c(=O)c2s1
Product: Cc1cc2nc(N3CCS(=O)c4ccccc4C3)nc(NCC(F)CN)c2s1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 3 by using 2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylthieno[3,2-d]pyrimidin-4(3H)-one and 2-fluoro-1,3-propanediamine. MS obsd. (ESI+) [(M+H)+] 420, 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.73 (d, J=6.6 Hz, 1H), 7.68 (d, J=6.8 Hz, 1H), 7.39-7.51 (m, 2H), 6.81 (s, 1H), 5.19 (d, J=14.7 Hz, 1H), 4.83 (d, J=9.3 Hz, 1H), 4.69 (br. s., 2H), 4.46 (br. s., 1H), 3.71-3.96 (m, 2H), 3.30-3.48 (m, 2H), 2.80-3.05 (m, 2H), 2.54 (s, 3H).
Reaction SMILES: C([BH3-])#N.[NH2:4][C:5]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[C:8]([CH3:15])=[CH:7][C:6]=1[OH:16].[CH2:17]([O:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([N:27]2[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]2)[CH2:23][CH2:22]1)[CH2:18][CH3:19].C(O)(=O)C>C1COCC1>[CH3:15][C:8]1[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:10][C:5]([NH:4][CH:30]2[CH2:29][CH2:28][N:27]([C@H:24]3[CH2:25][CH2:26][C@H:21]([O:20][CH2:17][CH2:18][CH3:19])[CH2:22][CH2:23]3)[CH2:32][CH2:31]2)=[C:6]([OH:16])[CH:7]=1
Reactant: CCCO[C@H]1CC[C@H](N2CCC(=O)CC2)CC1
Reactant: Cc1cc(O)c(N)cc1S(C)(=O)=O
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCO[C@H]1CC[C@H](N2CCC(Nc3cc(S(C)(=O)=O)c(C)cc3O)CC2)CC1
Temperature: 100 °C

Procedure:
Polymer supported cyanoborohydride (110 mg, 0.47 mmol, 4.3 mmol/g) was added to a solution of 2-amino-5-methyl-4-(methylsulfonyl)phenol (D87, 48 mg, 0.24 mmol), 1-[trans-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinone (D17, 65 mg, 0.26 mmol, this specific batch contained ˜25% 1-[trans-4-(propyloxy)cyclohexyl]-4-piperidinone) and acetic acid (0.07 mL, 1.19 mmol) in THF (2.5 mL). The mixture was heated by microwave at 100° C. for 30 min and then for a further 3×30 min. The reaction was then filtered and concentrated by rotary evaporation to give a yellow oil, which was purified by high pH MDAP to give 5-methyl-2-({1-[trans-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}amino)-4-(methylsulfonyl)phenol (D88, 49 mg, 46%) as a cream solid and 5-methyl-4-(methylsulfonyl)-2-({1-[trans-4-(propyloxy)cyclohexyl]-4-piperidinyl}amino)phenol (D89, 14 mg, 13%) as a yellow oil.
Reaction SMILES: [OH:1][CH:2]1[C:11]2[N:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:12][C:8]1[CH:9]=[N:10][C:11]2[C:2](=[O:1])[CH2:3][CH2:4][CH2:5][C:6]=2[CH:7]=1
Reactant: Cc1cnc2c(c1)CCCC2O
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1cnc2c(c1)CCCC2=O

Procedure:
8-Hydroxy-3-methyl-5,6,7,8-tetrahydroquinoline (42.5g) in methylene chloride (21/21) was stirred at room temperature with manganese dioxide (425g) for 16 hours. The manganese dioxide was removed by filtration and washed with methylene chloride. The filtrate was evaporated to dryness under reduced pressure and the residue was distilled to give 5,6-dihydro-3-methyl-7H-quinolin-8-one (30g) b.p. 142°-4° C at 0.5mm.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:24])[CH:14]2[CH:19]([C:20]=1[O:21][CH3:22])[CH:18]1[O:23][CH:15]2[CH:16]=[CH:17]1)[CH3:2]>CO.[Pd]>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:24])[CH:14]2[CH:19]([C:20]=1[O:21][CH3:22])[CH:18]1[O:23][CH:15]2[CH2:16][CH2:17]1)[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1C1=C(OC)C2C3C=CC(O3)C2C1=O
Agent: [Pd]
Solvent: CO
Product: CCc1cc(C)cc(CC)c1C1=C(OC)C2C3CCC(O3)C2C1=O
Reaction time: 1.5 h

Procedure:
To a solution of (1RS,2RS,6SR,7SR)-4-(2,6-diethyl-4-methylphenyl)-5-methoxy-10-oxa-tricyclo[5.2.1.02,6]deca-4,8-dien-3-one (0.052 g, 0.16 mmol) in methanol (10 ml) is added 5% palladium on carbon (10 mg). The reaction is stirred under an atmosphere of hydrogen for 90 minutes. The reaction is filtered through diatomaceous earth and the filter pad is washed with ethyl acetate (10 ml). The solvent is removed under reduced pressure to yield (1RS,2RS,6-SR,7SR)-4-(2,6-diethyl-4-methylphenyl)-5-methoxy-10-oxa-tricyclo[5.2.1.02,6]dec-4-en-3-one.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][CH:7]([CH2:11][CH3:12])[C:8]([OH:10])=[O:9].[Si:17]([O:24][C@H:25]1[CH2:34][C@H:33](O)[C@H:32]2[C:27]([CH:28]=[CH:29][C@H:30]([CH3:53])[C@@H:31]2[CH2:36][CH2:37][C@H:38]2[O:43][C:42](=[O:44])[CH2:41][C@H:40]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[CH2:39]2)=[CH:26]1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>>[Si:17]([O:24][C@H:25]1[CH2:34][C@H:33]([O:9][C:8](=[O:10])[CH:7]([O:6][C:5]2[CH:13]=[CH:14][CH:15]=[C:3]([N:2]([CH3:1])[CH3:16])[CH:4]=2)[CH2:11][CH3:12])[C@H:32]2[C:27]([CH:28]=[CH:29][C@H:30]([CH3:53])[C@@H:31]2[CH2:36][CH2:37][C@H:38]2[O:43][C:42](=[O:44])[CH2:41][C@H:40]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:47])[CH3:48])[CH2:39]2)=[CH:26]1)([C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:19])[CH3:18]
Reactant: CCC(Oc1cccc(N(C)C)c1)C(=O)O
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Product: CCC(Oc1cccc(N(C)C)c1)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21

Procedure:
A procedure similar to that described in Example 1, above, was followed, but using 766 mg of (2RS)-2-(3-dimethylaminophenoxy)butyric acid and 1.0 gof (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 1.26 g of the title compound as a pale yellow foam.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.CCCCCC.C([Li])CCC.[CH3:20][C:21]1[CH:22]=[C:23]([O:26][C:27]=1[CH3:28])[CH:24]=[O:25]>O1CCCC1.O>[CH3:20][C:21]1[CH:22]=[C:23]([CH:24]([C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=2)[OH:25])[O:26][C:27]=1[CH3:28]
Reactant: Cc1ccnc(Br)c1
Reactant: Cc1cc(C=O)oc1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: Cc1ccnc(C(O)c2cc(C)c(C)o2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 51.7 %

Procedure:
2-Bromo-4-picoline (1.5 g) was dissolved in tetrahydrofuran (40 ml) under an argon atmosphere to prepare a solution. A 1.6 M hexane solution (5.6 ml) of n-butyllithium was added dropwise to the solution at −78° C., and the mixture was then stirred at −78° C. for 30 min. A solution of 4,5-dimethylfurfural (1 g) in tetrahydrofuran (20 ml) was added dropwise thereto, and the temperature of the mixture was raised to room temperature with stirring. Water was added to the reaction solution to stop the reaction. The solvent was removed by distillation under the reduced pressure. Water was added to the residue, the mixture was extracted with ethyl acetate, and the ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using hexane-ethyl acetate to give (4,5-dimethylfuran-2-yl)-(4-methyl-pyridin-2-yl)-methanol (904 mg, yield 47%).
Reaction SMILES: [N:1]1([C:5]([C:7]2[N:8]=[N:9][C:10](Cl)=[CH:11][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[OH:14][C:15]1[CH:16]=[C:17]([CH:27]=[C:28]([O:30][C@@H:31]([CH3:35])[CH2:32][O:33][CH3:34])[CH:29]=1)[C:18]([NH:20][C:21]1[CH:25]=[CH:24][N:23]([CH3:26])[N:22]=1)=[O:19].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:1]1([C:5]([C:7]2[N:8]=[N:9][C:10]([O:14][C:15]3[CH:16]=[C:17]([CH:27]=[C:28]([O:30][C@@H:31]([CH3:35])[CH2:32][O:33][CH3:34])[CH:29]=3)[C:18]([NH:20][C:21]3[CH:25]=[CH:24][N:23]([CH3:26])[N:22]=3)=[O:19])=[CH:11][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1ccc(Cl)nn1)N1CCC1
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)N3CCC3)nn2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 130 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
A mixture of 3-(azetidin-1-ylcarbonyl)-6-chloropyridazine (45 mg, 0.23 mmol), 3-hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide (70 mg, 0.23 mmol) and potassium carbonate (63 mg, 0.46 mmol) in acetonitrile (3 mL) was stirred in a Smith Creator microwave at 130° C. for 1 hour. The solid was filtered off and the solvent was removed in vacuo. The residue was purified by reverse phase preparative HPLC, eluting with 5-95% acetonitrile in water (+0.2% TFA), followed by passage through a Silicycle Si-Carbonate cartridge, eluting with methanol, to give the desired product as a colourless solid (97 mg). 1H NMR δ (CDCl3): 1.34 (3H, d), 1.66 (3H, s), 2.33-2.41 (2H, m), 3.40 (3H, s), 3.48-3.52 (1H, m), 3.56-3.60 (1H, m), 3.79 (3H, s), 4.27 (2H, d), 4.58-4.62 (1H, m), 4.76 (2H, t), 6.79 (1H, d), 6.97 (1H, t), 7.25-7.29 (3H, m), 7.35-7.36 (1H, m), 8.26-8.28 (1H, m), 8.49 (1H, s); m/z 467 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[N:4][C:5]([OH:8])=[N:6][CH:7]=1.C(N(CC)CC)C.Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C(Cl)Cl>[CH2:25]([O:24][C:22](=[O:23])[O:8][C:5]1[N:4]=[C:3]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])[C:2]([F:1])=[CH:7][N:6]=1)[CH3:26]
Reactant: CN(C)C=Nc1nc(O)ncc1F
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Oc1ncc(F)c(N=CN(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.4 %

Procedure:
To a solution of N′-(5-fluoro-2-hydroxy-pyrimidin-4-yl)-N,N-dimethylformamidine (0.10, 0.54 mmol) in CH2Cl2 (2 mL) were added triethylamine (0.20 g, 2.0 mmol) and ethyl chloroformate (0.065 g, 0.60 mmol), and the mixture was agitated on an orbital shaker at room temperature overnight. The reaction was diluted with CH2Cl2 and the solution was washed with water, dried over MgSO4, filtered and evaporated. The crude product was purified by silica gel column chromatography (EtOAc/petroleum ether gradient) to yield 0.031 g (22%) of the title compound as a white solid: mp 124-126° C.; 1H NMR (300 MHz, CDCl3) δ 8.67 (s, 1H), 8.19 (d, J=2.2 Hz, 1H), 4.35 (q, J=7.14 Hz, 2H), 3.21 (s, 6H), 1.40 (t, J=7.14 Hz, 3H); HPLC-MS (ESI) m/z 258 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:15][C:8]([CH2:9][S:10][CH2:11][CH2:12]SC)=[CH:7][CH:6]=1)[CH3:3].[N+:16]([CH:19]=[C:20]([NH2:28])[NH:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)([O-:18])=[O:17]>>[CH3:1][N:2]([CH2:4][C:5]1[O:15][C:8]([CH2:9][S:10][CH2:11][CH2:12][NH:28][C:20]([NH:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:19][N+:16]([O-:18])=[O:17])=[CH:7][CH:6]=1)[CH3:3]
Reactant: NC(=C[N+](=O)[O-])NC1CCCCC1
Reactant: CSCCSCc1ccc(CN(C)C)o1
Product: CN(C)Cc1ccc(CSCCNC(=C[N+](=O)[O-])NC2CCCCC2)o1

Procedure:
24.54 grams of 2-[[5-[(dimethylamino)methyl]furfuryl]thio]ethylmethylsulphide are reacted with 37 grams of 2-nitro-N-cyclohexyl-1,1-ethenediamine at 80° C. for 3 hours. Th mixture is cooled and the procedure described in Example 1 is followed. The product melts at 97°-99° C. Spectrophotometric analyses confirm its structure.
Reaction SMILES: N1C=CC=CC=1.[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH2:12][C:13]([NH:15][CH:16]1[C:42](=[O:43])[N:18]2[CH:19]([C:26]([O:28][CH:29]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])[C:20]([CH2:24][OH:25])=[C:21]([CH3:23])[S:22][C@H:17]12)=[O:14].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH2:12][C:13]([NH:15][CH:16]1[C:42](=[O:43])[N:18]2[CH:19]([C:26]([O:28][CH:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[O:27])[C:20]([CH:24]=[O:25])=[C:21]([CH3:23])[S:22][C@H:17]12)=[O:14]
Reactant: CC1=C(CO)C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2S1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1=C(C=O)C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2S1
Reaction time: 1 h
Yield: 36.2 %

Procedure:
To 250 ml of CH2Cl2 containing 6.7 ml of pyridine at 20° C. was added 4.2 g of CrO3, and after stirring for 1 hour, a solution of 2.6 g of diphenylmethyl 7-(2-thienylacetamido)-2-methyl-3-hydroxymethylceph-2-em-4-carboxylate in 30 ml of CH2Cl2 was added to the mixture, followed by stirring vigorously for 5 minutes. 100 ml of 1M citric acid solution was added to the reaction solution, followed by stirring to separate out the CH2Cl2 layer. The CH2Cl2 layer was washed with H2O and saturated aqueous NaCl solution, successively, and dried over MgSO4, followed by distilling off the CH2Cl2 under reduced pressure. The residue was added on a column of silica gel, and the fractions eluted with CH2Cl2.ACOEt (20:1) were collected to distill off the solvent under reduced pressure, thus yielding 938 mg (36.2%) of diphenylmethyl 7-(2-thienylacetamido)-2-methyl-3-formylceph-2-em-4-carboxylate.
Reaction SMILES: [NH2:1][CH2:2][Si:3]([CH3:6])([CH3:5])[CH3:4].[Cl:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=O.O>ClCCl>[Cl:7][C:8]1[CH:9]=[C:10](/[CH:11]=[N:1]/[CH2:2][Si:3]([CH3:6])([CH3:5])[CH3:4])[CH:13]=[CH:14][CH:15]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: C[Si](C)(C)CN
Solvent: O
Solvent: ClCCl
Product: C[Si](C)(C)C/N=C/c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.9 %

Procedure:
To a solution of (aminomethyl)trimethylsilane (Fluka) (1.6 g, 16 mmol) in dichloromethane (100 mL) was added 3-chloro-benzaldehyde (Aldrich) (1.9 g, 14 mmol). The reaction mixture was stirred at room temperature for 3 h. Water was added. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated to give [1-(3-chloro-phenyl)-meth-(E)-ylidene]-trimethylsilanylmethyl-amine as a colorless oil (3 g, 95%).