Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([C:12](O)=[O:13])[O:11][C:6]=2[CH:5]=[C:4]([CH3:15])[CH:3]=1.B.S(C)C.CO>O1CCCC1>[CH3:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([CH2:12][OH:13])[O:11][C:6]=2[CH:5]=[C:4]([CH3:15])[CH:3]=1
Reactant: Cc1cc(C)c2c(c1)OC(C(=O)O)CC2
Agent: B
Solvent: CSC
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C)c2c(c1)OC(CO)CC2
Yield: 96 %

Procedure:
To a stirred mixture of 109 parts of 3,4-dihydro-5,7-dimethyl-2H-1-benzopyran-2-carboxylic acid in 135 parts of tetrahydrofuran were added, during a period of 20 minutes, 292 parts of a solution of borane, compound with thiobismethane, in tetrahydrofuran 2M (foaming). The whole was stirred and refluxed for 2 hours. The mixture was decomposed by the addition of 24 parts of methanol. After stirring for 10 minutes at reflux temperature, the solvent was distilled off. Water was added to the residue. Concentrate hydrochloric acid was added and the product was extracted with 1,1'-oxybisethane. The organic layer was washed with water and sodium chloride, dried, filtered and evaporated, yielding 97.5 parts (96%) of 3,4-dihydro-5,7-dimethyl-2H-1-benzopyran-2-methanol as an oily residue (intermediate 16).
Reaction SMILES: C([O:3][C:4]([CH:6]1[C:8]([CH3:10])([CH3:9])[CH:7]1[C:11]#[N:12])=[O:5])C.[OH-].[K+].Cl>O.C(O)C>[C:11]([CH:7]1[C:8]([CH3:10])([CH3:9])[CH:6]1[C:4]([OH:5])=[O:3])#[N:12]
Reactant: CCOC(=O)C1C(C#N)C1(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1(C)C(C#N)C1C(=O)O
Reaction time: 15 h
Yield: 76.2 %

Procedure:
A suspension of 33.4 g (0.2 mol) of 2-cyano-3,3-dimethyl-cyclopropane-carboxylic acid ethyl ester and 16.8 g (0.3 mol) of potassium hydroxide in 200 ml of water and 100 ml of ethanol was stirred at 20°-25° C. for 15 hours. The alcohol was then stripped off and the aqueous solution was acidified with dilute hydrochloric acid and extracted twice with 100 ml of ether (or methylene chloride) each time. The combined organic extracts were dried over Na2SO4 and concentrated and the residue was distilled. 21.2 g (76% of theory) of 2-cyano-3,3-dimethyl-cyclopropane-carboxylic acid were obtained in the form of an oil of boiling point 110°-120° C., which crystallized on cooling (melting point: 101°-106° C.). ##STR44##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:51]=[C:52]([O:56][CH3:57])[C:53]=1[O:54][CH3:55])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]([C:29]3[N:33]([CH2:34][C:35]4[N:36](CC5C=CC=CC=5)[CH:37]=[CH:38][N:39]=4)[C:32]4[CH:47]=[CH:48][CH:49]=[CH:50][C:31]=4[N:30]=3)=[O:28])[CH2:23][CH2:22]2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)=[O:7].C([O-])=O.[NH4+]>CO.[Pd]>[CH3:57][O:56][C:52]1[CH:51]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:53]=1[O:54][CH3:55])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][CH:24]([C:27]([C:29]3[N:33]([CH2:34][C:35]4[NH:39][CH:38]=[CH:37][N:36]=4)[C:32]4[CH:47]=[CH:48][CH:49]=[CH:50][C:31]=4[N:30]=3)=[O:28])[CH2:25][CH2:26]2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)c4nc5ccccc5n4Cc4nccn4Cc4ccccc4)CC3)(c3ccccc3)C2)cc(OC)c1OC
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)c4nc5ccccc5n4Cc4ncc[nH]4)CC3)(c3ccccc3)C2)cc(OC)c1OC
Reaction time: 18 h

Procedure:
Combine 1-(3,4,5-trimethoxy-benzoyl)-3-[2-[4-[1-(1-benzyl-imidazol-2-ylmethyl)-1H-benzoimidazole-2-carbonyl]-piperidin-1-yl]-ethyl]-3-phenyl-pyrrolidine (5 mmol) and 10% palladium-on-carbon (1.5 g) in methanol (50 mL). Add anhydrous ammonium formate (25 mmol). Heat to reflux. After 18 hours, filter, rinse with dichloromethane, and evaporate the filtrate in vacuo to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]([N+:20]([O-])=O)[C:10]=1[C:11]([OH:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[NH4+]>O>[NH2:20][C:14]1[C:10]([C:11]([OH:13])=[O:12])=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:17]([O:18][CH3:19])=[CH:16][CH:15]=1
Reactant: COc1ccc([N+](=O)[O-])c(C(=O)O)c1OCc1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(N)c(C(=O)O)c1OCc1ccccc1
Temperature: 70 °C
Yield: 87 %

Procedure:
A solution of ferrous sulphate heptahydrate (99 g) in water (410 ml) that had been heated to 70° C. was added to a mixture of 2-benzyloxy-3-methoxy-6-nitrobenzoic acid (Bull. Soc. Chim. France, 1965, 1417; 15.5 g) and concentrated aqueous ammonium hydroxide (370 ml) which was heated to 70° C. The resultant mixture was heated to reflux for 30 minutes. The mixture was filtered and the basicity of the filtrate was adjusted to pH8 by the addition of 2N aqueous hydrochloric acid and then the filtrate was acidified to pH4 by the addition of 1M aqueous citric acid solution. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and with brine, dried over magnesium sulphate and evaporated to give 6-amino-2-benzyloxy-3-methoxybenzoic acid (12.15 g); NMR Spectrum: (CDCl3) 3.9 (s, 3H), 5.22 (s, 2H), 6.5 (d, 1H), 7.05 (d, 1H), 7.35–7.55 (m, 5H): Mass Spectrum: M+H+ 274.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([F:18])[CH:12]=2)[CH:10]=1)=O.O.[NH2:26][NH2:27].C([O-])([O-])=O.[Na+].[Na+]>C(O)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[CH:10]=[C:5]([C:3]([NH:26][NH2:27])=[O:2])[CH:6]=[N:7][C:8]=2[O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:12][C:13]=1[F:18]
Reactant: NN
Reactant: COC(=O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)c(F)c2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NNC(=O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)c(F)c2)c1
Temperature: 85 °C
Yield: 64.9 %

Procedure:
5-(4-Chloro-3-fluoro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-3-pyridinecarboxylic acid methyl ester (97 mg, 267 μmol) was dissolved in ethanol (2 mL) to give a light yellow solution. Hydrazine monohydrate (134 mg, 130 μl, 2.67 mmol) was added under argon. The reaction mixture was stirred under argon at reflux temperature (85° C.) for 5 h. Subsequently the reaction mixture was poured into 10 mL saturated aqueous Na2CO3 solution and extracted with isopropyl acetate (2×20 mL). The organic layers were combined, dried with Na2SO4 and concentrated in vacuo to give the title compound (63 mg, 65%) as off-white solid; MS (ESI) 361.8 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:29])=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C@@H:10]3[O:27][CH2:26][C@@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]3[O:12][C:13](=[O:15])[CH3:14])[C:6]=2[CH:28]=1.[Br:30]N1C(=O)CCC1=O.N1C2C=CC=CC=2NC=1>O1CCCC1>[Br:30][C:8]1[N:7]([C@@H:10]2[O:27][CH2:26][C@@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]2[O:12][C:13](=[O:15])[CH3:14])[C:6]2[CH:28]=[C:2]([Cl:1])[C:3]([CH3:29])=[CH:4][C:5]=2[N:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](OC(C)=O)CO[C@H]1n1cnc2cc(C)c(Cl)cc21
Agent: c1ccc2[nH]cnc2c1
Solvent: C1CCOC1
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](OC(C)=O)CO[C@H]1n1c(Br)nc2cc(C)c(Cl)cc21
Yield: 75.9 %

Procedure:
The title compound was prepared according to General Procedure IV using 6-Chloro-5-methyl-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)-1H-benzimidazole (0.37 g, 0.87 mmol), 30 ml tetrahydrofuran (Aldrich Sure Seal, Milwaukee), and a total of 1.2 g (7.0 mmol) of N-bromosuccinimide that was added in ca 0.2 equivalents/benzimidazole every 15 min over 1 h. The product from work-up by General Procedure IV was purified on a silica gel column (2.5×20 cm, 230-400 mesh) with dichloromethane containing 0.5% methanol to give 2-Bromo-6-chloro-5-methyl-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)-1H-benzimidazole (0.33 g, 0.66 mmol, 75%); MS (ES+): m/z (rel. intensity) 526 (1.0, M+23 (Na)); 1H NMR (DMSO-d6) δ8.18 (s,1H), 7.62 (s, 1H), 5.97-5.904(d, 1H, J=9.4 Hz), 5.78-5.60 (m, 3H), 4.20-4.10 (m, 1H), 4.05-3.97 (m, 1H) 2.41 (s, 3H), 2.25 (s, 3H), 2.04 (s, 3H), 1.78 (s, 3H)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]([CH2:23][CH3:24])[C:11](=[O:25])[CH2:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:26]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:27]#[CH:28].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cu]I.Cl[Pd]Cl.CC#N>[CH2:30]([O:29][CH2:26][C:27]#[C:28][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]([CH2:23][CH3:24])[C:11](=[O:25])[CH2:10][N:9]=2)=[CH:4][CH:3]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCN1C(=O)CN=C(c2ccc(Br)cc2)c2cc(OC)c(OC)cc21
Reactant: C#CCOCc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CCN1C(=O)CN=C(c2ccc(C#CCOCc3ccccc3)cc2)c2cc(OC)c(OC)cc21
Temperature: 50 °C
Reaction time: 12 h
Yield: 37 %

Procedure:
Stir for 12 hours under an inert atmosphere at 50° C., a mixture of 100 mg (0.27 mmol) of 5-(4-bromophenyl)-1-ethyl-7,8-dimethoxy-1,3-dihydro-2H-1,4-benzodiazepin-2-one (IIbl), 194 mg (1.3 mmol) of [(prop-2-ynyloxy)methyl]benzene, 9.0 mg of CuI, 5.2 mg of PdCl2, 18.0 mg of PPh3, 0.5 ml of TEA, 2 ml of CH3CN. Evaporate to dryness and purify by silica chromatography (AcOEt 1/hexane 1). Recrystallize in EtO2/pentane. Yield: 37%. M: 64–66° C. 1H-NMR (CDCl3, 300 MHz): d 1.12 (s, 3H, CH3), 3.72–3.83 (m, 4H, 1H CH2+OCH3), 4.00 (AB system, ? d=0.63, JAB=13.5, 2H, —NCH2), 4.03 (s, 3H, OCH3), 4.43 (s, 2H, OCH2), 4.69 (m, 2H, ═C—CH2), 4.77 (m, 1H, OCH2), 6.65 (s, 1H Ar), 6.86 (s, 1H Ar), 7.27–7.63 (m, 9H Ar).
Reaction SMILES: C(=O)(OC1C=CC=C([N+]([O-])=O)C=1)OCC[O:5][CH2:6][CH2:7][O:8][C:9]1[CH:29]=[CH:28][C:12]2[C:13]#[C:14][C:15]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:19][C:16]=3[CH2:17][CH2:18][C:11]=2[CH:10]=1.CCN(CC)CC.[C:48]([NH:55][CH2:56][CH2:57][O:58][CH2:59][CH2:60][O:61][CH2:62][CH2:63][NH:64][C:65](=[O:79])[CH2:66][CH2:67][CH2:68][CH2:69][C@H:70]1[C@@H:78]2[C@@H:73]([NH:74][C:75]([NH:77]2)=[O:76])[CH2:72][S:71]1)([O:50][C:51]([CH3:54])(C)C)=[O:49]>CN(C=O)C>[O:76]=[C:75]1[NH:74][CH:73]2[CH2:72][S:71][CH:70]([CH2:69][CH2:68][CH2:67][CH2:66][C:65]([NH:64][CH2:63][CH2:62][O:61][CH2:60][CH2:59][O:58][CH2:57][CH2:56][NH:55][C:48](=[O:49])[O:50][CH2:51][CH2:54][O:5][CH2:6][CH2:7][O:8][C:9]3[CH:29]=[CH:28][C:12]4[C:13]#[C:14][C:15]5[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:19][C:16]=5[CH2:17][CH2:18][C:11]=4[CH:10]=3)=[O:79])[CH:78]2[NH:77]1
Reactant: CC(C)(C)OC(=O)NCCOCCOCCNC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reactant: CCCCOc1ccc2c(c1)CCc1cc(OCCOCCOC(=O)Oc3cccc([N+](=O)[O-])c3)ccc1C#C2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCOc1ccc2c(c1)CCc1cc(OCCOCCOC(=O)NCCOCCOCCNC(=O)CCCCC3SCC4NC(=O)NC43)ccc1C#C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
A solution of carbonate 16 (0.15 g, 0.28 mmol) in DMF (approximately 2 mL) was added to a solution of Et3N (0.5 g, 4.95 mmol) and N-Boc-N′-biotinyl-3,6-dioxaoctane-1,8-diamine (Ning et al., Angew. Chem. Int. Ed. 2008, 47:2253-2255) (0.01 g, 0.28 mmol) in DMF (10 mL) at room temperature. The reaction mixture was stirred overnight at room temperature, most solvent was evaporated under reduced pressure, and the residue was separated by chromatography on (CH2Cl2:MeOH 30:1) to provide 0.164 g (0.21 mmol, 75%) of 6b. 1H NMR δ 7.19 (d, J=8.4 Hz, 2H), 6.88 (dd, J=9.5, 2.5 Hz, 2H), 6.76 (td, J=8.2, 2.5, 2H), 6.74-6.65 (m, 1H), 6.54 (s, b, 1H), 5.74 (s, b, 1H), 5.60 (s, b 1H), 4.49-4.43 (m, 1H), 4.29-4.22 (m, 3H), 4.16-4.10 (m, 2H), 3.97 (t, J=6.5, 2H), 3.87-3.81 (m, 2H), 3.76 (m, 2H), 3.59-3.48 (m, 7H), 3.42 (m, 2H), 3.37-3.12 (m, 2H), 3.21-3.09 (m, 4H), 2.86 (dd, J=12.6, 4.7 Hz, 1H), 2.72 (d, J=12.7, 1H), 2.42 (d, J=10.9, 2H), 2.21 (t, J=7.4, 2H), 1.81-1.56 (m, 5H), 1.48 (sex, J=7.4 Hz, 2H), 1.44-1.36 (m, 2H), 1.32 (t, J=7.4 Hz, 1H), 0.98 (t, J=7.4, 3H); 13C NMR δ 173.4, 164.1, 158.7, 158.1, 156.5, 154.8, 126.66, 126.63, 116.80, 116.72, 116.59, 115.8, 111.91, 111.83, 110.67, 110.14, 70.09, 70.04, 69.95, 69.90, 69.80, 69.54, 67.78, 67.52, 63.88, 61.80, 60.2, 55.6, 45.6, 40.8, 40.5, 39.1, 36.63, 36.61, 35.9, 31.3, 28.22, 28.08, 25.6, 19.2, 13.8, 8.5.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([NH2:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[CH2:14]([NH:20][C@H:10]1[CH2:11][CH2:12][C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: O=C1CCC(c2ccccc2)CC1
Reactant: CCCCCCN
Product: CCCCCCN[C@H]1CC[C@H](c2ccccc2)CC1

Procedure:
from 4-phenylcyclohexanone and hexylamine. Colourless oil. Rf value: 0.25 (alumina, petroleum ether/ethyl acetate 9:1, v:v).
Reaction SMILES: [CH3:1]/[C:2](=[CH:7]\[CH2:8][CH3:9])/[CH:3]=[CH:4]/[CH2:5][OH:6].[C:10](OC(=O)C)(=[O:12])[CH3:11]>N1C=CC=CC=1>[C:10]([O:6][CH2:5]/[CH:4]=[CH:3]/[C:2](/[CH3:1])=[CH:7]/[CH2:8][CH3:9])(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: CC/C=C(C)/C=C/CO
Solvent: c1ccncc1
Product: CC/C=C(C)/C=C/COC(C)=O
Reaction time: 2 h
Yield: 83.3 %

Procedure:
To a solution of (E,E)-4-methyl-2,4-heptadien-1-ol (106 g) in pyridine (333 g) at 0° C. was added dropwise acetic anhydride (258 g). After two hours at room temperature, the reaction mixture was evaporated in vacuo. The residue was diluted with ethyl acetate, washed with 0.5N-hydrochloric acid and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was distilled to give (E,E)-1-acetoxy-4-methyl-2,4-heptadiene (117.65 g) as an oil.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].C(O)CCCCCCCC(O)C>>[CH2:10]([OH:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: OCCCCCCCCCCO
Agent: CC(O)CCCCCCCCO
Product: CCCCCCCCCCO
Yield: 31.8 %

Procedure:
3.67 g (21.1 mmol) of 1,10-decanediol (with a yield of 36%); 1.48 g (8.5 mmol) of 1,9-decanediol (15%); and 1.06 g (6.7 mmol) of 1-decanol (12%) were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:13](O)[CH3:14]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([O:6][CH2:13][CH3:14])=[O:5]
Reactant: COc1ccc(Br)c(C(=O)O)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(OC)ccc1Br
Temperature: 95 °C
Reaction time: 40.5 h

Procedure:
To a solution of 2-bromo-5-methoxybenzoic acid (5.00 g) in ethanol (100 mL) was added conc. sulfuric acid (10 drops), and the mixture was stirred at 95° C. for 40.5 hr. The reaction mixture was concentrated under reduced pressure and water was added. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (5.37 g) as a colorless oil.
Reaction SMILES: N[C@@H:2]1[C:17](=[O:18])[N:4]2[C:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[C:6]([CH3:9])[CH2:7][S:8][C@H:3]12.[BrH:19].N([O-])=O.[Na+].[Cl-].[Na+]>O.C(O)C>[Br:19][C@H:2]1[C:17](=[O:18])[N:4]2[C:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[C:6]([CH3:9])[CH2:7][S:8][C@H:3]12
Reactant: CC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Br
Agent: O=N[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@H](Br)[C@H]2SC1
Temperature: 0 °C
Yield: 50 %

Procedure:
To an ice-cooled mixture of t-butyl 7β-amino-3-methyl-3-cephem-4-carboxylate (1.3 g, 0.0048 mol), ethanol (30 ml), water (8.5 ml), hydrobromic acid (48%, 5.83 ml), sodium nitrite (0.48 g, 0.00696 mol) was added portionwise over 15 minutes and the mixture was stirred at ice-temperature (-5° C.) for 3 hours, saturated with sodium chloride, extracted with ethyl acetate (3 times). The combined ethyl acetate extract was washed with water, brine, dried and concentrated to give 800 mg (50%) of pure t-butyl 7α-bromo-3-methyl-3-cephem-4-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]([CH3:14])[CH3:13])=[N:7][CH2:6][CH:5]2[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=1.Cl>C(O)(=O)C.[Fe]>[ClH:1].[NH2:21][C:18]1[CH:17]=[CH:16][C:15]([CH:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=3)[C:8]([N:12]([CH3:14])[CH3:13])=[N:7][CH2:6]2)=[CH:20][CH:19]=1
Reactant: CN(C)C1=NCC(c2ccc([N+](=O)[O-])cc2)c2cc(Cl)ccc21
Agent: [Fe]
Agent: Cl
Solvent: CC(=O)O
Product: CN(C)C1=NCC(c2ccc(N)cc2)c2cc(Cl)ccc21
Reaction time: 2 h

Procedure:
100 mg of iron powder were added to a solution of 195 mg of 6-chloro-1-dimethylamino-4-(4-nitrophenyl)-3,4-dihydroisoquinoline in 3.5 ml of glacial acetic acid and then 1.8 ml of concentrated hydrochloric acid were added dropwise, and the mixture was boiled under reflux conditions for 2 hours. The solvent was removed by distillation, and the residue was mixed with water and made alkaline with 2N NaOH. This aqueous phase was extracted with ethyl acetate and purified by MPLC chromatography using an MPRC cartridge with a mixture of 10 parts by volume of ethyl acetate, 5 parts by volume of n-heptane, 5 parts by volume of dichloromethane, 5 parts by volume of methanol and 1 part by volume of concentrated aqueous ammonia solution. After removal of the solvent in a Rotavapor, the viscous amorphous residue was treated in ethyl acetate with ethereal hydrogen chloride solution, and the crystalline solid was filtered off.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]2[NH:15][CH2:16][CH2:17][CH:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)C)=[CH:5][CH:4]=1.[C:26]1(C(C)CCNC2CCCCC2C2C=CC(O)=CC=2)C=CC=CC=1>>[C:25]1([CH2:20][CH2:18][CH2:17][CH2:16][NH:15][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH:9]2[C:6]2[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:26]=1
Reactant: CC(CCNC1CCCCC1c1ccc(O)cc1)c1ccccc1
Reactant: COc1ccc(C2CCCCC2NCCC(C)c2ccccc2)cc1
Product: Oc1ccc(C2CCCCC2NCCCCc2ccccc2)cc1

Procedure:
Following the general method of example 1 (2RS,3SR)-[2-(4-methoxy-phenyl)-cyclohexyl]-(3-phenyl-butyl)-amine (0.95 g, 2.81 mmol) was converted to (1RS,2SR)-4-[2-(3-phenyl-butylamino)-cyclohexyl]-phenol, giving 0.45 g of a light brown solid. MS: m/e=324.3 (M+H+).
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:12][C:13]#[N:14].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOCC>[C:13]([CH2:12][O:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])#[N:14]
Reactant: Cc1cccc(C=O)c1O
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1cccc(C=O)c1OCC#N
Temperature: 55 °C

Procedure:
A mixture of 2-hydroxy-3-methylbenzaldehyde (10.2 g, 75.0 mmoles, Aldrich), bromoacetonitrile (5.70 mL, 82.5 mmoles), and potassium carbonate (11.4 g, 82.5 mmoles) in DMF (150 mL) is heated to 55° C. for 3 hours, cooled, then diluted with ether. The mixture is washed with distilled water, saturated NaCl solution, then the organic layer dried over MgSO4 and concentrated to give the title compound as a yellow solid. 1H NMR (300 MHz, CDCl3): δ10.20 (s, 1H), 7.70 (d, 1H), 7.53 (d, 1H), 7.29 (m, 1H), 4.81 (s, 2H), 2.42 (s, 3H).
Reaction SMILES: Cl.C[O:3][C:4](=[O:17])[CH2:5][C@@H:6]([NH2:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1.[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[C:21]([NH:28][S:29]([C:32]2[C:33]3[N:34]=[CH:35][CH:36]=[N:37][C:38]=3[CH:39]=[CH:40][CH:41]=2)(=[O:31])=[O:30])[CH:20]=1>>[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:16][C@@H:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[CH2:5][C:4]([OH:3])=[O:17])=[O:24])=[C:21]([NH:28][S:29]([C:32]2[C:33]3[N:34]=[CH:35][CH:36]=[N:37][C:38]=3[CH:39]=[CH:40][CH:41]=2)(=[O:30])=[O:31])[CH:20]=1
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nccnc12
Reactant: COC(=O)C[C@@H](N)Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Product: O=C(O)C[C@H](Cc1ccc(Cl)c(Cl)c1)NC(=O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nccnc12

Procedure:
(S)-3-(tert-Butoxycarbonylamino)-4-(3,4-dichloro-phenyl)-butyric acid was treated as in EXAMPLE 2, Part A, to produce (S)-3-amino-4-(3,4-dichloro-phenyl)-butyric acid methyl ester hydrochloride as a white solid. This ester was coupled to 4-chloro-2-(quinoxaline-5-sulfonylamino)-benzoic acid as in EXAMPLE 1, Part C. The resulting methyl ester was hydrolyzed as in EXAMPLE 2, Part E. HPLC: RT=9.78 min. MS (ESI−): mass calcd. for C25H19Cl3N4O5S, 592.01; m/z found, 593/595 [M−H]−. 1H NMR (500 MHz, CD3OD): 8.97 (d, J=1.8, 1H), 8.93 (d, J=1.8, 1H), 8.55 (dd, J=7.4, 1.3, 1H), 8.33 (dd, J=8.5, 1.3, 1H), 7.97-7.94 (m, 1H), 7.69 (d, J=2.0, 1H), 7.42 (d, J=8.2, 1H), 7.38-7.36 (m, 2H), 7.16 (dd, J=8.2, 2.0, 1H), 6.97 (dd, J=8.6, 2.0, 1H), 4.56-4.50 (m, 1H), 2.90 (dd, J=13.7, 6.1, 1H), 2.81 (dd, J=13.7, 7.7, 1H), 2.54 (dd, J=15.9, 6.2, 1H), 2.45 (dd, J=15.9, 7.4, 1H).
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[C:8]([F:24])=[CH:9][C:10]([O:22][CH3:23])=[CH:11][C:12]=3[C@@:13]32[CH2:20][CH2:19][S:18][C:17]([NH2:21])=[N:16]3)=[CH:4][CH:3]=1.[N-:25]=[N+:26]=[N-:27].[Na+].CN[C@@H]1CCCC[C@H]1NC.N#N>[Cu]I.O.CCO>[N:25]([C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[C:8]([F:24])=[CH:9][C:10]([O:22][CH3:23])=[CH:11][C:12]=3[C@@:13]32[CH2:20][CH2:19][S:18][C:17]([NH2:21])=[N:16]3)=[CH:4][CH:3]=1)=[N+:26]=[N-:27]
Reactant: COc1cc(F)c2c(c1)[C@]1(CCSC(N)=N1)c1cc(Br)ccc1O2
Reactant: [N-]=[N+]=[N-]
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: N#N
Solvent: CCO
Solvent: O
Product: COc1cc(F)c2c(c1)[C@]1(CCSC(N)=N1)c1cc(N=[N+]=[N-])ccc1O2
Temperature: 90 °C
Yield: 62.5 %

Procedure:
To a disposable vial was charged with (S)-7′-bromo-4′-fluoro-2′-methoxy-5,6-dihydrospiro[[1,3]thiazine-4,9′-xanthen]-2-amine (300 mg, 0.733 mmol), copper(I) iodide (27.9 mg, 0.147 mmol), sodium azide (143 mg, 2.199 mmol) and (+)-sodium 1-ascorbate (14.52 mg, 0.073 mmol). EtOH (1.2 mL) and water (0.5 mL) were added followed by addition of trans-N,N′-dimethyl-1,2-cyclohexanediamine (34.7 μl, 0.220 mmol). The vial was capped and subjected to three cycles of evacuation-backfilling with N2. Finally it was heated in oil bath at 90° C. for 3 hrs. The reaction mixture was allowed to cool to RT. Excess of water was added and a tan precipitate formed. It was collected through Buchner funnel to yield (S)-7′-azido-4′-fluoro-2′-methoxy-5,6-dihydrospiro[[1,3]thiazine-4,9′-xanthen]-2-amine (170 mg, 0.458 mmol, 62.4% yield) as tan solid.
Reaction SMILES: [O:1]=[C:2]([C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24](=[O:29])[CH2:23][CH2:22]2)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[CH2:8][CH2:7]1.[BH4-].[Na+].Cl>CO>[OH:1][CH:2]([C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24](=[O:29])[CH2:23][CH2:22]2)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:7][CH2:8][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[CH2:10][CH2:11]1
Reactant: O=C1CCc2cc(C(=O)CCCN3CCN(c4cccc(Cl)c4)CC3)ccc2N1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C1CCc2cc(C(O)CCCN3CCN(c4cccc(Cl)c4)CC3)ccc2N1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3.0 Grams of 6-{1-oxo-4-[4-(3-chlorophenyl)-1-piperazinyl]butyl}-3,4-dihydrocarbostyril was added to 100 ml of methanol, under stirring condition 1.2 g of sodium borohydride was added gradually to the solution and stirred at a room temperature for 5 hours. Then 5 ml of concentrated hydrochloric acid was added to the reaction mixture and the mixture was concentrated under a reduced pressure to dryness. Then to this dried matter was added 50 ml of 2%-sodium hydroxide aqueous solution and the organic layer was extracted with dichloromethane. The dichloromethane layer was washed with water, dried and the dichloromethane was removed by distillation. The residue thus obtained was purified by a silica gel column chromatography, and recrystallized from isopropanol to obtain 2.2 g of 6-{1-hydroxy-4[4-(3-chlorophenyl)-1-piperazinyl]butyl}-3,4-dihydrocarbostyril in colorless needle-like crystals.