Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[N:5]2.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6][NH:5]2
Reactant: Cc1ccc2nccnc2c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1ccc2c(c1)NCCN2
Temperature: 0 °C
Reaction time: 4 h
Yield: 42.8 %

Procedure:
To a solution of 6-methylquinoxaline (2 g, 13.87 mmol) and nickel (II) chloride hexahydrate (6.6 g, 27.74 mmol) in anhydrous methanol (70 mL) was added in portions, sodium borohydride (10.5 g, 277.43 mmol) while maintaining the temperature between 0° C. and 5° C. The reaction mixture was stirred at 0° C. for 20 minutes and at room temperature for 4 hours. Removal of the solvent under reduced pressure was ensued by acidification of the residue with 2N HCl (600 mL). The mixture was stirred at room temperature for 16 hours and filtered. The green filtrate was made basic (pH 10–11) using concentrated NH4OH (150 mL) and extracted with diethylether (3×200 mL). The ethereal extracts were successively washed with water (2×300 mL), a saturated aqueous solution of NaCl (150 mL), dried over MgSO4 and filtered. Removal of the solvent under reduced pressure gave 6-methyl-1,2,3,4-tetrahydroquinoxaline as a solid (880 mg, 43%).
Reaction SMILES: C(N(CCCC)CCCC)CCC.C(O)=O.I[C:18]1[C:19]([O:32][CH2:33][C:34]([C:36]2[S:40][CH:39]=[C:38]([C:41]([O:43][CH3:44])=[O:42])[CH:37]=2)=[CH2:35])=[CH:20][C:21]2[C:22]([CH3:31])([CH3:30])[CH2:23][CH2:24][C:25]([CH3:29])([CH3:28])[C:26]=2[CH:27]=1>C(#N)C.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[CH3:35][C:34]1([C:36]2[S:40][CH:39]=[C:38]([C:41]([O:43][CH3:44])=[O:42])[CH:37]=2)[CH2:33][O:32][C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][C:18]1=2)[C:25]([CH3:29])([CH3:28])[CH2:24][CH2:23][C:22]3([CH3:31])[CH3:30]
Reactant: C=C(COc1cc2c(cc1I)C(C)(C)CCC2(C)C)c1cc(C(=O)OC)cs1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCCCN(CCCC)CCCC
Solvent: CC#N
Solvent: O=CO
Product: COC(=O)c1csc(C2(C)COc3cc4c(cc32)C(C)(C)CCC4(C)C)c1
Temperature: 60 °C

Procedure:
A mixture of tributylamine (3.64 ml, 25.16 mmol), palladium diacetate (74 mg, 0.33 mmol), formic acid (0.28 ml, 7.28 mmol) and methyl 5-[1-(3-iodo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yloxymethyl)-vinyl]-3-thiophenecarboxylate (3.38 g, 6.62 mmol) in acetonitrile (100 ml), was heated at 60° C. for 4 h. The reaction medium was concentrated in a rotary evaporator under vacuum at 40° C., treated with water and extracted with ethyl ether. After decantation, the organic phase was washed twice with water, dried over magnesium sulfate and concentrated in a rotary evaporator under vacuum at 40° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]([NH:17]C(=O)C)([CH3:16])[CH3:15])[N:11]=[C:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH:9]=2)[CH:5]=[N:6][CH:7]=1.Cl.[OH-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]([NH2:17])([CH3:15])[CH3:16])[N:11]=[C:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CC(=O)NC(C)(C)c1cc(-c2cncc(Br)c2)cc(-c2ccccn2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(N)c1cc(-c2cncc(Br)c2)cc(-c2ccccn2)n1

Procedure:
N-[1-(5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-1-methyl-ethyl]-acetamide (Example 2.97; step1) (1 eq, 0.151 mmol, 62 mg) and SM HCl (20 eq, 3.01 mmol, 0.602 ml) are heated together at 100° C. overnight. The pH of the reaction mixture is adjusted to 8-9 by addition of sodium hydroxide (2M). The solution is dissolved in DCM and washed with water. The combined organic extracts are washed with brine, dried over MgSO4 and concentrated in vacuo to afford the title compound; [M+H]+ 369/371
Reaction SMILES: CN(C)C=O.Br[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].[I:18][C:19]1[CH:24]=[C:23]([I:25])[CH:22]=[C:21]([I:26])[C:20]=1[OH:27].C(=O)([O-])[O-].[K+].[K+]>O>[I:18][C:19]1[CH:24]=[C:23]([I:25])[CH:22]=[C:21]([I:26])[C:20]=1[O:27][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)CCCCCCBr
Reactant: Oc1c(I)cc(I)cc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCCCOc1c(I)cc(I)cc1I
Temperature: 25 °C
Reaction time: 24 h
Yield: 187.8 %

Procedure:
Dimethylformamide (DMF, 20 mL) was added with ethyl 7-bromoheptanoate (4.7 g) and 2,4,6-triiodophenol (2.4 g), further added with potassium carbonate (2.1 g) and stirred at room temperature for one day. The reaction solution was added with water and extracted twice with ethyl acetate, and the organic layer was washed three times with water and dried over anhydrous magnesium sulfate. Then, the solvent was removed, and the resulting residue was purified by silica gel column chromatography to obtain ethyl 7-(2,4,6-triiodophenoxy)heptanoate (6.0 g, yield: 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([N:21]([CH2:24]C)[CH2:22]C)[C:11](=[O:26])[C@:10]([CH2:28][C:29]([O:31]C)=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.CI>>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([N:21]([CH3:22])[CH3:24])[C:11](=[O:26])[C@:10]([CH2:28][C:29]([OH:31])=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)N1C(=O)[C@@](C)(CC(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Solvent: CI
Product: CN(C)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1

Procedure:
Methyl 2-((3R,5R,6S)-1-amino-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetate (Example 429 step C) was treated by a procedure similar to the one described in Example 429, using methyl iodide instead of ethyl iodide in Step C.
Reaction SMILES: [F:1][C@H:2]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][NH:4][CH2:3]1.CCN(C(C)C)C(C)C.CS(O[C@H:29]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=2)[C:30]1=[O:42])(=O)=O>CC#N>[F:1][C@H:2]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C@@H:29]2[CH2:33][CH2:32][N:31]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)[C:30]2=[O:42])[CH2:3]1
Reactant: Oc1ccc([C@H]2CCNC[C@H]2F)cc1
Reactant: Cc1ccc(CN2CC[C@H](OS(C)(=O)=O)C2=O)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(CN2CC[C@@H](N3CC[C@H](c4ccc(O)cc4)[C@H](F)C3)C2=O)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 28.7 %

Procedure:
To a solution of cis-4-(3-fluoropiperidin-4-yl)phenol (60 mg, 0.31 mmol) in 1.0 mL of CH3CN and DIPEA (0.2 mL, 1.2 mmol) at 80° C. was added a solution of (S)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl methanesulfonate (87 mg, 0.3 mmol) in 0.5 mL of CH3CN over 1.5 h. The mixture was then stirred at 80° C. for 16 h. The mixture was allowed to cool to rt and then concentrated. The residue was purified via silica gel chromatography (4 g of silica) eluting with a gradient of 0-100% EtOAc in hexanes to give a mixture of two diastereomers, which were further separated via chiral HPLC under the following conditions: Chiralcel OD column (21×250 mm, 10μ) eluting with an isocratic mixture of 30% B where solvent A=0.1% diethylamine in n-heptane and solvent B=100% ethanol. The absolute stereochemistry of the 2 products has not been assigned and is shown and named for convenience. The first eluting isomer (Example 112, P-1) was (R)-3-((3S,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (33.8 mg, 0.086 mmol, 28% yield). 1H NMR (500 MHz, methanol-d4) δ 7.21-7.07 (m, 6H), 6.78-6.68 (m, 2H), 4.70 (d, J=48.8 Hz, 1H), 4.41 (dd, J=58.0, 14.5 Hz, 2H), 3.61 (t, J=8.8 Hz, 1H), 3.30-3.03 (m, 5H), 2.77-2.60 (m, 1H), 2.51 (t, J=11.1 Hz, 1H), 2.32 (s, 3H), 2.31-2.15 (m, 2H), 2.01 (dq, J=13.2, 8.4 Hz, 1H), 1.69 (dd, J=13.1, 2.6 Hz, 1H), (M+H)+=383.25. HPLC RT under separation conditions=8.87 min. The second eluting isomer (Example 112, P-2) was (R)-3-((3R,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (35.2 mg, 0.084 mmol, 27.3% yield), 1H NMR (500 MHz, methanol-d4) δ 7.19-7.08 (m, 6H), 6.74 (d, J=8.4 Hz, 2H), 4.66 (d, J=47.9 Hz, 1H), 4.41 (dd, J=53.7, 14.8 Hz, 2H), 3.58 (t, J=8.8 Hz, 1H), 3.42 (t, J=10.8 Hz, 1H), 3.30-3.14 (m, 2H), 3.05-2.88 (m, 2H), 2.79-2.51 (m, 2H), 2.33 (s, 3H), 2.31-2.13 (m, 2H), 2.06-1.90 (m, 1H), 1.67 (d, J=10.8 Hz, 1H), (M+H)+=383.25. HPLC RT under separation conditions=11.97 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][N:5]2[C:9]([CH:10]=1)=[C:8]([C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:7]([CH3:21])=[C:6]2[C:22](=[O:34])[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[C:25]([O:32][CH3:33])[CH:24]=1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>>[C:35]([NH:1][C:2]1[CH:3]=[CH:4][N:5]2[C:9]([CH:10]=1)=[C:8]([C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:7]([CH3:21])=[C:6]2[C:22](=[O:34])[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[C:25]([O:32][CH3:33])[CH:24]=1)(=[O:37])[CH3:36]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(C(=O)c2c(C)c(C(=O)OCc3ccccc3)c3cc(N)ccn23)ccc1[N+](=O)[O-]
Product: COc1cc(C(=O)c2c(C)c(C(=O)OCc3ccccc3)c3cc(NC(C)=O)ccn23)ccc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
A suspension of 1.5 g (3.26 mmol) of benzyl [7-amino-3-(3-methoxy-4-nitrobenzoyl)-2-methylindolizin-1-yl]carboxylate in 10 mL of acetic anhydride is heated at 100° C. for 15 minutes.
Reaction SMILES: [CH3:1][CH:2]([C:4]12[CH2:10][CH:9]1[C:7](=[O:8])[CH2:6][CH2:5]2)[CH3:3].[CH:11](C1CCC(=O)C=1)(C)C>>[CH3:1][CH:2]([C:4]12[CH2:10][CH:9]1[C:7]([OH:8])([CH3:11])[CH2:6][CH2:5]2)[CH3:3]
Reactant: CC(C)C1=CC(=O)CC1
Reactant: CC(C)C12CCC(=O)C1C2
Product: CC(C)C12CCC(C)(O)C1C2
Yield: 57 %

Procedure:
In the process, however, a relatively greater number of steps have to be pursued up to the course of synthesis of sabina ketone (6). In addition, since sabine ketone is obtainable from the starting material 3-isopropyl-2-cyclopenten-1-one only in about 57% yield, the total yield of sabinene hydrate results in lower value. Moreover, according to the process, operations and works are complicated and laborious, as it requires isolation procedures for each intermediate. Further, it is necessary to use valuable reagents and chromate compound hazardous in handling. Therefore, sabinene hydrates cannot be produced efficiently or economically, in particular, in large scale. Furthermore, by the process, cis-sabinene hydrate (formula 8) is produced preferentially and trans-sabinene hydrate (formula 7) appears only in a considerably minor amount. That is to say, a ratio of formation of trans-compound to cis-compound is 1:8.5, so that the process does not suit an industrial synthesis of trans-sabinene hydrate. Also, yield of trans- and cis-sabinene hydrates from sabina ketone is about 11%, and yield from 3-isopropyl-2-cyclopenten-1-one is about 6.3%.
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C)C=O.O[CH:11]([C:13]1[CH:25]=[CH:24][C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][C:15]=2[CH:14]=1)[CH3:12]>C(Cl)Cl>[Cl:3][CH:11]([C:13]1[CH:25]=[CH:24][C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][C:15]=2[CH:14]=1)[CH3:12]
Reactant: CC(O)c1ccc2c(c1)Cc1ccccc1-2
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(Cl)c1ccc2c(c1)Cc1ccccc1-2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Thionyl chloride (1.1 ml) and catalytically effective amount of N,N-dimethylformamide were added to a solution of 2-(1-hydroxyethyl)-9H-fluorene (1.05 g) in methylene chloride (15 ml) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes and then heated under reflux for 1 hour. By evaporating the solvent under reduced pressure, 2-(1-chloroethyl)-9H-fluorene was obtained.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:14]([C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH2:25][CH2:26][NH:27][C:28](=[O:42])[C:29]3[CH:34]=[CH:33][C:32]([C:35]4[CH:40]=[CH:39][N:38]=[C:37](Cl)[N:36]=4)=[CH:31][CH:30]=3)[CH:23]=2)[NH:18][CH:17]=1)#[N:15]>>[C:14]([C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH2:25][CH2:26][NH:27][C:28](=[O:42])[C:29]3[CH:34]=[CH:33][C:32]([C:35]4[CH:40]=[CH:39][N:38]=[C:37]([NH:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][N:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)[N:36]=4)=[CH:31][CH:30]=3)[CH:23]=2)[NH:18][CH:17]=1)#[N:15]
Reactant: NCCCCCCN1CCCCC1
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Product: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(NCCCCCCN5CCCCC5)n4)cc3)cc12

Procedure:
Using 6-piperidin-1-ylhexylamine (reference example 93f) and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates. MS (ion spray) m/z 550 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:15]=2)[C:10]([C:25]2[N:26]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:27]3[C:32]([CH:33]=2)=[CH:31][C:30]([OH:34])=[CH:29][CH:28]=3)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[Br:48][CH2:49][CH2:50]Br>>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:14][CH:15]=2)[C:10]([C:25]2[N:26]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:27]3[C:32]([CH:33]=2)=[CH:31][C:30]([O:34][CH2:50][CH2:49][Br:48])=[CH:29][CH:28]=3)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrCCBr
Reactant: CC(C)(C)OC(=O)n1nc(-c2cc3cc(O)ccc3n2C(=O)OC(C)(C)C)c2cc(OCc3ccccc3)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)(C)OC(=O)n1nc(-c2cc3cc(OCCBr)ccc3n2C(=O)OC(C)(C)C)c2cc(OCc3ccccc3)ccc21
Temperature: 25 °C

Procedure:
A suspension of 2.22 g of 5-benzyloxy-3-(1-tert-butoxycarbonyl-5-hydroxy-1H-indol-2-yl)indazole-1-carboxylic acid tert-butyl ester and of 3.90 g of cesium carbonate in 22 ml of 1,2-dibromoethane is heated at 80° C. for 40 hours and then cooled to ambient temperature and evaporated under reduced pressure in a rotary evaporator. The reaction crude is purified by flash chromatography (silica 40-63 μm), eluent: dichloromethane; 2 g of 5-benzyloxy-3-[5-(2-bromoethoxy)-1-tert-butoxycarbonyl-1H-indol-2-yl]-indazole-1-carboxylic acid tert-butyl ester are isolated.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1.[CH2:22]([Sn](CCCC)(CCCC)C=C)[CH2:23]CC.[NH4+].[Cl-].CCOC(C)=O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:22]([C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1)=[CH2:23]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Brc1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=Cc1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 20.7 %

Procedure:
To a degassed solution 6-((6-bromo-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quinoline (22.2) (1.2 g, 3.52 mmol) in DMF (10 mL) was added Pd(PPh3)4 (610 mg, 0.528 mmol). The solution was stirred for 20 min, then tributyl(vinyl)stannane (1.227 g, 3.87 mmol) was added. The reaction mixture was heated at 120° C. for 5 h. Aqueous NH4Cl solution was added to quench the reaction, followed by addition of EtOAc. The mixture was filtered through celite and the filtrate was washed with saturated NaHCO3 and NH4Cl solutions. The organic layer was separated, dried over Na2SO4 and concentrated to give the crude product, which was purified with Analogix system on silica gel (hexanes:EtOAc) to afford 210 mg (20%) of the title compound. LCMS (method B): [MH]+=288, tR=2.05 min.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH2:7].Cl[CH2:13][CH2:14][O:15][CH2:16][CH2:17][OH:18].C(N(CC)CC)C>CN(C)C=O>[OH:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][NH:7][C:6]1[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=1[O:4][CH2:3][CH2:2][OH:1]
Reactant: OCCOCCCl
Reactant: Nc1ccccc1OCCO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: OCCOCCNc1ccccc1OCCO
Temperature: 90 °C
Reaction time: 96 h
Yield: 53 %

Procedure:
6 g (39.17 mmol) 2-(2-hydroxyethoxy)aniline A3, 5 ml (5.85 g, 47 mmol) 2-(2-chloroethoxy)ethanol and 8.19 ml (5.95 g, 58.75 mmol) triethylamine were dissolved in 20 ml dimethylformamide and stirred for 4 days at 90° C. After cooling, the solution was filtered, the precipitate washed with dichioromethane and the filtrate concentrated in vacuo. The residue was taken up in chloroform and washed twice with a small quantity of water. The chloroform solution was then dried over sodium sulfate and concentrated. The viscous crude product was purified by column chromatography on silica gel 60 with toluene/acetone 1:2 as the mobile phase. 5 g of brown, viscous oil were obtained; yield 53%.
Reaction SMILES: Br[CH:2](Br)[C:3]1[C:4]([CH3:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.[CH3:11][CH:12]1[CH2:16][CH2:15][CH:14]([CH3:17])[C:13]1=[O:18]>>[CH3:11][C:12]12[C:13](=[O:18])[C:14]([CH3:17])([CH2:15][CH2:16]1)[CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2]2
Reactant: Cc1ccccc1C(Br)Br
Reactant: CC1CCC(C)C1=O
Product: CC12CCC(C)(Cc3ccccc3C1)C2=O

Procedure:
A process for the preparation of the compounds of the present invention which are substituted by alkyl substituents, e.g., methyl substituents in the 8 and/or 11 positions, begins with the treatment of an α,α-dihaloxylene with an alkylated or dialkylated derivative of the appropriate cycloalkanone-enamine. Thus, for example, α,α-dibromoxylene is treated with the pyrrolidine enamine of 2,5-dimethylcyclopentanone to produce the corresponding 6,9-dimethyl-5,6,7,8,9,10-hexahydro-6,9-methanobenzocyclooctene-11-one, followed by thallation as described hereinabove, to introduce the corresponding 2'-hydroxy compound and subsequent conversion to the oxime, followed by catalytic reduction to the desired d,1-11-endo-amino-6,9-dimethyl-5,6,7,8,9,10-hexahydro-6,9-methanobenzocyclooctene.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[F:18][C:19]([F:32])([F:31])[CH2:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([C:28](O)=[O:29])=[N:26][CH:27]=1>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:28]([C:25]3[CH:24]=[CH:23][C:22]([O:21][CH2:20][C:19]([F:32])([F:31])[F:18])=[CH:27][N:26]=3)=[O:29])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Reactant: O=C(O)c1ccc(OCC(F)(F)F)cn1
Product: C[C@]1(c2cc(NC(=O)c3ccc(OCC(F)(F)F)cn3)ccc2F)N=C(N)OC[C@@H]1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and 5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid following procedure I yielded the title compound as a white solid. MS (ISP): m/z=445.3 [M+H]+.
Reaction SMILES: O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:12][O:13][C:14]1[CH:56]=[CH:55][C:17]([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[N:31]=[CH:30][C:29]([C:32]4[N:33]([CH2:47][O:48][CH2:49][CH2:50][Si:51]([CH3:54])([CH3:53])[CH3:52])[CH:34]=[C:35]([C:37](OCC5C=CC=CC=5)=[O:38])[N:36]=4)=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)=[CH:16][CH:15]=1.S([O-])([O-])(=O)=O.[Na+].[Na+]>O>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][O:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[N:31]=[CH:30][C:29]([C:32]4[N:33]([CH2:47][O:48][CH2:49][CH2:50][Si:51]([CH3:53])([CH3:52])[CH3:54])[CH:34]=[C:35]([CH2:37][OH:38])[N:36]=4)=[CH:28][CH:27]=3)=[CH:24][CH:25]=2)=[CH:55][CH:56]=1
Reactant: COc1ccc(COc2ccc(-c3ccc(-c4nc(C(=O)OCc5ccccc5)cn4COCC[Si](C)(C)C)cn3)cc2)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(COc2ccc(-c3ccc(-c4nc(CO)cn4COCC[Si](C)(C)C)cn3)cc2)cc1
Reaction time: 0.5 h

Procedure:
To a tetrahydrofuran (40 mL) suspension of lithium aluminum hydride (0.24 g) was added dropwise a tetrahydrofuran (30 mL) solution of benzyl 2-(6-{4-[(4-methoxybenzyl)oxy]phenyl}pyridin-3-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-4-carboxylate (2 g) under ice-cooling. After stirring for 30 minutes, sodium sulfate (720 mg) and water (0.48 mL) were added to the mixture. The mixture was stirred at room temperature for 1 hour, and filtered. The filtrate was concentrated under reduced pressure, the obtained residue was pulverized by adding ether, and collected by filtration to obtain [2-(6-{4-[(4-methoxybenzyl)oxy]phenyl}pyridin-3-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-4-yl]methanol.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C@@H:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@H:21]3[S:20][CH2:19][CH:18]2[OH:36])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[C:44](OC(=O)C)(=[O:46])[CH3:45]>N1C=CC=CC=1>[C:1]1([CH:7]([O:14][C:15]([C@@H:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@H:21]3[S:20][CH2:19][CH:18]2[O:36][C:44](=[O:46])[CH3:45])=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2[C@@H]1SCC(O)[C@@H]2C(=O)OC(c1ccccc1)c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)OC1CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Reaction time: 16 h

Procedure:
A mixture of 0.312 g of 3 -hydroxy-7β-phenylacetylamino-cepham-4α-carboxylic acid diphenylmethyl ester in 15 ml of pyridine and 7 ml of acetic anhydride is left to stand for 16 hours at 0° C and after addition of 50 ml of toluene is evaporated under reduced pressure. The residue is taken up in ethyl acetate; the organic solution is washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried over sodium sulphate and evaporated under reduced pressure. The residue is purified by means of preparative thin layer chromatography; a silica gel plate of 100 cm length is used and development is carried out with a 1:1 mixture of toluene and ethyl acetate. 3 -Acetoxy-7β-phenylacetylaminocepham-4α-carboxylic acid diphenylmethyl ester of Rf = 0.47 is obtained, melting at 162°-164° C after crystallisation from a mixture of methylene chloride and pentane; [α]D20 = + 55° ± 1° (c = 0.492 in chloroform); ultraviolet absorption spectrum (in 95% strength ethanol): λmax = 253 mμ (ε = 700), 258 mμ (ε = 820) and 265 mμ (ε = 660): infrared absorption spectrum (in methylene chloride): characteristic bands at 2.96μ, 5.66μ, 5.77μ, 5.97μ, 6.28μ and 6.71μ.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19](O)=[O:20])[CH2:13][CH2:12]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:19](=[O:20])[CH2:18][CH2:17][N:14]2[CH2:13][CH2:12][N:11]([CH3:10])[CH2:16][CH2:15]2)=[N:6][CH:7]=1
Reactant: NNc1ccc(F)cn1
Reactant: CN1CCN(CCC(=O)O)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CN1CCN(CCC(=O)NNc2ccc(F)cn2)CC1
Reaction time: 18 h
Yield: 70.3 %

Procedure:
5-fluoro-2-hydrazinopyridine (295 mg, 2.32 mmol) and 3-(4-methyl-1-piperazinyl)propionic acid (400 mg, 2.32 mmol) were dissolved in DCM (15 mL). EDC (536 mg, 2.79 mmol) and HOBt (31.0 mg, 0.23 mmol) were added and the reaction stirred for 18 h. The mixture was loaded onto an SCX-2 cartridge, which was washed with MeOH product eluted with 2M NH3 in MeOH. Further purification by FCC, using 0-10% [2M NH3 in MeOH] in DCM, afforded the title compound (458 mg, 1.63 mmol, 73%). 1H NMR (400 MHz, CDCl3): 2.32 (3H, s), 2.48-2.54 (2H, t, J 6.0), 2.54-2.70 (8H, br s), 2.69-2.75 (2H, t, J 6.0), 6.60-6.65 (1H, dd, J 8.9, 3.3), 6.75-6.78 (1H, d, J 4.4), 7.25-7.34 (1H, m), 8.02-8.05 (1H, d, J 3.0), 10.50 (1H, s).