Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23](O)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[F:26][C:27]([F:31])([F:30])[CH2:28][NH2:29]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([NH:29][CH2:28][C:27]([F:31])([F:30])[F:26])=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1-c1ccc(F)cc1
Reactant: NCC(F)(F)F
Product: CC(C)(C)n1ncc(-c2nc(CC(=O)NCC(F)(F)F)cs2)c1-c1ccc(F)cc1

Procedure:
Using 2-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetic acid and 2,2,2-trifluoroethanamine and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([F:20])[CH:19]=1)[NH2:16].CC(C)([O-])C.[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH:3]=1)[NH:16][C:15]1[CH:14]=[C:13]([F:12])[CH:19]=[C:18]([F:20])[CH:17]=1
Reactant: Nc1cc(F)cc(F)c1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Cl)cc1Nc1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-chloro-2-fluoro-1-nitrobenzene (2.500 g, 14.24 mmol) and 3,5-difluoroaniline (2.206 g, 17.09 mmol) in DMF (22.61 mL) was added potassium tert-butoxide (3.20 g, 28.5 mmol) under argon and the solution was stirred at rt overnight. The solution was poured into water and extracted with DCM, and the organic extracts were purified by column chromatography on a silica gel column using 5 to 10% gradient of EtOAc in hexane as eluent to give 5-chloro-N-(3,5-difluorophenyl)-2-nitroaniline as an orange solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 6.98 (tt, J=9.34, 2.20 Hz, 1H) 7.02-7.11 (m, 3H) 7.35 (d, J=2.15 Hz, 1H) 8.14 (d, J=9.00 Hz, 1H) 9.40 (s, 1H).
Reaction SMILES: [BH4-].[Na+].[N+:3]([C:6]1[O:7][C:8]2[C:20]([CH:21]=[O:22])=[CH:19][CH:18]=[CH:17][C:9]=2[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O-:5])=[O:4].[OH-].[Na+].Cl>O.C(COC)OC>[OH:22][CH2:21][C:20]1[C:8]2[O:7][C:6]([N+:3]([O-:5])=[O:4])=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:9]=2[CH:17]=[CH:18][CH:19]=1
Reactant: O=Cc1cccc2c(-c3ccccc3)c([N+](=O)[O-])oc12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=[N+]([O-])c1oc2c(CO)cccc2c1-c1ccccc1
Reaction time: 0.5 h

Procedure:
To a stirred mixture of 0.11 g. of sodium borohydride in 5 ml. of glyme is added dropwise 1.7 g. (0.0064 mole) of 2-nitro-3-phenyl-7-benzofuranaldehyde in 45 ml. of glyme. After 30 minutes, a small portion of 10 percent sodium hydroxide solution is added, then 20 ml. of water, then enough 6N hydrochloric acid to acidify the mixture. The mixture is then extracted with dichloromethane, the extracts are washed twice with water and dried. Evaporation provides a residue which solidifies. Recrystallization twice from a benzene-hexane mixture provides yellow 7-hydroxymethyl-2-nitro-3-phenylbenzofuran, m.p. 128.5°-130° C.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[C:12]([C:23]([NH2:25])=[O:24])[CH:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[NH:10][N:9]=2)[CH2:4][CH2:3]1.[CH2:26]([S:28](Cl)(=[O:30])=[O:29])[CH3:27].C(N(CC)CC)C>C(Cl)Cl>[CH2:26]([S:28]([N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[C:12]([C:23]([NH2:25])=[O:24])[CH:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[NH:10][N:9]=2)[CH2:4][CH2:3]1)(=[O:30])=[O:29])[CH3:27]
Reactant: CCS(=O)(=O)Cl
Reactant: NC(=O)c1cc(-c2cccnc2)cc2c(C3CCNCC3)n[nH]c12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4cccnc4)cc23)CC1

Procedure:
This compound was prepared in a fashion analogous to the procedure described in Example 3. Thus 3-(4-piperidinyl)-5-(3-pyridinyl)-1H-indazole-7-carboxamide hydrochloride (Intermediate 21) (0.09 mmol) was reacted with ethane sulfonyl chloride (0.01 mL, 0.217 mmol) in the presence of triethylamine (0.04 mL, 0.468 mmol) in methylene chloride (10 mL) to give the title compound (4.9 mg, 13% for the last two steps)
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20](=[N:26][OH:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(Cl)Cl.C(OCC)(=O)C>[OH:27][N:26]=[C:20]([CH2:19][C:4]1[C:3]2[C:7](=[CH:8][C:9]([Br:11])=[CH:10][C:2]=2[Br:1])[NH:6][CH:5]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: Brc1cc(Br)c2cc[nH]c2c1
Reactant: CCOC(=O)C(CBr)=NO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)C(Cc1c[nH]c2cc(Br)cc(Br)c12)=NO

Procedure:
Mix 4,6-dibromoindole (2.09 g, 7.58 mmol), potassium carbonate (1.57 g, 11.4 mmol) and anhydrous methylene chloride (30 mL). Stir and add a solution of ethyl 3-bromo-2-hydroxyiminopropanoate (1.59 g, 7.58 mmol) in methylene chloride (20 mL). Stir under a nitrogen atmosphere for 48 hours. Take the solution up in ethyl acetate and wash with water (100 mL), saturated sodium hydrogen carbonate (100 mL) and brine (100 mL). Dry (MgSO4) and evaporate the solvent in vacuo and purify by silica gel chromatography to give the title compound.
Reaction SMILES: [CH:1]1([C:4]2[C:5]3[N:6]([CH:20]=[CH:21][N:22]=3)[CH:7]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)[CH:9]=2)[CH2:3][CH2:2]1.[I:23]Cl>>[CH:1]1([C:4]2[C:5]3[N:6]([C:20]([I:23])=[CH:21][N:22]=3)[CH:7]=[C:8]([C:10]3[CH:11]=[CH:12][C:13]([C:16]([F:18])([F:17])[F:19])=[CH:14][CH:15]=3)[CH:9]=2)[CH2:2][CH2:3]1
Reactant: ClI
Reactant: FC(F)(F)c1ccc(-c2cc(C3CC3)c3nccn3c2)cc1
Product: FC(F)(F)c1ccc(-c2cc(C3CC3)c3ncc(I)n3c2)cc1
Yield: 99 %

Procedure:
Prepared from 8-cyclopropyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (example C.25 step 4) (2.2 g, 7 mmol) and iodine monochloride as described in example C.20 step 3. Obtained the title compound as a grey solid (3.1 g, 99%). MS (ISP) 429.2 [(M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[C:10]([CH3:14])[NH:11]2)=[CH:7][CH:6]=1)=[O:4].[Cl:15][C:16]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:17]=1[CH2:18]Cl>O1CCOCC1.[Ag-]=O>[Cl:15][C:16]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:17]=1[CH2:18][C:9]1[C:8]2[C:12](=[CH:13][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)[NH:11][C:10]=1[CH3:14]
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: COC(=O)c1ccc2cc(C)[nH]c2c1
Agent: O=[Ag-]
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(Cc3ccc(Cl)cc3Cl)c(C)[nH]c2c1
Temperature: 90 °C
Yield: 20.6 %

Procedure:
6-(Methoxycarbonyl)-2-methylindole (3.03 g), 2,4-dichlorobenzyl chloride (4.69 g) and silver(I) oxide (5.56 g) are suspended in 1,4-dioxane (50 ml), and stirred under heat at 90° C. for 19.5 hours. The solid is separated through filtration, and the filtrate is concentrated. The resulting residue is purified through silica gel column chromatography to obtain 3-(2,4-dichlorobenzyl)-6-(methoxycarbonyl)-2-methylindole (58) (1.15 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([Cl:20])[CH:19]=3)[N:12]=[C:11]([C:21]([OH:23])=O)[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C([C:43]([N:45]3[CH2:49][C:48](=[O:50])[NH:47][CH2:46]3)=O)C=2)C=C(F)C=1.O=C1CNCCN1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([Cl:20])[CH:19]=3)[N:12]=[C:11]([C:21]([N:47]3[CH2:46][CH2:43][NH:45][CH2:49][C:48]3=[O:50])=[O:23])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2cncc(Cl)c2)n1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccccn3)n2)CN1
Agent: O=C1CNCCN1
Product: O=C1CNCCN1C(=O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2cncc(Cl)c2)n1

Procedure:
75 mg (0.21 mmol) of the compound of Example 26A is reacted analogously to the synthesis of the compound of Example 1 with 23 mg (0.23 mmol) of 2-oxopiperazine. 77 mg (83% of theory) of the title compound is obtained.
Reaction SMILES: O[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.CN(C)C=O.P(Br)(Br)([Br:19])=O.N1C=CC=CC=1>C1(C)C=CC=CC=1.O>[Br:19][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1
Reactant: O=P(Br)(Br)Br
Reactant: O=[N+]([O-])c1cc(Br)cnc1O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc(Br)cnc1Br
Temperature: 25 °C
Reaction time: 14 h

Procedure:
2-Hydroxy-3-nitro-5-bromopyridine (1 eq) was suspended in toluene (3 vol) and N,N-dimethylformamide (0.1 eq) was added. The mixture was protected from light. A solution of phosphorus oxybromide (1.2 eq) in toluene (2 vol) was added to the pyridine mixture over 1.5 h at about 90° C. and the reaction was aged for about 14 h at 90° C. The reaction mixture was cooled to room temperature and water (10 vol) and toluene (5 vol) were added. The layers were cut and the organic layer was washed with 1N NaOH (2×10 vol) and H2O (5 vol). The batch was concentrated under reduced pressure to yield the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=[C:7]([CH3:21])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:20])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:19])[C:16]([OH:18])=O)=[O:5])[CH3:2].[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH2:1]([O:3][C:4]([CH:6]=[C:7]([CH3:21])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:20])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:19])[C:16]([N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)C=C(C)CCC=C(C)CCC=C(C)C(=O)O
Reactant: C1CCNCC1
Product: CCOC(=O)C=C(C)CCC=C(C)CCC=C(C)C(=O)N1CCCCC1

Procedure:
Starting materials: 11-ethoxycarbonyl-2,6,10-trimethyl-2,6,10-undecatrienoic acid and piperidine.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([NH:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:14]([CH:16]=1)[NH2:15].Cl.[Cl:25][C:26]([Cl:32])([Cl:31])[C:27](=N)OC.O>C(O)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]2[N:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:27]([C:26]([Cl:32])([Cl:31])[Cl:25])=[N:15][C:14]=2[CH:16]=1
Reactant: COC(=N)C(Cl)(Cl)Cl
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NC1CCOCC1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: ClC(Cl)(Cl)c1nc2cc(-c3nc4ccccc4o3)ccc2n1C1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.5 %

Procedure:
To a solution of 5-(benzoxazol-2-yl)-2-(tetrahydropyran-4-yl)aminoaniline (see Working Example 20-2) (150 mg, 0.485 mmol) in acetic acid (3 mL) was added methyl 2,2,2-trichloroacetimidate hydrochloride (94.1 mg, 0.533 mmol), and this was stirred at room temperature for 4 hours. After the reaction was complete, water was added, and the precipitated crystals were filtered, and after being washed with water were dried to yield the title compound (196 mg, 93% yield) as gray crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:14][C:15](=[O:20])[CH2:16][C:17]([OH:19])=O)[CH:6]=[CH:7][C:8]=1[C:9]1[O:13][CH:12]=[N:11][CH:10]=1.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:14][C:15](=[O:20])[CH2:16][C:17]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=2)=[O:19])[CH:6]=[CH:7][C:8]=1[C:9]1[O:13][CH:12]=[N:11][CH:10]=1
Reactant: Cc1cccc(N)c1
Reactant: COc1cc(NC(=O)CC(=O)O)ccc1-c1cnco1
Product: COc1cc(NC(=O)CC(=O)Nc2cccc(C)c2)ccc1-c1cnco1

Procedure:
56 was prepared from 56A by a route analogous to that used for the preparation of 5, replacing aniline with m-toluidine. LC/MS: ret. timeA=3.783 min., MS (M+H)+=366.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:10]([C:11]([C:13]2[N:14]=[C:15]([CH3:25])[S:16][C:17]=2[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:12])[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][CH:6]([CH3:26])[CH2:7]2.[F:27][C:28]([F:39])([F:38])[C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](O)=[O:33]>>[CH3:26][CH:6]1[CH2:5][C@H:4]2[C@H:8]([CH2:9][N:10]([C:11]([C:13]3[N:14]=[C:15]([CH3:25])[S:16][C:17]=3[C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)=[O:12])[C@@H:3]2[CH2:2][NH:1][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][CH:37]=[C:29]([C:28]([F:27])([F:38])[F:39])[CH:30]=2)[CH2:7]1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2cccc(C(F)(F)F)c2)c1

Procedure:
prepared by reaction of [(1S,2S,5R)-2-aminomethyl-7-methyl-3-aza-bicyclo[3.3.0]oct-3-yl]-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 3-(trifluoromethyl)-benzoic acid acid.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][C:8]([Si:11]([CH3:33])([CH3:32])[O:12][CH2:13][C@@H:14]([O:16][C:17]1[CH:18]=[C:19]([CH:28]=[C:29]([OH:31])[CH:30]=1)[C:20]([NH:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1)=[O:21])[CH3:15])([CH3:10])[CH3:9].[N:34]1([C:38]([C:40]2[CH:45]=[CH:44][C:43](Br)=[CH:42][N:41]=2)=[O:39])[CH2:37][CH2:36][CH2:35]1>CC(N(C)C)=O>[N:34]1([C:38]([C:40]2[N:41]=[CH:42][C:43]([O:31][C:29]3[CH:28]=[C:19]([CH:18]=[C:17]([O:16][C@@H:14]([CH3:15])[CH2:13][O:12][Si:11]([C:8]([CH3:9])([CH3:10])[CH3:7])([CH3:33])[CH3:32])[CH:30]=3)[C:20]([NH:22][C:23]3[S:24][CH:25]=[CH:26][N:27]=3)=[O:21])=[CH:44][CH:45]=2)=[O:39])[CH2:37][CH2:36][CH2:35]1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(O)cc(C(=O)Nc2nccs2)c1
Reactant: O=C(c1ccc(Br)cn1)N1CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Oc2ccc(C(=O)N3CCC3)nc2)cc(C(=O)Nc2nccs2)c1
Temperature: 160 °C

Procedure:
Cesium carbonate (0.478 g, 1.47 mmol) was added to a mixture of 3-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-5-hydroxy-N-1,3-thiazol-2-ylbenzamide (200 mg, 0.49 mmol), bromotris(triphenylphosphine)copper (46 mg, 0.049 mmol) and 2-(azetidin-1-ylcarbonyl)-5-bromopyridine (130 mg, 5.39 mmol) in DMA (5.0 mL) and the stirred mixture heated at 160° C. in a ‘Biotage initiator Microwave’ for 3 hours. The mixture was allowed to reach RT and pressure and was partitioned between ethyl acetate (50 mL) and water (50 mL). The ethyl acetate layer was separated, washed with water (5×50 mL), brine (50 mL), dried (MgSO4) and evaporated to a residue which was chromatographed on silica, eluting with a gradient of 0-100% ethyl acetate in isohexane, to give the desired compound. (47 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH:14]([CH3:16])[CH:13]2[CH:9]1[CH2:10][N:11](C(OCC)=O)[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>Cl>[CH2:1]([N:8]1[CH2:15][CH:14]([CH3:16])[CH:13]2[CH:9]1[CH2:10][NH:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)N1CC2C(C)CN(Cc3ccccc3)C2C1
Agent: Cl
Product: CC1CN(Cc2ccccc2)C2CNCC12

Procedure:
10 g (26.3 mmol) of ethyl 2-benzyl-4-methyl-2,7-diazabicyclo[3.3.0]octane-7-carboxylate are refluxed overnight together with 100 ml of concentrated hydrochloric acid. The mixture is concentrated, the concentrate is taken up in 20 ml of water, the mixture is rendered alkaline using potassium carbonate and extracted five times using 50 ml portions of chloroform, and the extracts are dried over potassium carbonate, concentrated and distilled.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH:13]([OH:18])[CH2:14][C:15](O)=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.O(C(C)C)C(C)C>C1COCC1.CO>[OH:18][CH:13]([CH2:14][CH2:15][OH:16])[CH2:12][NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CC(O)CNC(=O)OCc1ccccc1
Solvent: CO
Solvent: CC(C)OC(C)C
Solvent: CC(=O)O
Product: O=C(NCC(O)CCO)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1 M BH3.THF complex (80 mL, 80 mmol) was added dropwise over 30 min to a solution of 4-(((benzyloxy)carbonyl)amino)-3-hydroxybutanoic acid (prepared as described in Tetrahedron (1994), 50(47), 13347-68, 13.5 g, 53.3 mmol) in THF (53 mL) at 0° C. and the RM was stirred at RT overnight. 10% acetic acid in MeOH (250 mL) was added and the mixture was stirred at RT overnight. The solvent was evaporated off under reduced pressure and the residue was dissolved in EtOAc, washed with aq. sat. NaHCO3 solution and brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a residue was treated with iPr2O, filtered and dried to afford the title compound as a white solid. UPLC-MS (Condition 8) tR=0.61 min, m/z=240 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1H NMR (400 MHz, DMSO-d6) δ ppm 1.29-1.45 (m, 1H) 1.48-1.61 (m, 1H) 2.98 (t, J=5.56 Hz, 2H) 3.49 (dt, J=11.62, 5.56 Hz, 2H) 3.54-3.65 (m, 1H) 4.35 (t, J=5.01 Hz, 1H) 4.58 (d, J=5.26 Hz, 1H) 5.02 (s, 2H) 7.16 (t, J=5.62 Hz, 1H) 7.26-7.44 (m, 5H).
Reaction SMILES: [CH:1]1([C:6]2[NH:11][C:10](=[O:12])[C:9]([CH:13]([NH:16][C:17]([C:19]3([CH3:26])[CH2:24][CH2:23][CH:22]([CH3:25])[CH2:21][CH2:20]3)=O)[CH2:14][CH3:15])=[N:8][N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O>>[CH:1]1([C:6]2[NH:11][C:10](=[O:12])[C:9]3=[C:13]([CH2:14][CH3:15])[N:16]=[C:17]([C:19]4([CH3:26])[CH2:24][CH2:23][CH:22]([CH3:25])[CH2:21][CH2:20]4)[N:8]3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCC(NC(=O)C1(C)CCC(C)CC1)c1nnc(C2CCCC2)[nH]c1=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1nc(C2(C)CCC(C)CC2)n2nc(C3CCCC3)[nH]c(=O)c12

Procedure:
In analogy to the procedure for Example 1, 200 mg (0.55 mmol) crude N-[1-(3-cyclopentyl-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)propyl]-1,4-dimethylcyclohexanecarboxamide, 165 mg (1.1 mmol) phosphoric trichloride are stirred at reflux for 4 hours, proportionate amounts of the solvents are used. The isomers are purified by chromatography (preparative HPLC).
Reaction SMILES: S(=O)(=O)(O)O.NC1C(=O)N2C(C([O-])=O)=C(C[N+]3(C)CCCC3)CS[C@H]12.Cl.[NH2:27][CH:28]1[C:53](=[O:54])[N:30]2[C:31]([C:37]([O:39][CH:40]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[O:38])=[C:32]([CH2:35][Cl:36])[CH2:33][S:34][C@H:29]12.[CH:55](=O)[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>>[CH:55](=[N:27][CH:28]1[C:53](=[O:54])[N:30]2[C:31]([C:37]([O:39][CH:40]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)=[O:38])=[C:32]([CH2:35][Cl:36])[CH2:33][S:34][C@H:29]12)[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1
Reactant: O=Cc1ccccc1
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Agent: C[N+]1(CC2=C(C(=O)[O-])N3C(=O)C(N)[C@H]3SC2)CCCC1
Agent: Cl
Agent: O=S(=O)(O)O
Product: O=C(OC(c1ccccc1)c1ccccc1)C1=C(CCl)CS[C@@H]2C(N=Cc3ccccc3)C(=O)N12

Procedure:
Temperature stable crystalline mono-hydrochloric and sulfuric acid addition salts of 7-amino-3-(1-methylpyrrolidinio)methyl-3-cephem-4-carboxylate substantially free of Δ2 isomer are intermediates for the preparation of broad spectrum 7-[α-(2-aminothiazol-4-yl)-α-(Z)-methoxyiminoacetamido]-3-[(1-methyl-1-pyrrolidinio)methyl]-3-cephem-4-carboxylates. The monohydrochloric acid addition salt intermediate is prepared by a process comprising the steps of (1) neutralizing diphenylmethyl 7-amino-3-chloromethyl-3-cephem-4-carboxylate hydrochloride, (2) reacting the resulting free base with benzaldehyde to produce diphenylmethyl 7-benzylideneamino-3-chloromethyl-3-cephem-4-carboxylate, (3) reacting the resulting product with sodium iodide to convert the chloromethyl group to iodomethyl, (4) reacting the resulting product with N-methylpyrrolidine to give the quaternized product diphenylmethyl 7-benzylideneamino-3-(1-methylpyrrolidinio)methyl-3-cephem-4-carboxylate iodide, and (5) reacting with hydrochloric acid to form said intermediate.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1.[CH3:14][C:15]([Si:18](Cl)([CH3:20])[CH3:19])([CH3:17])[CH3:16].N1C=CN=C1.O>CN(C=O)C>[Si:18]([O:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1)([C:15]([CH3:17])([CH3:16])[CH3:14])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)Cc1ccc(CO)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92 %

Procedure:
To a solution of methyl p-hydroxymethylphenylacetate (3.30 g, 18.3 mmol, prepared according to the method of G. Biagi et al., E. Ed. Farmaco., 43, 597 (1988)) in 6.6 ml DMF was added TBDMS-Cl (3.31 g, 22.0 mmol) and imidazole (3.12 g, 45.8 mmol), and the resulting solution was stirred at ambient temperature for 18 hours. The mixture was poured into 100 ml H2O and extracted (EtOAc, 4×50 ml). The combined extracts were dried (MgSO4), filtered and concentrated. The crude material was chromatographed (EtOAc:hexane, 5:95) to afford the title compound (5.0 g, 92% yield) as an oil.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:36])[S:4]([N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[S:18][C:17]([NH:19][C:20]([N:22]([CH:29]3[CH2:34][CH2:33][CH:32]([CH3:35])[CH2:31][CH2:30]3)[CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[O:21])=[N:16][CH:15]=2)[CH2:9][CH2:8]1)(=[O:6])=[O:5].[CH:37]1([C:42](Cl)=[O:43])[CH2:41][CH2:40][CH2:39][CH2:38]1>>[CH3:2][N:3]([CH3:36])[S:4]([N:7]1[CH2:8][CH2:9][N:10]([CH2:13][C:14]2[S:18][C:17]([NH:19][C:20]([N:22]([CH:23]3[CH2:28][CH2:27][N:26]([C:42]([CH:37]4[CH2:41][CH2:40][CH2:39][CH2:38]4)=[O:43])[CH2:25][CH2:24]3)[CH:29]3[CH2:30][CH2:31][CH:32]([CH3:35])[CH2:33][CH2:34]3)=[O:21])=[N:16][CH:15]=2)[CH2:11][CH2:12]1)(=[O:5])=[O:6]
Reactant: CC1CCC(N(C(=O)Nc2ncc(CN3CCN(S(=O)(=O)N(C)C)CC3)s2)C2CCNCC2)CC1
Reactant: O=C(Cl)C1CCCC1
Agent: Cl
Product: CC1CCC(N(C(=O)Nc2ncc(CN3CCN(S(=O)(=O)N(C)C)CC3)s2)C2CCN(C(=O)C3CCCC3)CC2)CC1
Yield: 49.2 %

Procedure:
Prepared as described in general procedure (N) using 4-{2-[3-(4-methyl-cyclohexyl)-3-piperidin-4-yl-ureido]-thiazol-5-ylmethyl}-piperazine-1-sulfonic acid dimethylamide hydrochloride (50 mg, 0.088 mmol), TEA (31 μL, 0.22 mmol) and cyclopentane carbonyl chloride (13 μL, 0.11 mmol) to afford 27 mg (49%) of the desired product after purification.
Reaction SMILES: CC1C=CC=CC=1[CH2:4][CH2:5][Si:6]([CH3:21])([CH3:20])[O:7][Si:8]([CH3:19])([CH3:18])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17].C([Si](C)(C)O[Si](C)(C)C=C)=C>>[CH3:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][CH2:9][Si:8]([CH3:19])([CH3:18])[O:7][Si:6]([CH3:20])([CH3:21])[CH:5]=[CH2:4]
Reactant: Cc1ccccc1CC[Si](C)(C)O[Si](C)(C)CCc1ccccc1C
Agent: C=C[Si](C)(C)O[Si](C)(C)C=C
Product: C=C[Si](C)(C)O[Si](C)(C)CCc1ccccc1C
Reaction time: 2 h
Yield: 106.5 %

Procedure:
The following were charged to a 1 L roundbottom flask equipped with a stirrer and thermometer: 200 g 1.3-di(2-methylphenethyl)tetramethyldisiloxane as prepared in Example 3, 600 g 1,3-divinyltetramethyldisiloxane, and 5 g thoroughly dehydrated activated clay. This was followed by heating to 80° to 85° C. and stirring for 2 hours. The reaction mixture was then filtered and the filtrate was heated in vacuo to afford 160 g 1-(2-methylphenethyl)-3-vinyltetramethyldisiloxane.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1.Cl[CH:14]([O:16]C(Cl)Cl)Cl.O>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[O:16])[C:5]2[O:9][CH2:8][C:7]([CH3:10])([CH3:11])[C:6]=2[CH:12]=1
Reactant: ClC(Cl)OC(Cl)Cl
Reactant: CC1(C)COc2ccc(Br)cc21
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CC1(C)COc2c(C=O)cc(Br)cc21
Temperature: 25 °C
Yield: 62.4 %

Procedure:
To a stirred, cooled (ice-bath) solution of 5-bromo-3,3-dimethyl-2,3-dihydrobenzofuran (Intermediate 2, 0.4 g, 1.57 mmol) in anhydrous dichloromethane(4 mL), titanium tetrachloride (0.172 mL, 1.57 mmol) was added followed by dichloromethyl ether (0.14 mL, 1.57 mmol). The reaction mixture was allowed to warm to room temperature and at the end of 3 hr, the reaction mixture was poured into iced water and extracted with diethyl ether. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to a residue that on flash column chromatography using 2.5% ethyl acetate in hexane as the eluent afforded the title compound (0.25 g, 63%).