Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21](I)[C:16]2=[CH:15][N:14]=1.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[C:33]3[C:38](=[CH:39][CH:40]=2)[CH2:37][N:36]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:35][CH2:34]3)O1>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21]([C:31]3[CH:32]=[C:33]4[C:38](=[CH:39][CH:40]=3)[CH2:37][N:36]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:35][CH2:34]4)[C:16]2=[CH:15][N:14]=1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc2C1
Reactant: COc1cc(OC)c(F)c(-c2ncc3c(I)n[nH]c3n2)c1F
Product: COc1cc(OC)c(F)c(-c2ncc3c(-c4ccc5c(c4)CCN(C(=O)OC(C)(C)C)C5)n[nH]c3n2)c1F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 4, Step 2 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine and tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate. LCMS (M+H)+=524.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[S:11](Cl)(=O)=O>Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[SH:11]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1
Agent: Cl
Product: Nc1ccc(Cl)c(S)c1
Yield: 116.9 %

Procedure:
A solution of anhydrous stannous chloride (152.5 g) in conc. hydrochloric acid (150 ml) was cooled to 0° C., and 2-chloro-5-nitrobenzenesulfonyl chloride (34.3 g) was added thereto while stirring. The resultant mixture was heated at 100° C. for 15 minutes while stirring, followed by being allowed to stand. Conc. hydrochloric acid (230 ml) was added to the reaction mixture. The precipitated crystals were collected by filtration, neutralized with a 4% aqueous sodium carbonate solution and extracted with ethyl acetate. The organic layer was dried and concentrated to give 25.0 g of 2-chloro-5-aminothiophenol.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([CH3:19])[C:9]=1[NH:10][C:11]1[C:16]([Cl:17])=[CH:15][N:14]=[C:13]([Cl:18])[N:12]=1)=[O:4].C(Cl)Cl.[Br:23]N1C(=O)CCC1=O>CC(O)=O>[CH3:1][NH:2][C:3]([C:5]1[S:6][C:7]([Br:23])=[C:8]([CH3:19])[C:9]=1[NH:10][C:11]1[C:16]([Cl:17])=[CH:15][N:14]=[C:13]([Cl:18])[N:12]=1)=[O:4]
Reactant: CNC(=O)c1scc(C)c1Nc1nc(Cl)ncc1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: ClCCl
Product: CNC(=O)c1sc(Br)c(C)c1Nc1nc(Cl)ncc1Cl
Reaction time: 16 h
Yield: 30.7 %

Procedure:
To a solution of 3-(2,5-dichloro-pyrimidin-4-ylamino)-4-methyl-thiophene-2-carboxylic acid methylamide (0.22 g, 0.7 mmol) in 1:1 DCM:AcOH was added N-bromosuccinimide (0.37 g, 2.1 mmol). The mixture was stirred for 16 hours. Evaporation and chromatography on silica gel with 3:1 methylene chloride/ethyl acetate gave 85 mg of 5-bromo-3-(2,5-dichloro-pyrimidin-4-ylamino)-4-methyl-thiophene-2-carboxylic acid methylamide (31%): 1H NMR (300 MHz, CDCl3) δ 8.16 (s, 1H), 6.45 (br, 1H), 2.83 (d, 3H), 2.04 (s, 3H); MS (m/e): 395.1 (M+1).
Reaction SMILES: [H-].[Na+].[CH2:3]([CH2:10][S:11]([NH:14][CH2:15][CH2:16][OH:17])(=[O:13])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:19]1[N:24]2[CH:25]=[CH:26][N:27]=[C:23]2[CH:22]=[CH:21][CH:20]=1.O>CN(C)C=O.C(OCC)(=O)C>[CH2:3]([CH2:10][S:11]([NH:14][CH2:15][CH2:16][O:17][C:19]1[N:24]2[CH:25]=[CH:26][N:27]=[C:23]2[CH:22]=[CH:21][CH:20]=1)(=[O:13])=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=S(=O)(CCc1ccccc1)NCCO
Reactant: Clc1cccc2nccn12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=S(=O)(CCc1ccccc1)NCCOc1cccc2nccn12
Yield: 39.4 %

Procedure:
To a suspension of 60% sodium hydride in oil (0.20 g, 5 mmoles) in dimethylformamide (20 ml) was added 2-(N-benzylmethylsulfonylamino)-1-ethanol (1.14 g, 5 mmoles) with stirring under ice-cooling and the mixture was stirred at room temperature for 30 minutes. To this reaction mixture was added 5-chloroimidazo[1,2-a]pyridine (0.763 g, 5 mmoles) with stirring under ice-cooling, followed by stirring at 80° C. for 16 hours. After cooling, water was added to the reaction mixture, which was extratced with ethyl acetate and dried. After the solvent was distilled off, the residue was purified by column chromatography [eluent:ethyl acetate/hexane (1:1)→ethyl acetate/hexane (2:1)] to obtain 0.68 g of the desired product (39.4%, pale yellow oily product).
Reaction SMILES: O([C:8]1[C:21]2[C:12](=[N:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=1)C1C=CC=CC=1.[NH2:22][CH2:23][CH2:24][NH:25][CH2:26][CH2:27][OH:28]>>[CH:18]1[C:19]2[C:14](=[N:13][C:12]3[C:21]([C:20]=2[NH:22][CH2:23][CH2:24][NH:25][CH2:26][CH2:27][OH:28])=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:15]=[CH:16][CH:17]=1
Reactant: c1ccc(Oc2cccc3nc4ccccc4cc23)cc1
Reactant: NCCNCCO
Product: OCCNCCNc1c2ccccc2nc2ccccc12

Procedure:
A mixture of phenoxyacridine (S1) (2.71 g, 0.01 mol) and 2-(2-aminoethylamino)ethanol (S3)
Reaction SMILES: [I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[O:6][C:7]=1[C:8]1[CH:13]=CC=CC=1.[CH3:21][C:22](=NO)[C:23](=O)CC.C1C2C(=CC=CC=2)C=CC=1C=O>>[CH2:8]([C:7]1[O:6][C:5]([C:14]2[CH:15]=[CH:16][C:17]3[C:18](=[CH:21][CH:22]=[CH:23][CH:20]=3)[CH:19]=2)=[N:4][C:3]=1[CH2:2][I:1])[CH3:13]
Reactant: Cc1ccc(-c2nc(CI)c(-c3ccccc3)o2)cc1
Reactant: CCC(=O)C(C)=NO
Agent: O=Cc1ccc2ccccc2c1
Product: CCc1oc(-c2ccc3ccccc3c2)nc1CI

Procedure:
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, pentane-2,3-dione-2-oxime and naphthalene-2-carbaldehyde gave 5-ethyl-4-iodomethyl-2-naphthalen-2-yloxazole.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7](Cl)[N:8]=[CH:9]2)=[CH:4][CH:3]=1.[CH3:13][O-:14].[Na+]>COCCOCCOC.C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([O:14][CH3:13])[N:8]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: Clc1cc2ccc(Br)cc2cn1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: COCCOCCOC
Solvent: O
Product: COc1cc2ccc(Br)cc2cn1
Temperature: 150 °C
Yield: 87.2 %

Procedure:
A mixture of 7-bromo-3-chloroisoquinoline (100 mg, 0.4 mmol) and sodium methoxide (113 mg, 2.1 mmol) in diglyme (1 mL) was heated to 150° C. for 1 hour. The reaction was cooled to room temperature and diluted with toluene and water. The layers were separated and the aqueous layer was extracted with toluene (3×). The combined organics were washed with water and brine, dried over sodium sulfate, filtered, and concentrated to an oil. The oil was dried under vacuum overnight to give the title compound (83 mg, 85%) as a yellow solid. +ESI (M+H+1) 240.1; 1H NMR (400 MHz, CDCl3, δ): 8.87 (s, 1H), 8.01-8.05 (m, 1H), 7.58-7.64 (m, 1H), 7.53-7.58 (m, 1H), 6.97 (s, 1H), 4.02 (s, 3H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=1[CH:4]=O.[CH2:11]([NH2:14])[CH2:12][NH2:13]>O>[Br:10][C:7]1[CH:8]=[CH:9][C:2]2[NH:14][CH2:11][CH2:12][N:13]=[CH:4][C:3]=2[CH:6]=1
Reactant: NCCN
Reactant: O=Cc1cc(Br)ccc1F
Solvent: O
Product: Brc1ccc2c(c1)C=NCCN2
Temperature: 140 °C

Procedure:
A 5 mL microwave tube was charged with 2-fluoro-5-bromobenzaldehyde (1 g) and ethylenediamine (3 mL). The mixture was heated to 140° C. for 300 s using microwave irradiation. The reaction was diluted with water and extracted with diethyl ether. The organics were extracted with 1N HCl, and the pH of the aqueous layer was adjusted to ˜8 with 2.5M NaOH. The basic water layer was extracted again with diethyl ether. The organics were dried over magnesium sulfate, filtered and concentrated to dryness. Reconcentration from diethyl ether afforded 7-bromo-2,3-dihydro-1H-1,4-benzodiazepine as a yellow crystalline solid. H1 NMR (d6-dmso): 8.04 (s, 1H), 7.46 (d, 1H), 7.19 (dd, 1H), 7.07 (br t, 1H), 6.64 (d, 1H), 3.82 (m, 2H), 3.17 (m, 2H). Mass (ES+)=225.0 (100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(#N)C>[S:21]([O:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:23])(=[O:22])[CH3:20]
Reactant: COc1ccc(CO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(COS(C)(=O)=O)cc1
Reaction time: 2 h

Procedure:
Combine 4-methoxybenzyl alcohol (45.4 mmol), N,N-diisopropylethylamine (12.9 g, 100 mmol), and acetonitrile (60 mL). Cool in an ice bath. Add methanesulfonyl chloride (6.76 , 49.0 mmol). After 2 hours, partition the reaction mixture between water and ethyl acetate. Separate the layers and extract the organic layer with 1 M hydrochloric acid solution and then a saturated solution of sodium bicarbonate. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[N:10]([CH2:31][CH3:32])[CH2:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1B1OC(C)(C)C(C)(C)O1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:34]([O:36][C:37](=[O:54])[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[C:41](Br)[CH:40]=1)[CH3:35]>>[CH2:34]([O:36][C:37](=[O:54])[CH2:38][C:39]1[CH:40]=[C:41]([C:13]2[CH:14]=[CH:15][C:16]([C:18]([F:21])([F:19])[F:20])=[CH:17][C:12]=2[CH2:11][N:10]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:33])[CH2:31][CH3:32])[C:42]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[CH:43][CH:44]=1)[CH3:35]
Reactant: CCOC(=O)Cc1ccc(OCc2ccccc2)c(Br)c1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)OCc1ccccc1
Product: CCOC(=O)Cc1ccc(OCc2ccccc2)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)OCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: ethyl-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-carbamic acid benzyl ester and (4-benzyloxy-3-bromo-phenyl)-acetic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[Br:21][C:22]1[CH:23]=[C:24]([C:28](O)=[O:29])[CH:25]=[N:26][CH:27]=1>>[Br:21][C:22]1[CH:27]=[N:26][CH:25]=[C:24]([CH:23]=1)[C:28]([NH:20][C:10]1[CH:11]=[N:12][C:13]([O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH:9]=1)=[O:29]
Reactant: O=C(O)c1cncc(Br)c1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1)c1cncc(Br)c1

Procedure:
The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (example E) and 5-bromo-3-pyridinecarboxylic acid (CAN 20826-04-4) as starting materials; LC-MS (UV peak area/ESI) 92.7%, 485.9662 (M−H)−.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:18][O:19][C:20]1[N:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.O.ClCCl>ClCCl>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH:6]2[CH2:5][CH2:4][CH2:3][CH2:2][O:1]2)=[CH:24][N:25]=1
Reactant: C1=COCCC1
Reactant: COc1ccc(O)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(OC2CCCCO2)cn1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
10.1 g (119.9 mmol, 1.5 eq.) of 3,4-dihydro-2H-pyran and 1.4 g (8.0 mmol, 0.1 eq.) of 4-toluenesulphonic acid were added to a solution of 10.0 g (79.9 mmol) of 6-methoxypyridin-3-ol in 150 ml of dichloromethane, and the mixture was stirred at RT for 5 d. After addition of water/dichloromethane and phase separation, the aqueous phase was extracted with dichloromethane. The combined organic phases were dried (sodium sulphate), filtered and concentrated under reduced pressure. Yield: 17.3 g (100% of theory)
Reaction SMILES: [O:1]=[C:2]1[C@@H:7]2[CH2:8][C@@H:4]([CH:5]=[CH:6]2)[N:3]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[BH4-].[Na+].Cl>O1CCCC1.O>[OH:1][CH2:2][C@@H:7]1[CH2:8][C@H:4]([NH:3][C:9](=[O:10])[O:11][C:12]([CH3:14])([CH3:13])[CH3:15])[CH:5]=[CH:6]1
Reactant: CC(C)(C)OC(=O)N1C(=O)[C@H]2C=C[C@@H]1C2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1C=C[C@H](CO)C1
Reaction time: 2 h
Yield: 90 %

Procedure:
A solution of (1S,4R)-tert-butyl 3-oxo-2-azabicyclo[2.2.1]hept-5-ene-2-carboxylate (part a of this example, 95.50 g, 0.456 mole) in tetrahydrofuran (500 ml)-water (50 ml) was added over 10 minutes to a vigorously stirred solution of sodium borohydride (Aldrich, 21.96 g, 0.580 mole as 99%) in water (100 ml). The temperature was maintained below 35° C. After 2 hours, the solution was cooled to maintain the temperature below 25° C. while concentrated hydrochloric acid (50 ml) was added over 10 minutes. Additional water (100 ml) was added to dissolve solid and the solution was extracted with toluene (4×300 ml). The combined organic layers were washed with 9:1 saturated sodium sulfate/saturated sodium carbonate (200 ml) and dried (sodium sulfate). Evaporation of solvents under reduced pressure left a colorless syrup which crystallized on stirring with hexanes (200 ml) to provide title compound as a fine white powder (87.16 g, 90%), m.p. 72–73° C.; 1H-NMR (DMSO-d6) δ 6.78 (d, J=7.6 Hz, 1H), 5.80 and 5.60 (two m, 2H), 4.58 (t, J=5.25 Hz, 2H), 4.45 (m, 1H), 3.35 (m overlapping water), 2.60 (m, 1H), 2.30 (m, 1H), 1.38 (s, 9H), 1.20 (m, 1H); [α]58920+2.80° (c 5.0, methanol).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([CH3:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30](=[O:50])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[C:41]([CH2:42][O:43][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][O:45]3)=[N:40][CH:39]=[N:38]2)[CH:32]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:18])[CH3:19])[CH3:15])[C:11]([CH3:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30](=[O:50])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[C:41]([CH2:42][O:43][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][O:45]3)=[N:40][CH:39]=[N:38]2)[CH:32]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2ncnc2COC2CCCCO2)c1
Reactant: Cc1cc(N)c(NC(=O)OC(C)(C)C)cc1N(C)CC(C)C
Product: Cc1cc(NC(=O)CC(=O)c2cccc(-n3ncnc3COC3CCCCO3)c2)c(NC(=O)OC(C)(C)C)cc1N(C)CC(C)C

Procedure:
The title compound was prepared from [2-amino-5-(isobutyl-methyl-amino)-4-methyl-phenyl]-carbamic acid tert-butyl ester (Example J38) (1.0 g, 3.25 mmol) and (RS)-[3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,4]triazol-1-yl]-phenyl}-propionic acid tert-butyl ester (Example K24) (1.31 g, 3.25 mmol) according to the general procedure M. Obtained as a light yellow foam (970 mg, 47%).
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:26][O:27][CH2:28][CH2:29][O:30]C=O)[C:10]([NH:12][CH:13]2[C:24](=[O:25])[N:15]3[C:16]([C:21]([OH:23])=[O:22])=[C:17]([CH3:20])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl.CO>O1CCCC1>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:26][O:27][CH2:28][CH2:29][OH:30])[C:10]([NH:12][CH:13]2[C:24](=[O:25])[N:15]3[C:16]([C:21]([OH:23])=[O:22])=[C:17]([CH3:20])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCOC=O)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCO)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 45.2 %

Procedure:
A mixture of 7-[2-(2-formamidothiazol-4-yl)-2-(2-formyloxyethoxyimino)acetamido]-3-methyl-3-cephem-4-carboxylic acid (syn isomer, 2.0 g.), conc. hydrochloric acid (1.35 g.), methanol (20 ml.) and tetrahydrofuran (20 ml.) was stirred at room temperature for 6 hours. After evaporating the reaction mixture in vacuo, the residue was subjected to column chromatography on non-ionic adsoption resin "Diaion HP-20" (trademark, manufactured by Mitsubishi Chemical Industries Ltd.) and eluted with 20% isopropyl alcohol. The eluate was concentrated in vacuo to give 7-[2-(2-aminothiazol-4-yl)-2-(2-hydroxyethoxyimino)acetamido]-3-methyl-3-cephem-4-carboxylic acid (syn isomer, 0.8 g.).
Reaction SMILES: C([Cl:4])(=O)C.[CH3:5][O:6][C:7](=[O:39])[C@H:8]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32](=[O:34])[CH3:33])=[C:27]([O:35][C:36](=[O:38])[CH3:37])[CH:26]=1)[NH:9][C:10](=[O:23])[CH2:11][NH:12]C(OCC1C=CC=CC=1)=O>CO.C(O)(=O)C.Cl.CCOCC.[Pd]>[ClH:4].[CH3:5][O:6][C:7](=[O:39])[C@H:8]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32](=[O:34])[CH3:33])=[C:27]([O:35][C:36](=[O:38])[CH3:37])[CH:26]=1)[NH:9][C:10](=[O:23])[CH2:11][NH2:12]
Reactant: COC(=O)[C@H](Cc1ccc(OC(C)=O)c(OC(C)=O)c1)NC(=O)CNC(=O)OCc1ccccc1
Reactant: CC(=O)Cl
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOCC
Solvent: CC(=O)O
Product: COC(=O)[C@H](Cc1ccc(OC(C)=O)c(OC(C)=O)c1)NC(=O)CN
Temperature: 25 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
Next, 3.00 g (6.17 millimole) of the above isolated ester was dissolved in methanol (100 ml) and glacial acetic acid (5 ml). The solution was then shaken in a Parr apparatus for 16 hours over 10% Pd/C (0.4 g) under a hydrogen atmosphere (35 lbs). The solution was then filtered and concentrated in vacuo at room temperature. The residue obtained was dissolved in 10 ml of glacial acetic acid, saturated with hydrogen chloride and treated with 10 ml of acetyl chloride. The solution was stirred at room temperature overnight in a tightly sealed reaction flask and then diluted to 125 ml with ether to give a light brown gum. The ether was decanted and the residue was suspended in anhydrous ether (100 ml). The suspended solid was dispersed with a spatula and allowed to stir unit it became homogeneous. It was then filtered and the residue was dried in a vacuum oven at 60° C to yield 0.58 g (mp 80°-100° C, 24% yield) of glycyl-3,4-diacetyloxy-L-phenylalanine-methyl ester hydrochloride from carbobenzyloxyglycyl-3,4-diacetyloxy-L-phenylalanine-methyl ester. The nmr spectrum was consistent with the proposed structure of the compound obtained and upon analysis of the compound, the following data was obtained. Analysis Calculated for: C16H21O7N2Cl: C, 49.42; H, 5.44; and N, 7.21. Found: C, 49.65; H, 5.50; and N, 7.47.
Reaction SMILES: [Cl:1][C:2]1[C:6]([C:7](OC)=[O:8])=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[S:4][N:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[Cl:1][C:2]1[C:6]([CH2:7][OH:8])=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[S:4][N:3]=1
Reactant: COC(=O)c1c(Cl)nsc1-c1ccc(OC)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(-c2snc(Cl)c2CO)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Into a 25-mL round-bottom flask (1 atm) purged and maintained with an inert atmosphere of nitrogen, was placed methyl 3-chloro-5-(4-methoxyphenyl)-1,2-thiazole-4-carboxylate (450 mg, 1.59 mmol, 1.00 equiv), tetrahydrofuran (25 mL). This was followed by the addition of LAH (90 mg, 2.37 mmol, 1.50 equiv), in portions at 0° C. The resulting solution was stirred for 30 min at 0° C. in a water/ice bath. The reaction was then quenched by the addition of 2 mL of MeOH. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (20/80). This resulted in 223 mg (55%) of [3-chloro-5-(4-methoxyphenyl)-1,2-thiazol-4-yl]methanol as a light yellow solid.
Reaction SMILES: Cl.Cl.Cl.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([NH:18][C:19]2[S:20][C:21]3[CH2:22][NH:23][CH2:24][CH2:25][C:26]=3[N:27]=2)[CH:9]=[CH:10][C:11]=1[N:12]1[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]1.[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1.C(N(CC)CC)C>C(Cl)Cl>[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([N:23]2[CH2:24][CH2:25][C:26]3[N:27]=[C:19]([NH:18][C:8]4[CH:9]=[CH:10][C:11]([N:12]5[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]5)=[C:6]([O:5][CH3:4])[CH:7]=4)[S:20][C:21]=3[CH2:22]2)=[O:34])=[CH:31][CH:30]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COc1cc(Nc2nc3c(s2)CNCC3)ccc1-n1cnc(C)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(Nc2nc3c(s2)CN(C(=O)c2ccc(F)cc2)CC3)ccc1-n1cnc(C)c1

Procedure:
90 mg (0.2 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-amine trihydrochloride and 33 mg (0.2 mmol) 4-fluorobenzoyl chloride were suspended in methylene chloride (2 ml) and 101 mg (1 mmol) triethyl amine was added at room temperature. The reaction was stirred over night, diluted with methylene chloride, washed once with water, once with brine, dried over sodium sulphate, filtered and the solvent was evaporated under reduced pressure. The reaction was purified on silica gel with methylene chloride/methanol 19/1 yielding 52 mg (56%) (4-fluoro-phenyl)-{2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl}-methanone as a yellow solid. MS ISP (m/e): 464.1 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm) 10.34 (s, 1H), 7.57-7.49 (m, 3H), 7.34-7.24 (m, 4H), 7.02 (d, 1H), 4.70-4.45 (br m, 2H), 4.00-3.55 (br m, 2H), 3.78 (s, 3H), 2.73 (m, 2H), 2.14 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][N:25]1[CH:29]=[C:28]([C:30](O)=[O:31])[C:27]([CH3:33])=[N:26]1>>[Cl:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:30]([C:28]2[C:27]([CH3:33])=[N:26][N:25]([CH3:24])[CH:29]=2)=[O:31])=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c(-c2cccc(Cl)c2)s1
Reactant: Cc1nn(C)cc1C(=O)O
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cn(C)nc2C)c(-c2cccc(Cl)c2)s1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-[5-(3-chloro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 1,3-Dimethyl-1H-pyrazole-4-carboxylic acid. LC-MS (basic): tR=0.78 min; [M+H]+=470.3.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]=[C:10]([C:18](=O)[CH3:19])[C:11]([O:13][CH:14]1[CH2:17][CH2:16][CH2:15]1)=[O:12].[NH2:21][C:22]([CH2:28][F:29])=[CH:23][C:24]([O:26][CH3:27])=[O:25]>C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:10]([C:11]([O:13][CH:14]2[CH2:17][CH2:16][CH2:15]2)=[O:12])=[C:18]([CH3:19])[NH:21][C:22]([CH2:28][F:29])=[C:23]1[C:24]([O:26][CH3:27])=[O:25]
Reactant: CC(=O)C(=Cc1cccc(Cl)c1Cl)C(=O)OC1CCC1
Reactant: COC(=O)C=C(N)CF
Solvent: CCOC(C)=O
Product: COC(=O)C1=C(CF)NC(C)=C(C(=O)OC2CCC2)C1c1cccc(Cl)c1Cl
Temperature: 25 °C

Procedure:
The product of step (a) (1.7 g, 5.4 mmoles) and methyl 3-amino-4-fluoro-2-butenoate (0.72 g, 5.4 mmoles) were mixed and heated to 95° (oil bath temperature) under an atmosphere of nitrogen for 6 hours. The oil was allowed to cool to room temperature. Chromatography on silica eluting with petroleum ether (60°-80° )/ethyl acetate mixtures, afforded the title compound as a yellow solid, which was recrystallised from petroleum ether (60°-80° ) to afford the title compound 0.37 g, mp 148°-9°.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[CH:24]([C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1)([CH3:26])[CH3:25]>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:8][CH2:9][C:4]([C:1]([NH:31][C:30]4[CH:32]=[CH:33][C:27]([CH:24]([CH3:26])[CH3:25])=[CH:28][CH:29]=4)=[O:3])([CH2:11][CH2:10]2)[CH2:5][CH2:6]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: CC(C)c1ccc(N)cc1
Product: CC(C)c1ccc(NC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)cc1
Yield: 53.3 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-isopropylaniline (46.0 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-[4-(1-methylethyl)phenyl]amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (36.3 mg).