Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][N:14]([C:16]([N:18]3[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20][CH2:19]3)=[O:17])[CH2:13][CH:12]([C:26](O)=[O:27])[CH2:11]2)=[CH:6][CH:5]=1.O[N:31]=[C:32]([NH2:37])[CH2:33][CH2:34][O:35][CH3:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:29][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:11][CH:12]([C:26]3[O:27][N:37]=[C:32]([CH2:33][CH2:34][O:35][CH3:36])[N:31]=3)[CH2:13][N:14]([C:16]([N:18]3[CH2:23][CH2:22][S:21](=[O:24])(=[O:25])[CH2:20][CH2:19]3)=[O:17])[CH2:15]2)=[CH:8][CH:9]=1
Reactant: COCCC(N)=NO
Reactant: O=C(O)C1CC(c2ccc(OC(F)F)cc2)CN(C(=O)N2CCS(=O)(=O)CC2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCc1noc(C2CC(c3ccc(OC(F)F)cc3)CN(C(=O)N3CCS(=O)(=O)CC3)C2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
300 mg (0.69 mmol) of the compound from Example 37A and 246 mg (2.08 mmol) of N′-hydroxy-3-methoxypropanimidamide were initially charged in 2.6 ml of DMF and reacted with 396 mg (1.0 mmol) of HATU and 0.36 ml (269 mg, 2.1 mmol) of N,N-diisopropylethylamine. The reaction mixture was stirred at RT for 15 minutes and then partitioned between water and ethyl acetate. The organic phase was washed repeatedly with water, dried over sodium sulphate and concentrated under reduced pressure. The residue was dissolved in 2.0 ml of DMF and converted in a microwave at 180° C. for 2 minutes. The reaction mixture was purified by means of preparative HPLC. Yield: 141 mg (38% of theory)
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[OH-].[Na+].CN(C)[CH2:10][CH2:11][C:12]([C:14]1[O:15][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)=[CH:17][CH:18]=1)=O>CO>[NH2:5][C:3]([N:2]1[CH2:10][CH2:11][C:12]([C:14]2[O:15][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)=[CH:17][CH:18]=2)=[N:1]1)=[S:4]
Reactant: NNC(N)=S
Reactant: CN(C)CCC(=O)c1ccc(-c2cccc(Cl)c2)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC(=S)N1CCC(c2ccc(-c3cccc(Cl)c3)o2)=N1

Procedure:
Thiosemicarbazide (1.0 equiv.) was dissolved in MeOH upon heating under nitrogen. Aqueous sodium hydroxide (6 M, 9.0 equiv.) was added to the reaction. A methanol solution of 3-(dimethylamino)-1-[5-(3-chlorophenyl)(2-furyl)]propan-1-one (1.0 equiv) was then added dropwise to the reaction mixture. The solvent was removed and the residue was dissolved in DCM and washed with water, brine, dried over MgSO4, and concentrated. The final compound was purified by preparative-HPLC to give amino {3-[5-(3-chlorophenyl)(2-furyl)](2-pyrazolinyl)}methane-1-thione; LC/MS m/z 306.2 (MH+); Rt=3.06 minutes .
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[C:42]([CH2:47][C:48]2[S:49][C:50](Br)=[CH:51][CH:52]=2)[CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:59]1[N:64]=[CH:63][CH:62]=[CH:61][N:60]=1)CCC.O>CN1CCCC1=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[C:42]([CH2:47][C:48]2[S:49][C:50]([C:59]3[N:64]=[CH:63][CH:62]=[CH:61][N:60]=3)=[CH:51][CH:52]=2)[CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Reactant: Clc1ccc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(Br)s1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCCC1=O
Solvent: O
Product: Clc1ccc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(-c2ncccn2)s1
Temperature: 25 °C
Yield: 46.5 %

Procedure:
A mixed solution of the above 1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-3-(5bromo-2-thienylmethyl)-4-chlorobenzene 53 (200 mg), tri-n-butyl(2-pyrimidinyl)tin 54 (137 mg) and bis(triphenylphosphine)palladium(II)dichloride (9 mg) in N-methyl-2-pyrrolidinone (5 ml) was stirred at 100° C. four 7 hours under argon atmosphere. The mixture was cooled to room temperature, and water was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with water and subsequently with brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-2:1) to give 1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-4-chloro-3-(5-(2-pyrimidinyl)-2-thienylmethyl)benzene 55 (93 mg) as pale brown oil. APCI-Mass m/Z 826/828 (M+NH4).
Reaction SMILES: C(O[C:4](=[O:21])[C:5](=[CH:11][NH:12][C:13]1[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[CH2:9]([O:8][C:6]([C:5]1[C:4](=[O:21])[C:14]2[C:13](=[CH:18][CH:17]=[C:16]([O:19][CH3:20])[N:15]=2)[NH:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)C(=CNc1ccc(OC)nc1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2ccc(OC)nc2c1=O
Temperature: 25 °C
Yield: 73.1 %

Procedure:
Dowtherm A (Fluka, 500 mL) was brought to boiling (250° C.) in a 2 L 3-neck flask fitted with a still-head and a reflux condenser. 2-[(6-Methoxypyridin-3-ylamino)methylene]malonic acid diethyl ester (100 g, 0.34 mole) was added portion-wise over 5 min. The solution was heated at reflux for an additional 15 min, allowing some solvent to distil over. The resulting solution was cooled to room temperature and diluted with hexane (750 mL). The mixture was cooled in ice for 1 h, then the brown solid was filtered off, washed with hexane, and dried under vacuum to afford the title compound (61.72 g, 73%).
Reaction SMILES: C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][CH:21]=1.[NH:31]1[CH2:36][CH2:35][C:34](=[O:37])[CH2:33][C:32]1=[O:38]>CN(C)C=O.ClCCl>[F:29][C:19]([F:18])([F:30])[C:20]1[CH:21]=[CH:22][C:23]([C:24]([CH:33]2[C:34](=[O:37])[CH2:35][CH2:36][NH:31][C:32]2=[O:38])=[O:26])=[CH:27][CH:28]=1
Reactant: O=C1CCNC(=O)C1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CCNC(=O)C1C(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 15.4 %

Procedure:
Dry triethylamine (3.24 g) was added at 0°-5° C. to a stirred solution of diethyl cyanophosphate (1.96 g), 4-trifluoromethylbenzoic acid (2.28 g) and piperidine-2,4-dione (1.13 g) in dry dimethylformamide (50 ml) and the mixture stirred at ambient temperature for 5 hours. The mixture was diluted with dichloromethane (70 ml) and the solution washed successively with 2N hydrochloric acid (70 ml) and water (5×30 ml). The dichloromethane solution was dried over magnesium sulphate and evaporated under reduced pressure to give a brown solid which was recrystallised from toluene (11 ml) to give 3-(4-trifluoromethylbenzoyl)piperidine-2,4-dione (0.44 g), mp 197°-200° C., as a pale green crystalline solid.
Reaction SMILES: C([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([C:14]2[S:15][C:16]([C:19]3[C:23]([CH3:24])=[C:22]([C:25]([F:28])([F:27])[F:26])[O:21][N:20]=3)=[CH:17][CH:18]=2)=[O:13])[CH2:7]1)=O)C.[NH3:29]>>[CH3:24][C:23]1[C:19]([C:16]2[S:15][C:14]([C:12]([N:8]3[CH2:9][CH2:10][CH2:11][C@H:6]([C:4]([NH2:29])=[O:3])[CH2:7]3)=[O:13])=[CH:18][CH:17]=2)=[N:20][O:21][C:22]=1[C:25]([F:27])([F:28])[F:26]
Reactant: CCOC(=O)[C@H]1CCCN(C(=O)c2ccc(-c3noc(C(F)(F)F)c3C)s2)C1
Reactant: N
Product: Cc1c(-c2ccc(C(=O)N3CCC[C@H](C(N)=O)C3)s2)noc1C(F)(F)F
Yield: 86 %

Procedure:
A solution of (S)-1-[5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl) -thiophene-2-carbonyl]-piperidine-3-carboxylic acid ethyl ester (Example 65, 88 mg, 0.20 mmol) in 7N methanolic ammonia (5 mL) was heated at 60° C. in a sealed vial for 48 hr. After this time the reaction mixture was evaporated and triturated and filtered with the aid of water. The filtered solids were air dried to afford product as a colorless solid (67 mg, 86%). LC/MS 5.52 min, [M+1]+ 388.
Reaction SMILES: Br[CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:7][CH:6]=1)O.[CH3:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.[O:23]1CCCC1>>[N:11]1([C:8]2[CH:9]=[CH:10][C:5]([CH:3]3[CH2:2][CH:17]([CH3:16])[CH2:18][CH2:19][N:20]3[CH2:21][CH2:22][OH:23])=[CH:6][CH:7]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: CC1CCNCC1
Reactant: C1CCOC1
Reactant: OC(CBr)c1ccc(-n2ccnc2)cc1
Product: CC1CCN(CCO)C(c2ccc(-n3ccnc3)cc2)C1

Procedure:
Add α-(bromomethyl)-4-(1H-imidazol-1-yl)benzenemethanol (8.88 g, 33.24 mmol) to a room temperature solution of 4-methylpiperidine (11.8 mL, 99.73 mmol) in tetrahydrofuran (90mL). Stir the resultant mixture for 2.5 days and concentrate in vacuo. Chromatograph the residue on alumina (neutral, activity III, 100 g) using first methylene chloride than 2% methanol in methylene chloride as eluent. Collect the product fraction and concentrate in vacuo to give a solid. Recrystallize the solid from petroleum ether/ethyl acetate (ca. 4+1). Drying at 50° C. for 2 hr at p=1.0 mm affords the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[N:5][C:4](=[O:7])[N:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17](Cl)=[O:18]>[N+](C1C=CC=CC=1)([O-])=O>[CH3:1][C:2]1[NH:3][C:4](=[O:7])[NH:5][C:6]=1[C:17]([C:13]1[S:12][CH:16]=[CH:15][CH:14]=1)=[O:18]
Reactant: CC1=NC(=O)N=C1
Reactant: O=C(Cl)c1cccs1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: Cc1[nH]c(=O)[nH]c1C(=O)c1cccs1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of 7.3 g of 4-methylimidazol-2-one and 10.8 g of aluminum chloride in 150 ml of nitrobenzene is added 12.0 g of 2-thienoyl chloride. The mixture is stirred at 60° C. for 3 hours, cooled and poured over ice water. The organic portion is extracted into ethyl acetate, dried and the organic solvent evaporated to give the title compound. M.P. 212°-215° C.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[N+:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([O-:8])=[O:7]>>[N+:6]([C:9]1[CH:10]=[C:11]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:12]=[CH:13][CH:14]=1)([O-:8])=[O:7]
Reactant: O=S(=O)(O)Cl
Reactant: O=[N+]([O-])c1ccccc1
Product: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Temperature: 82.5 °C
Reaction time: 3 h

Procedure:
Chlorosulfonic acid (475 g) was taken in a 1 L three neck round bottom flask equipped with a guard tube and liquid addition funnel. Chlorosulfonic acid was cooled in an ice bath to 5-10° C. and nitrobenzene was added to the acid slowly, at such a rate that the temperature is maintained below 10° C. Reaction mixture was then brought to 25° C. and then slowly heated in an oil bath to 80-85° C. Reaction mixture was stirred further at 80-85° C. for 3 hours. After the completion of reaction (TLC), the reaction mixture was cooled to 10° C. and poured onto the ice-water mixture along with stirring and maintaining the temperature below 10° C.; the resulting slurry is then filtered on buchner funnel. Solid cake on funnel is washed with 500 mL of water. Resulting solid cake is dried on phosphorous pentoxide in a desiccator to obtain the D1 as off white solid.
Reaction SMILES: ClCCl.[O:4]1[C@@:21]2([CH3:22])[C@@H:5]1[CH2:6][C@@H:7]1[C:12]([C:13](O)=[O:14])=[CH:11][O:10][C@@H:9]([O:16][C:17](=[O:20])[NH:18][CH3:19])[C@H:8]12.[N-]=[N+]=[N-].C1(OP([O-])(OC2C=CC=CC=2)=O)C=CC=CC=1.Cl.[CH3:44][NH2:45]>ClCCl.CO.C(N(CC)CC)C>[CH3:44][NH:45][C:13]([C:12]1[C@H:7]2[CH2:6][C@@H:5]3[O:4][C@:21]3([CH3:22])[C@@H:8]2[C@H:9]([O:16][C:17](=[O:20])[NH:18][CH3:19])[O:10][CH:11]=1)=[O:14]
Reactant: CNC(=O)O[C@@H]1OC=C(C(=O)O)[C@H]2C[C@@H]3O[C@]3(C)[C@H]12
Reactant: CN
Agent: Cl
Agent: O=P([O-])(Oc1ccccc1)Oc1ccccc1
Agent: [N-]=[N+]=[N-]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CNC(=O)O[C@@H]1OC=C(C(=O)NC)[C@H]2C[C@@H]3O[C@]3(C)[C@H]12
Temperature: 25 °C
Reaction time: 15 h
Yield: 46.8 %

Procedure:
A dichloromethane solution containing 395 mg of (1S,4aS,6S,7R,7aR)-6,7-epoxy-1,4a,5,6,7,7a-hexahydro-7-methyl-1-(methylcarbamoyloxy) cyclopenta [c]-pyrane-4-carboxylic acid described in Example 1 was cooled with ice followed by addition of 0.49 ml of triethylamine, 0.38 ml of diphenylphosphate azide and 118 mg of methylamine hydrochloride and stirring for 15 hours at room temperature. The reaction mixture was then extracted with dichloromethane. After washing the organic phase with dilute hydrochloric acid, saturated aqueous sodium bicarbonate and brine, it was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel chromatography to obtain colorless needles from the dichloromethane-methanol eluate in the form of (1S,4aS,6S,7R,7aR)-6,7-epoxy-1,4a,5,6,7,7a-hexahydro-7-methyl-1-(methylcarbamoyloxy) cyclopenta [c]-pyrane-4-carboxylic acid methylamide (194 mg, yield: 47%). The physicochemical properties of this compound are described in Table 3, Compound No. 15.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][C@@H:6]([NH:8][C:9]([C:11]2[S:12][C:13]([Cl:16])=[CH:14][CH:15]=2)=[O:10])[CH2:5][N:4]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[C:24](Cl)(=[O:26])[CH3:25].CCN(C(C)C)C(C)C.Cl>C(Cl)Cl>[C:24]([NH:1][CH2:2][C@@H:3]1[CH2:7][C@@H:6]([NH:8][C:9]([C:11]2[S:12][C:13]([Cl:16])=[CH:14][CH:15]=2)=[O:10])[CH2:5][N:4]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1C[C@H](NC(=O)c2ccc(Cl)s2)C[C@H]1CN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NC[C@@H]1C[C@@H](NC(=O)c2ccc(Cl)s2)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
70.0 mg (0.2 mmol) tert. Butyl (2S,4R)-2-aminomethyl-4-[(5-chloro-thiophene-2-carbonyl)-amino]-pyrrolidine-1-carboxylate are dissolved in 5 ml DCM and combined successively at −10° C. with 15.4 μl (0.2 mmol) acetyl chloride and 67 μl (0.4 mmol) DIPEA. The mixture is stirred for two hours at 0° C. Then it is made weakly acidic by the careful addition of dil. hydrochloric acid and extracted three times with ethyl acetate. The combined organic phases are dried on sodium sulphate, filtered and evaporated down i. vac.
Reaction SMILES: [CH3:1][C@:2]1([NH:21][C:22]2[CH:27]=[N:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=2)[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:8]([C:10]1[C:15](N2N=CC=N2)=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:9].[CH3:32][C@:33]1(NC2C=NC(C(F)(F)F)=CN=2)[CH2:37]CC[C@@H]1N.C1(C2C(C(O)=O)=NC=CC=2)CC1.C(N(CC)CC)C>>[CH:37]1([C:15]2[C:10]([C:8]([NH:7][C@H:3]3[CH2:4][CH2:5][CH2:6][C@:2]3([CH3:1])[NH:21][C:22]3[CH:27]=[N:26][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:24][N:23]=3)=[O:9])=[N:11][CH:12]=[CH:13][CH:14]=2)[CH2:33][CH2:32]1
Reactant: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1NC(=O)c1ncccc1-n1nccn1
Reactant: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1N
Agent: O=C(O)c1ncccc1C1CC1
Solvent: CCN(CC)CC
Product: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1NC(=O)c1ncccc1C1CC1

Procedure:
Prepared according to the procedure for N-[(1S,2S)-2-methyl-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxamide (Example 77) from (1S,2S)-1-methyl-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine (Intermediate 25; 48 mg, 0.15 mmol), 3-cyclopropylpyridine-2-carboxylic acid (Intermediate 16; 33 mg, 0.20 mmol) and triethylamine (0.077 ml, 0.55 mmol) except this was purified by column chromatography (silica, 0-50% ethyl acetate/petrol) followed by column chromatography (silica, 0-2.5% methanol/DCM) to afford the title compound.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[OH:9][C:10]1[C:20]2[CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][CH2:15][C:14]=2[NH:13][C:12](=[O:28])[CH:11]=1>C(Cl)Cl>[Br:8][C:11]1[C:12](=[O:28])[NH:13][C:14]2[CH2:15][CH2:16][N:17]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:18][CH2:19][C:20]=2[C:10]=1[OH:9]
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c(=O)cc(O)c2CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2[nH]c(=O)c(Br)c(O)c2CC1
Reaction time: 3 h
Yield: 82.6 %

Procedure:
NBS (0.668 mmol, 119 mg) was added in one portion to a stirred solution of tert-butyl 4-hydroxy-2-oxo-1,2,5,6,8,9-hexahydro-7H-pyrido[2,3-d]azepine-7-carboxylate (0.607 mmol, 170 mg) in DCM (3 ml) at room temperature. After 3 h of stirring, the reaction was quenched with sat. aq. NaHCO3 and extracted with DCM. The organic layer was dried, concentrated in vacuo and purified purified by column chromatography to provide 180 mg (83%) of tert-butyl 3-bromo-4-hydroxy-2-oxo-1,2,5,6,8,9-hexahydro-7H-pyrido[2,3-d]azepine-7-carboxylate. Ag2CO3 (0.42 mmol, 116 mg) was added to a solution of tert-butyl 3-bromo-4-hydroxy-2-oxo-1,2,5,6,8,9-hexahydro-7H-pyrido[2,3-d]azepine-7-carboxylate (75.0 mg, 0.21 mmol) in DCM (1.5 ml) at room temperature. After 10 min of stirring, Mel (0.23 mmol, 15 μl) was added. After 5 h of stirring, sat. aq. NH4Cl was added and the mixture was extracted with DCM. The organic layer was washed with water, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography to provide 52 mg (67%) of tert-butyl 3-bromo-4-hydroxy-2-methoxy-5,6,8,9-tetrahydro-7H-pyrido[2,3-d]azepine-7-carboxylate. The correct regioselectivity was confirmed by NOESY. 1H-NMR (CDCl3) δ 13.21 (1H), 3.85 (3H), 3.65 (2H), 3.55 (2H), 3.05 (2H), 2.85 (2H), 1.49 (9H) ppm. To a solution of tert-butyl 3-bromo-4-hydroxy-2-methoxy-5,6,8,9-tetrahydro-7H-pyrido[2,3-d]azepine-7-carboxylate (51 mg, 0.137 mmol) was added HC1 (2 N in Et2O, 3 ml) at room temperature. After 10 h of stirring, the reaction was quenched with sat. aq. NaHCO3 and extracted with DCM. The organic layer was dried and concentrated in vacuo to provide 33 mg (89%) of 3-bromo-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-4-ol. 1H-NMR (CDCl3) δ 12.02 (br s, 1H), 9.21 (br s, 1H), 3.79 (3H), 3.25 (m, 2H), 3.15 (m, 2H), 3.06 (m, 2H), 2.92 (m, 2H) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]([C:26]([O:28][CH2:29][CH3:30])=[O:27])([CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([CH3:25])[CH:17]=1)[CH2:7][C:8]([O:10]C(C)(C)C)=[O:9])=[O:5])[CH3:2].FC(F)(F)C(O)=O.C(OC(C)C)(C)C>ClCCl>[CH2:1]([O:3][C:4]([C:6]([C:26]([O:28][CH2:29][CH3:30])=[O:27])([CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([CH3:25])[CH:17]=1)[CH2:7][C:8]([OH:10])=[O:9])=[O:5])[CH3:2]
Reactant: CCOC(=O)C(CC(=O)OC(C)(C)C)(Cc1cn(C)c2ccccc12)C(=O)OCC
Solvent: CC(C)OC(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(CC(=O)O)(Cc1cn(C)c2ccccc12)C(=O)OCC
Yield: 63.5 %

Procedure:
Produced analogously to Example A1b) from tert.-butyl β,β-bis-(ethoxycarbonyl)-1-methyl-1H-indol-3-butanoate through the action of trifluoroacetic acid in dichloromethane in a yield of 63.5% of theory. Colourless crystals of Mp. 127-130° C. (diisopropylether).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([Cl:9])[CH:3]=1.C(N(CC)CC)C.[CH3:17][C:18]1([CH3:25])[C:22]([CH3:24])([CH3:23])[O:21][BH:20][O:19]1>O1CCOCC1>[Cl:9][C:4]1[CH:3]=[C:2]([B:20]2[O:21][C:22]([CH3:24])([CH3:23])[C:18]([CH3:25])([CH3:17])[O:19]2)[CH:7]=[CH:6][C:5]=1[NH2:8]
Reactant: Nc1ccc(Br)cc1Cl
Reactant: CC1(C)OBOC1(C)C
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC1(C)OB(c2ccc(N)c(Cl)c2)OC1(C)C
Temperature: 80 °C

Procedure:
Dissolve 4-bromo-2-chloro-phenylamine (4.2 g, 20 mmol) in dioxane (80 mL) in a RBF under nitrogen. Add triethylamine (10 mL, 3.6 equiv.) then sparge with nitrogen to de-gas. Add 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (8.5 mL, 2.9 equiv.) dropwise via syringe over approximately 5 minutes. Sparge an additional 5 minutes with nitrogen then add [1,1′-Bis(diphenyl-phosphino)ferrocene] dichloropalladium(II) (0.603 g, 3.7 mol %, 1:1 complex with dichloromethane). Place under nitrogen and heat at 80° C. overnight. After the reaction cools, filter via Celite® washing with hexanes. Concentrate filtrate to dryness and use crude.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[C:13]([OH:15])=[O:14])([O-:3])=[O:2].O=S(Cl)Cl.Cl.[CH3:21]O>>[CH3:21][O:14][C:13]([C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:9][N:8]=1)=[O:15]
Reactant: CO
Reactant: O=C(O)c1n[nH]c2ccc([N+](=O)[O-])cc12
Agent: Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1n[nH]c2ccc([N+](=O)[O-])cc12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 5-nitro-1H-indazole-3-carboxylic acid 17AP (10.74 g, 51.88 mmol) in MeOH (145 ml) at 0° C. was added SOCl2 (35 ml) dropwise. After stirring for 10 min at 0° C., the reaction mixture was refluxed overnight. HCl gas was evolved (Condenser was equipped with empty balloon to trap HCl). It was then cooled to room temperature, solid was collected by filtration and washed with MeOH to give desired 5-nitro-1H-indazole-3-carboxylic acid methyl ester 18AP (7 g, 61%).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C@@H:6]1[C:18](=[O:19])[N:8]2[C:9]([C:15]([OH:17])=[O:16])=[C:10]([O:13][CH3:14])[CH2:11][S:12][C@H:7]12)=[O:4].[N-:20]=[N+:21]=[N-:22].[Na+]>C(O)C.O>[N:20]([CH2:2][C:3]([NH:5][C@@H:6]1[C:18](=[O:19])[N:8]2[C:9]([C:15]([OH:17])=[O:16])=[C:10]([O:13][CH3:14])[CH2:11][S:12][C@H:7]12)=[O:4])=[N+:21]=[N-:22]
Reactant: COC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)CBr)[C@H]2SC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)CN=[N+]=[N-])[C@H]2SC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution, prepared at 30° C., of 7β-bromoacetylamino-3-methoxy-3-cephem-4-carboxylic acid (about 0.15 mmol), prepared according to the process described in Example 43, in 10 ml of ethanol and 0.3 ml of water is mixed with a solution of 0.03 g of sodium azide in 0.5 ml of water. The reaction mixture is stirred for 15 hours at room temperature with exclusion of light and is then worked up according to the process described in Example 41. 7β-Azidoacetylamino-3-methoxy-3-cephem-4-carboxylic acid is thus obtained, which in a thin layer chromatogram (silica gel; system: n-butanol/pyridine/acetic acid/water, 42:24:4:30) shows an Rf value of 0.40; ultraviolet absorption spectrum (in ethanol): λmax at 264 mμ; infrared absorption spectrum (in mineral oil): characteristic bands at 4.65μ and 5.64μ.