Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:31])[CH:3]([CH2:29][CH3:30])[CH:4]([C:10]1[CH:28]=[CH:27][C:13]2[N:14]=[C:15]([C:17]3[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=3)[S:16][C:12]=2[CH:11]=1)[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.[Li+].[OH-]>O.O1CCOCC1>[CH3:1][N:2]([CH3:31])[CH:3]([CH2:29][CH3:30])[CH:4]([C:10]1[CH:28]=[CH:27][C:13]2[N:14]=[C:15]([C:17]3[CH:26]=[CH:25][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=3)[S:16][C:12]=2[CH:11]=1)[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1
Reactant: CCC(C(c1ccc2nc(-c3ccc(C(=O)OC)cc3)sc2c1)n1ccnc1)N(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCC(C(c1ccc2nc(-c3ccc(C(=O)O)cc3)sc2c1)n1ccnc1)N(C)C
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A mixture of methyl 4-(6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoate (115 mg, 0.265 mmol) and LiOH (31.7 mg, 1.33 mmol) in water (1.5 mL) and dioxane was heated to 50° C. and stirred for 2 h. The solvent was evaporated, water was added and neutralized to pH 7 and evaporated. The residue was dissolved in 35% methanol in DCM, loaded onto a PTLC plate and eluted with 30% methanol in DCM. To afford 4-(6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoic acid. MS ESI: m/z 421.17 [M+1+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([OH:15])[CH:10]([N+:12]([O-])=O)[CH3:11])[CH:5]=[CH:6][CH:7]=1.O>CCO.[Fe]>[NH2:12][CH:10]([CH3:11])[CH:9]([OH:15])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: CC(C(O)Cc1cccc(Br)c1)[N+](=O)[O-]
Agent: [Fe]
Solvent: CCO
Solvent: O
Product: CC(N)C(O)Cc1cccc(Br)c1
Temperature: 25 °C
Yield: 68.3 %

Procedure:
To a solution of 1-(3-bromophenyl)-3-nitrobutan-2-ol (1.0 g, 3.6 mmol) in EtOH (20 mL)/H2O (1 mL), iron powder (2.0 g, 36 mmol) was added in one portion. The suspension was refluxed overnight, cooled to RT, and filtered. The filtrate was evaporated, diluted with H2O (30 mL), and extracted with EtOAc (50 mL×3). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (Petroleum ether:EtOAc=3:1) to afford 3-amino-1-(3-bromophenyl)butan-2-ol (600 mg, 68%). MS (ES+) C10H14BrNO requires: 243, 245 found: 244, 246[M+2+H]+(1:1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[C:9]2[CH:10]=[CH:11][N:12]=[CH:13][C:14]=2[CH:15]=[CH:16][CH:17]=1)(=[O:7])=[O:6].[Cl:18][C:19]1[CH:28]=[CH:27][C:22]([CH:23]=[CH:24][CH:25]=O)=[CH:21][CH:20]=1.[Na].C(OCC)(=O)C>CO>[Cl:18][C:19]1[CH:28]=[CH:27][C:22]([CH:23]=[CH:24][CH2:25][NH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]2[C:9]3[CH:10]=[CH:11][N:12]=[CH:13][C:14]=3[CH:15]=[CH:16][CH:17]=2)(=[O:7])=[O:6])=[CH:21][CH:20]=1
Reactant: O=CC=Cc1ccc(Cl)cc1
Reactant: NCCNS(=O)(=O)c1cccc2cnccc12
Agent: [Na]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=S(=O)(NCCNCC=Cc1ccc(Cl)cc1)c1cccc2cnccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.5 %

Procedure:
2.01 g of N-(2-aminoethyl)-5-isoquinolinesulfonamide was dissolved in 30 ml of methanol, to the solution was added 1.60 g of p-chlorocinnamaldehyde, and the mixture was stirred for one hour at a room temperature. After an addition of 350 mg of sodium tetrahydrideborate in portions with ice cooling, the mixture was stirred for 30 minutes. After an addition of ethyl acetate, the reaction mixture was sequentially washed three times with water, and then twice with a saturated sodium chloride aqueous solution, and dried over magnesium sulfate. The mixture was filtered and evaporated to remove the solvent under a reduced pressure. A residue was purified using a silica gel column (silica gel 80 g, eluant: 5% methanol in chloroform), and resulting crystals were washed with benzene/hexane (1:1), to obtain 2.30 g of the title compound as colorless crystals.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:33][C:34]([F:45])([F:44])[C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([C:39]3[CH:38]=[CH:37][CH:36]=[C:35]([C:34]([F:45])([F:44])[F:33])[CH:40]=3)[C:18]([C:23]([N:25]3[CH2:30][CH2:29][S:28](=[O:31])(=[O:32])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCS(=O)(=O)CC1)n2-c1cccc(C(F)(F)F)c1)N1CCN(C2CCCC2)CC1
Yield: 40 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone (example 34), 3-(trifluoromethyl)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light yellow solid (40%).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]([CH3:16])[C:13]([OH:15])=O)[CH:7]=[CH:6]2)#[N:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[F:33][C:34]1[CH:39]=[CH:38][C:37]([C:40](=[NH:43])[NH:41]O)=[CH:36][CH:35]=1>CC#N>[F:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[N:43]=[C:13]([CH:12]([N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:20])([F:19])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)[CH3:16])[O:15][N:41]=2)=[CH:36][CH:35]=1
Reactant: CC(C(=O)O)n1ccc2c(C(F)(F)F)c(C#N)ccc21
Reactant: N=C(NO)c1ccc(F)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: CC(c1nc(-c2ccc(F)cc2)no1)n1ccc2c(C(F)(F)F)c(C#N)ccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 7.7 %

Procedure:
To 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]propanoic acid (0.06 g, 0.212 mmol) in CH3CN (3 mL) was added CDI (0.034 g, 0.212 mmol). After 5 min, 4-fluoro-N-hydroxybenzenecarboximidamide (0.033 g, 0.212 mmol) was added. The resulting mixture was stirred at rt and then heated to 150° C. in a microwave for 20 min. Concentration was followed by column chromatography (EtOAc/hexanes) to obtain the desired product (0.0065 g, 8% yield): MS (APCl) m/z 401 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3](=[O:27])[CH:4]([N:9]1[C:15](=[O:16])[CH2:14][CH2:13][N:12]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[CH2:11][CH2:10]1)[CH2:5][CH2:6][CH2:7]Br.[CH3:29][C:30]1([OH:36])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+]>CC#N.CCOC(C)=O>[CH3:1][N:2]([CH3:28])[C:3](=[O:27])[CH:4]([N:9]1[C:15](=[O:16])[CH2:14][CH2:13][N:12]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[CH2:11][CH2:10]1)[CH2:5][CH2:6][CH2:7][N:33]1[CH2:34][CH2:35][C:30]([OH:36])([CH3:29])[CH2:31][CH2:32]1
Reactant: CN(C)C(=O)C(CCCBr)N1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Reactant: CC1(O)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CN(C)C(=O)C(CCCN1CCC(C)(O)CC1)N1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Reaction time: 16 h
Yield: 34.9 %

Procedure:
A solution of 107 mg (0.23 mmol) of (rac)-5-bromo-2-[7-oxo-4-(3-trifluoromethyl-phenyl)-[1,4]diazepan-1-yl]-pentanoic acid dimethylamide in 4 ml of CH3CN was treated with 115 mg (0.28 mmol) of 4-methyl-piperidin-4-ol (intermediate 8) and 63 mg (0.46 mmol) of potassium carbonate. After 16 h at RT, the reaction mixture was diluted with AcOEt and a white solid was filtered off. The filtrate was evaporated and chromatographed by amine-silica gel column (AcOEt:MeOH 19:1) to yield 40 mg (35%) of the title compound as yellow oil. MS: 499.2 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH:11]=[C:12]([CH:15]=[O:16])[O:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)[C:20]([F:23])([F:22])[F:21].[F-].[Cs+].C(OCC)(=O)C>O1CCCC1>[CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH:11]=[C:12]([CH:15]([OH:16])[C:20]([F:23])([F:22])[F:21])[O:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1cc(=O)c(OCc2ccccc2)co1
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=c1cc(C(O)C(F)(F)F)occ1OCc1ccccc1
Reaction time: 0.17 h
Yield: 57 %

Procedure:
The entire experiment was performed under an inert atmosphere by bubbling argon gas into the ice-salt cooled reaction mixture. To a cloudy solution of 5-benzyloxy-4-oxo-4H-pyran-2-carbaldehyde (5.00 g, 21.7 mmol) in dry tetrahydrofuran (185 mL) previously purged with argon for 35 min was added trimethyl(trifluoromethyl)silane (10.8 g, 76.0 mmol) dropwise, followed by caesium fluoride (0.34 g, 2.2 mmol). The color of the reaction mixture turned to yellow and almost clear within a min. TLC was used to monitor the reaction (eluant: 50:50, ethyl acetate:hexanes, v:v). The reaction was completed within 10 min. The reaction mixture was quenched with a 6.0N hydrochloric acid solution (20 mL) under cooling, followed by addition of a brine solution (50 mL). The mixture was stirred for 10 min, and then transferred to a separatory funnel. The organic THF fraction was collected, and then concentrated in vacuo to about 10 mL using the rotary evaporator. The residual solution was diluted with dichloromethane (80 mL). The mixture was transferred to a separatory funnel, and the separated dichloromethane layer was collected, dried over Na2SO4 and filtered. Upon concentration under reduced pressure, a first crop of the titled compound was obtained as a solid product (3.72 g, 57% yield, HPLC Method 1 (Example 24), RT=16.8 min, HPLC purity (peak percent area): 96% at λ=280 nm). 1H NMR (DMSO-d6+D2O) 6 ppm: 8.20 (s, 1H), 7.36 (br m, 5H), 6.57 (s, 1H), 5.11 (q, J=7 Hz, 1H), 4.92 (s, 2H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:32]=[CH:31][C:6]2[CH2:7][CH2:8][CH2:9][CH:10]([N:12]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:13][C@H:14]([OH:23])[CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][C:5]=2[CH:4]=1.[C:33]([O:37][C:38](=[O:41])[CH:39]=[CH2:40])([CH3:36])([CH3:35])[CH3:34]>CO>[C:33]([O:37][C:38](=[O:41])[CH2:39][CH2:40][NH:1][CH2:2][C:3]1[CH:32]=[CH:31][C:6]2[CH2:7][CH2:8][CH2:9][CH:10]([N:12]([CH2:13][C@H:14]([OH:23])[CH2:15][O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:11][C:5]=2[CH:4]=1)([CH3:36])([CH3:35])[CH3:34]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: NCc1ccc2c(c1)CC(N(Cc1ccccc1)C[C@H](O)COc1ccccc1)CCC2
Solvent: CO
Product: CC(C)(C)OC(=O)CCNCc1ccc2c(c1)CC(N(Cc1ccccc1)C[C@H](O)COc1ccccc1)CCC2
Reaction time: 18 h

Procedure:
To a solution of (2S)-1-[N-(3-aminomethyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)benzylamino]-3-phenoxy-2-propanol (100 mg) in methanol (2 ml) was added tert-butylacrylate (0.033 ml) at room temperature, and the mixture was stirred at the same temperature for 18 hours. The resulting mixture was evaporated in vacuo. The residue was chromatographed (hexane-ethyl acetate) over silica gel to afford 3-(8-[N-benzyl-(2S)-(2-hydroxy-3-phenoxypropyl)amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylmethylamino]-propionic acid tert-butyl ester (100 mg).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([O:22]CC)=[O:21]>CC(C)=O>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([O:1][CH2:19][C:20]([OH:22])=[O:21])=[CH:3][CH:4]=1
Reactant: Oc1ccnc2ccccc12
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(O)COc1ccnc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.5 %

Procedure:
The mixture of 4-hydroxyquinoline (290 mg, 2.0 mmol), potassium carbonate (910 mg, 6.6 mmol), ethyl bromoacetate (500 mg, 3.0 mmol) and acetone (25 ml) was refluxed for 8 h. After cooling, the mixture was filtered to remove potassium carbonate. The filtrate was concentrated under reduced pressure. To this residue, 10 ml dioxane and 14 ml 5% sodium hydroxide solution were added. After the mixture was stirred at room temperature overnight, it was acidified with concentrated hydrochloric acid to pH 3, and then extracted three times with ethyl acetate (20 ml each). Water layer was placed in cold room, and solid came out. The crystals were filtered with suction and washed with water, and then dried to give 120 mg quinoline-4-oxyacetic acid as gray crystals, mp 274-276° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH:7]([CH2:16][CH2:17][CH2:18][N:19](C)[CH3:20])[C:6]=2[CH:22]=1.N#CN>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH:7]([CH2:16][CH2:17][CH2:18][NH:19][CH3:20])[C:6]=2[CH:22]=1
Reactant: CN(C)CCCC1c2ccccc2CCc2ccc(Cl)cc21
Agent: N#CN
Product: CNCCCC1c2ccccc2CCc2ccc(Cl)cc21

Procedure:
3-Chloro-10,11-dihydro-5-(3-dimethylaminopropyl)-5H-dibenzo[a,d]cycloheptene is converted to the corresponding cyanamide by following the procedure of Example 6 A. Upon hydrolysis, according to the procedure of Example 6 B., there is obtained 3-chloro-10,11-dihydro-5-(3-methylaminopropyl)-5H-dibenzo[a,d]cycloheptene. This may be converted to its hydrochloride salt directly by treatment with ethanolic hydrogen chloride as described in Example 6 B. After recrystallization from a mixture of isopropyl alcohol and ether, the hydrochloride salt melts at 192.5°-193.5° C., dec.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:16])[CH:14]=3)[N:9]3[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:8]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:22]([O:24][C:25](=[O:30])[C:26](Br)([CH3:28])[CH3:27])[CH3:23]>>[CH2:22]([O:24][C:25](=[O:30])[C:26]([O:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:8]1=[C:7]2[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([CH3:28])[CH3:27])[CH3:23]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Oc1ccc2c(c1)c(-c1ccccc1)c1n2CCCCC1
Product: CCOC(=O)C(C)(C)Oc1ccc2c(c1)c(-c1ccccc1)c1n2CCCCC1

Procedure:
In accordance with a procedure analogous to that of Example 10, the above compound was prepared from 7,8,9,-10-tetrahydro-11-phenyl-6H-azepino[1,2-a]-indole-2-ol and 2-bromo-2-methyl-propanoic acid ethylester.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[Cl:17][C:18](Cl)([O:20]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:18]([Cl:17])=[O:20])[CH2:4][CH2:3]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CN1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(C(=O)Cl)CC1
Temperature: 0 °C

Procedure:
To solution of methyl piperazine (166 uL, 1.50 mmol) In anhydrous dichloromethane (2 mL), diisopropyl ethyl amine (300 uL, 1.72 mmol) was added. The reaction was cooled to 0° C. under N2. Triphosgene (240 mg, 0.809 mmol) was added and the reaction was allowed to warm to rt. The chloride was used immediately without purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])=O)=[CH:20][C:19]=2[F:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:35][N:36]1[C:45]2[NH:44][C:43]3[CH:46]=[CH:47][CH:48]=[CH:49][C:42]=3[NH:41][CH2:40][C:39]=2[CH:38]=[N:37]1>ClCCl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:41]3[CH2:40][C:39]4[CH:38]=[N:37][N:36]([CH3:35])[C:45]=4[NH:44][C:43]4[CH:46]=[CH:47][CH:48]=[CH:49][C:42]3=4)=[O:26])=[CH:20][C:19]=2[F:27])[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: Cn1ncc2c1Nc1ccccc1NC2
Reactant: CC(C)(C)OC(=O)N1CCN(CCCOc2ccc(C(=O)O)cc2F)CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1ncc2c1Nc1ccccc1N(C(=O)c1ccc(OCCCN3CCN(C(=O)OC(C)(C)C)CC3)c(F)c1)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 48 %

Procedure:
A solution of 4-[3-(4-carboxy-2-fluoro-phenoxy)-propyl]-piperazine-1-carboxylic acid tert-butyl ester from Example E39 (865 mg, 2.3 mmol) in dichloromethane (50 ml) was treated with triethylamine (to pH9), WSCD (865 mg, 4.5 mmol) and DMAP (276 mg, 2.3 mmol), and the mixture was stirred at room temperature for 10 min. 3-Methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E11 (541 mg, 2.7 mmol) was added. The mixture was heated at reflux for 18 h then concentrated in vacuo. The residue was dissolved in EtOAc, washed with saturated NaHCO3 then brine and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 10% methanol:90% dichloromethane) to yield the title compound (615 mg, 48%).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[OH:18][C:19]1[C:23]([OH:24])=[C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:21]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[C:20]=1[C:38]([O:40][CH2:41][CH3:42])=[O:39]>CCO>[CH2:1]([O:18][C:19]1[C:23]([OH:24])=[C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:21]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[C:20]=1[C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1c(O)c(O)c(C(=O)OCC)n1-c1ccc(OC)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)c1c(O)c(OCc2ccccc2)c(C(=O)OCC)n1-c1ccc(OC)cc1
Temperature: 50 °C
Reaction time: 18 h
Yield: 46 %

Procedure:
Benzyl bromide (2.13 ml, 17.9 mmol) was added dropwise to a suspension of DIPEA (3.12 mL, 17.9 mmol) and diethyl 3,4-dihydroxy-1-(4-methoxyphenyl)-1H-pyrrole-2,5-dicarboxylate (UL2-001) (5 g, 14.3 mmol) in EtOH (200 mL). The reaction mixture was stirred at 50° C. for 18 h. Additional benzyl bromide (0.85 mL, 7.20 mmol) and DIPEA (1.25 mL, 7.20 mmol) were added and the reaction stirred at 60° C. for 24 h, after which further portions of benzyl bromide (0.85 ml, 7.20 mmol) and DIPEA (1.25 mL, 7.20 mmol) were added and the reaction mixture stirred at 60° C. for 24 h. The reaction mixture was allowed to cool to RT, and partitioned between EtOAc (200 mL) and sat. NaHCO3 (aq.) (200 mL), the organic layer was separated and washed with sat. NaHCO3 (aq.) (2×200 mL) dried (MgSO4), filtered and solvents removed in vacuo to give an orange oil. The residue was purified by silica gel chromatography (80 g, 0-100% EtOAc in isohexane) to afford a yellow solid. The product was recrystallised from EtOH (100 mL) to afford diethyl 3-(benzyloxy)-4-hydroxy-1-(4-methoxyphenyl)-1H-pyrrole-2,5-dicarboxylate (23) (2.89 g, 37%) as a pale yellow solid: m/z 440 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 8.82 (s, 1H), 7.52-7.30 (m, 5H), 7.16-7.03 (m, 2H), 6.94-6.83 (m, 2H), 5.09 (s, 2H), 4.10-3.91 (m, 4H), 3.79 (s, 3H), 1.02-0.92 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([CH2:8][CH2:9][CH2:10][CH2:11][C:12](O)=[O:13])=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([Cl:19])=[O:13])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)CCCCC(=O)c1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)CCCCC(=O)c1ccc(Cl)cc1
Yield: 100 %

Procedure:
5-(4-Chlorobenzoyl)pentanoic acid (9.6g) was dissolved in dry toluene (80 ml) and thionyl chloride (10 ml) added. The reaction mixture was heated to reflux for 4 hours. The excess toluene and thionyl chloride were removed in vacuo, more toluene was added and again removed in vacuo affording 5-(4-chlorobenzoyl)pentanoyl chloride (10.4g 100%) as a pale brown solid.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][CH:3]=[CH:2]1.CCN(CC)CC.Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>C(Cl)Cl>[CH2:4]1[C:5]2([CH2:10][CH2:9][N:8]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH2:7][CH2:6]2)[CH2:1][CH:2]=[CH:3]1
Reactant: C1=CCC2(C1)CCNCC2
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCC2(CC=CC2)CC1
Reaction time: 1 h
Yield: 70.9 %

Procedure:
To a solution of 8-azaspiro[4.5]dec-2-ene (2.74 g, 20 mmol) in Et3N (4.2 mL, 30 mmol) and DCM (100 mL) at 0° C. was added dropwise benzyl chloroformate (3.4 mL, 24 mmol). After 1 h, the solution was partitioned between H2O-DCM and the aqueous phase was extracted several times with DCM. The combined organic fractions were dried (Na2SO4), concentrated and purified via column chromatography (silica, 10% EtOAc in hexanes) yielding the title compound (3.85 g, 71%) as a yellow oil: LCMS (ES) m/e 272 (M+H)+.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[N:4]1.[C:8]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:13]=[CH:12][CH:11]=[C:10]([N:14]2[CH:18]=[C:17]([C:19](Cl)=[O:20])[N:16]=[CH:15]2)[CH:9]=1.O>CN(C=O)C>[C:8]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:13]=[CH:12][CH:11]=[C:10]([N:14]2[CH:18]=[C:17]([C:19]([N:3]3[CH:7]=[CH:6][CH:5]=[N:4]3)=[O:20])[N:16]=[CH:15]2)[CH:9]=1
Reactant: O=C(Cl)c1cn(-c2cccc(-c3ccccc3)c2)cn1
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1cn(-c2cccc(-c3ccccc3)c2)cn1)n1cccn1
Reaction time: 0.5 h

Procedure:
To a stirred, ice-cooled solution of sodium hydride (45 mg, 1.14 mmol) in anhydrous DMF (10 ml) was added pyrazole (77 mg, 1.14 mmol) and stirring was continued for 30 min. under nitrogen. A solution of compound 11a (0.27 g, 0.95 mmol) in DMF (10 ml) was added slowly and the resultant mixture was stirred at ambient conditions overnight. Water (80 ml) was added and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the concentrate was purified by column chromatography on silica gel eluting with a mixture of ethyl acetate and petroleum ether (1:1) to afford 178. (60 mg, 20%). Mp 124-127° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([CH2:23][C:24]2[CH:29]=[CH:28][C:27](F)=[CH:26][CH:25]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:31](OC1N=NC(Cl)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.[Cl-].CC1C=C(C=CC=1)C[Zn+]>>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH3:31])[CH:25]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Reactant: Fc1ccc(Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1
Agent: Cc1cccc(C[Zn+])c1
Agent: [Cl-]
Product: Cc1cccc(Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)c1
Yield: 66 %

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-[(4-fluorophenyl)methyl]pyridazine (Intermediate 51) from 3,4-bis(benzyloxy)-6-chloropyridazine (Intermediate 1) and (3-methylbenzyl)zinc(II) chloride in 66% yield.
Reaction SMILES: [NH2:1][CH:2]1[C:25](=[O:26])[N:4]2[C:5]([C:22]([OH:24])=[O:23])=[C:6]([CH:9]([S:16][C:17]3[NH:21][N:20]=[N:19][N:18]=3)[CH2:10][CH2:11][NH:12][C:13]([NH2:15])=[O:14])[CH2:7][S:8][C@H:3]12.CC(C)=O.[CH3:31][CH2:32][C:33](Cl)=[S:34].[OH-].[Na+]>C(=O)(O)[O-].[Na+]>[CH3:31][CH2:32][C:33]([NH:1][CH:2]1[C:25](=[O:26])[N:4]2[C:5]([C:22]([OH:24])=[O:23])=[C:6]([CH:9]([S:16][C:17]3[NH:18][N:19]=[N:20][N:21]=3)[CH2:10][CH2:11][NH:12][C:13]([NH2:15])=[O:14])[CH2:7][S:8][C@H:3]12)=[S:34]
Reactant: CCC(=S)Cl
Reactant: NC(=O)NCCC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCC(=S)NC1C(=O)N2C(C(=O)O)=C(C(CCNC(N)=O)Sc3nnn[nH]3)CS[C@H]12
Reaction time: 0.33 h

Procedure:
To a sitrred, cooled (-20°) solution of 10.4 g. (0.026 mol.) of 7-amino-3-[1-(2-ureidoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid in 220 ml of 3% sodium bicarbonate and 220 ml. of acetone is added dropwise a solution of 3.66 g. (0.029 mol.) of methylthioacetyl chloride in 52 ml. of acetone, during which time the pH of the reaction mixture is maintained at 8.0 by addition of 10% sodium hydroxide. After addition the reaction mixture is stirred an additional 20 minutes at -15°, then is warmed to 25° and extracted with ether. The remaining aqueous phase is cooled, 250 ml. of ethyl acetate is added and the slurry is acidified with 3N hydrochloric acid. The layers are separated and the aqueous phase is extracted twice more with ethyl acetate. The combined extracts are dried (MgSO4) and evaporated to dryness to yield the title compound.