Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]([CH3:29])=[C:11]([CH3:28])[C:12]=1[C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21]C)=[C:17]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:16]=1)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.C(Cl)Cl>C(Cl)Cl>[CH2:1]([C:8]1[O:9][C:10]([CH3:29])=[C:11]([CH3:28])[C:12]=1[C:13]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:16]=1)=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)c2c(Cc3ccccc3)oc(C)c2C)cc1C1CCCC1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1oc(Cc2ccccc2)c(C(=O)c2ccc(O)c(C3CCCC3)c2)c1C
Yield: 36.1 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 3 using (2-benzyl-4,5-dimethyl-furan-3-yl)-(3-cyclopentyl4-methoxy-phenyl)-methanone (17.7 g, 45.5 mmol) and 1M boron tribromide/CH2Cl2 (34.8 mL) in CH2Cl2. Purification on Biotage KP-Sil eluting with a 2, 5 & 10% EtOAc/pet. ether step gradient gave 6.15 g (36%) of the title compound. 1H NMR (DMSO-d6) δ1.40-1.46 (m, 2 H), 1.59-1.72 (m, 4 H), 1.78 (s, 3 H), 1.90-1.94 (m, 2 H), 2.16 (s, 3 H), 3.18 (quinet, 1 H), 3.81 (s, 2 H), 6.87 (d, 1 H), 7.06 (d, 2 H), 7.16-7.25 (m, 3 H), 7.46 (dd, 1 H), 7.55 (s, 1 H), 10.33 (s, 1 H).
Reaction SMILES: Cl.Cl.[NH2:3][NH2:4].[CH3:5][C:6]1[C:7](=O)[O:8][C:9](=[O:12])[C:10]=1[CH3:11]>O>[CH3:5][C:6]1[C:7](=[O:8])[NH:3][NH:4][C:9](=[O:12])[C:10]=1[CH3:11]
Reactant: CC1=C(C)C(=O)OC1=O
Reactant: NN
Agent: Cl
Solvent: O
Product: Cc1c(C)c(=O)[nH][nH]c1=O
Temperature: 100 °C
Yield: 62.5 %

Procedure:
Hydrazine dihydrochloride (83.6 g) was dissolved in water (20 ml), heated to 100° C., and 3,4-dimethylfuran-2,5-dione (100.4 g) was introduced while stirring. Then the mixture was heated to reflux for 3 h. Subsequently, the precipitate formed was filtered off with suction, washed with water and dried. The residue was suspended in EA (2 l), filtered off with suction, and was dried. 69.7 g of the title compound were obtained. LC-MS rt: 0.19 min [M+H]+: 141.1 (met. b)
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=O)=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2([OH:23])[CH2:22]O[CH2:20]2)=[C:15]([O:24][CH3:25])[CH:14]=1.[CH3:26]C(=CC)C.Cl([O-])=O.[Na+].[OH2:35].[OH2:36].P([O-])(O)(O)=O.[Na+]>CC#N.O.C(O)(C)(C)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:36])=[O:35])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2([OH:23])[CH2:20][CH2:26][CH2:22]2)=[C:15]([O:24][CH3:25])[CH:14]=1
Reactant: COc1cc(-c2cc3c(C=O)c[nH]c3cc2F)ccc1C1(O)COC1
Reactant: O
Reactant: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: CC#N
Product: COc1cc(-c2cc3c(C(=O)O)c[nH]c3cc2F)ccc1C1(O)CCC1
Temperature: 0 °C
Yield: 8.1 %

Procedure:
6-fluoro-5-[4-(3-hydroxyoxetan-3-yl)-3-methoxyphenyl]-1H-indole-3-carbaldehyde (86 mg, 0.2534 mmol) was dissolved in MeCN (6 mL) and warm t-butanol (6 mL). 2-methyl-2-butene (4 mL) was then added and cooled to 0° C. Sodium chlorite (342 mg, 5.07 mmol) and sodium dihydrogen phosphate dihydrate (791 mg, 5.07 mmol) were dissolved in water (3 mL). The aqueous solution was added to the organic solution dropwise via addition funnel and the ice bath was removed and the mixture was allowed to warm to room temperature. The reaction was quenched with saturated aqueous sodium sulfite, concentrated to remove the organics and extracted with EtOAc (20 mL×3). The combined organics were washed with brine (20 mL), dried and concentrated to give a crude residue, which was purified by prep HPLC to afford the title compound (7.3 mg, 8.1%) as an off-white solid.
Reaction SMILES: CC1C(C)=CC=CC=1OCCCC(N1[C:19]2[C:14](=[C:15]([B:20]3[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]3)[CH:16]=[CH:17][CH:18]=2)CCC1)=O.BrC1C=CC=C2C=1CCCN2C(=O)CCCOC1C=CC=C(C)C=1C.BrC1C=C(C=CC=1)[CH2:63][O:64][C:65]([NH:67][CH2:68][CH2:69][C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71])=[O:66]>>[CH3:26][C:23]1([CH3:25])[C:22]([CH3:27])([CH3:28])[O:21][B:20]([C:15]2[CH:14]=[C:19]([CH:18]=[CH:17][CH:16]=2)[CH2:63][O:64][C:65]([NH:67][CH2:68][CH2:69][C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71])=[O:66])[O:24]1
Reactant: Cc1cccc(OCCCC(=O)N2CCCc3c(B4OC(C)(C)C(C)(C)O4)cccc32)c1C
Reactant: CC(C)(C)OC(=O)CCNC(=O)OCc1cccc(Br)c1
Agent: Cc1cccc(OCCCC(=O)N2CCCc3c(Br)cccc32)c1C
Product: CC(C)(C)OC(=O)CCNC(=O)OCc1cccc(B2OC(C)(C)C(C)(C)O2)c1

Procedure:
The title compound was prepared using a procedure analogous to 4-(2,3-dimethylphenoxy)-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-1(2H)-yl)butan-1-one except that 1-(5-bromo-3,4-dihydroquinolin-1(2H)-yl)-4-(2,3-dimethylphenoxy)butan-1-one was replaced with tert-butyl 3-((3-bromobenzyloxy)carbonylamino)propanoate. LCMS, [M+Na]+=428.2.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([OH:10])[N:4]=1)[NH2:2].[OH-].[Na+].[C:13](=S)=[S:14]>C(O)C>[OH:10][C:5]1[N:4]2[C:13]([SH:14])=[N:2][N:1]=[C:3]2[CH:8]=[C:7]([CH3:9])[N:6]=1
Reactant: S=C=S
Reactant: Cc1cc(NN)nc(O)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc2nnc(S)n2c(O)n1
Yield: 53.8 %

Procedure:
The product obtained in Step 2 (1.0 g) was added to a solution of 0.29 g of sodium hydroxide in 20 ml of 80% ethanol, 1.31 g of carbon disulfide was further added, and the mixture was refluxed for 24 hours. After concentrating under reduced pressure, the residue was dissolved in 10 ml of water and the pH was adjusted to 2.0 with 1N hydrochloric acid. The formed crystals were collected by filtration and washed with 10 ml of water and 10 ml of ethanol, affording 0.7 g of the objective compound as pink crystals.
Reaction SMILES: [NH3:1].[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:15]2[CH:16]=[C:17]([I:20])[CH:18]=[CH:19][C:14]=2[NH:13][C:12](=S)[CH2:11][N:10]=1.CO>O1CCCC1>[NH2:1][C:12]1[CH2:11][N:10]=[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[F:2])[C:15]2[CH:16]=[C:17]([I:20])[CH:18]=[CH:19][C:14]=2[N:13]=1
Reactant: N
Reactant: Fc1ccccc1C1=NCC(=S)Nc2ccc(I)cc21
Solvent: CO
Solvent: C1CCOC1
Product: NC1=Nc2ccc(I)cc2C(c2ccccc2F)=NC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
50 ml of 25% aqueous ammonia solution were added to a solution of 2.3 g of 5-(2-fluorophenyl)-7-iodo-3H-1,4-benzodiazepine-2(1H)-thione (A. Walser, T. Flynn, C. Mason, H. Crowley, C. Maresco, B. Yaremko & M. O'Donell, J.Med.Chem., 1991, 34, 1209) in 120 ml of tetrahydrofuran. After the addition of 5 ml of methanol the solution was stirred at room temperature for 24 h. and then evaporated in a vacuum. The residue was partitioned between saturated aqueous sodium hydrogen carbonate solution and chloroform. The aqueous phase was extracted a further three times with chloroform. The chloroform extracts were dried over sodium sulphate and evaporated in a vacuum. The residue was recrystallized from ethyl acetate. There were obtained 2.73 g of 2-amino -7-iodo-5-(2-fluorophenyl)-3H-1,4-benzodiazepine of m.p. 219-221° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH2:5]Cl)=[O:4].[CH:7]1[CH:12]=[CH:11][C:10]([P:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][CH:8]=1>C1COCC1.CCOCC>[Cl-:1].[Cl:1][CH2:2][C:3](=[O:4])[CH2:5][P+:13]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:10]1[CH:9]=[CH:8][CH:7]=[CH:12][CH:11]=1
Reactant: O=C(CCl)CCl
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(CCl)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Cl-]
Yield: 170.1 %

Procedure:
The procedure of Tome et al., Tetrahedron Letters, Volume 37, pp 6951-6954 (1996), was followed. 1,3-Dichloroacetone (8.0 g) and Ph3P (15.0 g) were stirred in THF (38 mL) at reflux for 4 h. The cooled suspension was diluted with ether, filtered and the solid was washed with ether and dried to give (3-chloro-2-oxopropyl)triphenylphosphonium chloride (20.86 g) as a white solid. This material was dissolved in a mixture of water (110 mL) and MeOH (110 mL) and treated with NaHCO3 (10.3 g). The resulting white precipitate was collected by filtration, washed with water and dried in vacuo to give 1-chloro-3-(triphenylphosphanylidene)-2-propanone (18.25 g). A solution of this phosphorane (18.2 g) and 3-chlorophenol (7.28 g) was stirred with K2CO3 (28.57 g) in DMSO (91 mL) at 62° C. for 18 then diluted with water (2 L), extracted with ether (3×1 L), dried (MgSO4), filtered and concentrated to give 1-(3-chlorophenoxy)-3-(triphenylphosphanylidene)-2-propanone (21.7 g) as a tan solid. 1H NMR (CDCl3): δ 4.02 (s, 2H), 4.23-4.35 (d, 1H), 7.42-7.72 (m, 15H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[CH3:17][S:18]([O:1][CH2:2][CH2:3][CH:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CCOS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 121.5 %

Procedure:
The reaction was prepared in 2 batches, with both batches purified together. The amounts of reactants and product reflect the sum of both batches. To 1,1-dimethylethyl 4-(2-hydroxyethyl)-1-piperidinecarboxylate (172 g, 750 mmol) in DCM (4 L) was added TEA (304 g, 1.50 mol). The mixture was cooled 0° C. and methanesulfonyl chloride (190 g, 827 mmol) was added dropwise. The reaction mixture was stirred at rt for 2 h. The reaction was determined to be complete by TLC. The reaction was diluted with DCM and washed with saturated Na2CO3 and the aqueous layer was separated. The organic layer was dried (Na2SO4), and rotovapped down to provide the title compound of Step B (280 g, 911 mmol, 61%). 1H NMR (400 MHz, CDCl3) δ 0.95-1.15 (m, 2H), 1.38 (s, 9H), 1.47-1.68 (m, 5H), 2.53-2.70 (m, 2H), 2.94 (s, 3H), 3.95-4.10 (m, 2H), 4.21 (t, J=8.8 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.ClC1N=CN=C(C(NC2C=CC(O)=CC=2)=O)C=1.[NH2:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][N:33]=[CH:32]2.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:28][C:29]2[CH:30]=[C:31]3[C:35](=[CH:36][CH:37]=2)[NH:34][N:33]=[CH:32]3)=[O:9])[CH:3]=1
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: O=C(Cl)c1cc(Cl)ncn1
Agent: O=C(Nc1ccc(O)cc1)c1cc(Cl)ncn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Nc1ccc2[nH]ncc2c1)c1cc(Cl)ncn1

Procedure:
To a cooled (0° C.) solution of 6-chloropyrimidine-4-carbonyl chloride in DCM (60 mL), obtained as described above for Intermediate 7, step 1 (798 mg; 4.51 mmol) was added dropwise, during a period of 30 minutes, a solution of 5-aminoindazole (Aldrich, 500 mg; 3.76 mmol) and DIEA (1.29 ml; 7.51 mmol) in dry DMF (5 mL). At the end of addition the reaction mixture was concentrated in vacuo, diluted with water and extracted with EtOAc. A white precipitate separated from the organic phase. It was filtered and dried in vacuo to afford the title compound as a beige solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[N:24]1[CH:29]=[C:28](B(O)O)[CH:27]=[N:26][CH:25]=1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:28]5[CH:29]=[N:24][CH:25]=[N:26][CH:27]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: OB(O)c1cncnc1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cncnc4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.105 mmol) and pyrimidine-5-boronic acid (Frontier Scientific, Logan, USA, 16 mg, 0.129 mmol) to give the title compound as a white solid. (HPLC: tR 2.24 min (Method A); M+H=372 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.20 (s, 1H), 9.02 (s, 1H), 8.93 (s, 2H), 8.20-8.12 (m, 2H), 8.06-7.99 (m, 1H), 7.62-7.56 (m, 1H), 3.90 (s, 3H), 3.58 (s, 3H), 1.97 (s, 3H))
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4].[CH:13]1[N:14]=[C:15]([NH2:56])[C:16]2[N:21]=[CH:20][N:19]([C@@H:22]3[O:26][C@H:25]([CH2:27][O:28][P:29]([O:32][P:33]([O:36][CH2:37][C@H:38]4[O:42][C@@H:41]([N:43]5[CH:48]=[C:47]([C:49]([NH2:51])=[O:50])[CH2:46][CH:45]=[CH:44]5)[C@H:40]([OH:52])[C@@H:39]4[OH:53])([OH:35])=[O:34])([OH:31])=[O:30])[C@@H:24]([OH:54])[C@H:23]3[OH:55])[C:17]=2[N:18]=1>>[OH:12][CH2:11][C@@H:9]([C@H:7]([C@@H:5]([C@@H:3]([CH2:2][OH:1])[OH:4])[OH:6])[OH:8])[OH:10].[CH:45]1[CH:44]=[N+:43]([C@@H:41]2[O:42][C@H:38]([CH2:37][O:36][P:33]([O:32][P:29]([O:28][CH2:27][C@H:25]3[O:26][C@@H:22]([N:19]4[C:17]5[N:18]=[CH:13][N:14]=[C:15]([NH2:56])[C:16]=5[N:21]=[CH:20]4)[C@H:23]([OH:55])[C@@H:24]3[OH:54])([OH:31])=[O:30])([OH:35])=[O:34])[C@@H:39]([OH:53])[C@H:40]2[OH:52])[CH:48]=[C:47]([C:49]([NH2:51])=[O:50])[CH:46]=1
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Product: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO

Procedure:
Activity: The inventive sorbitol dehydrogenase catalyzes dehydrogenation oxidation of D-sorbitol in the presence of NAD+ to produce D-fructose, and also catalyzes the reverse reaction which reduces D-fructose in the presence of NADH to produce D-sorbitol and NAD+.
Reaction SMILES: CCCCCC.C([Li])CCC.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH:27]([C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=1)([CH3:29])[CH3:28].O>C1COCC1>[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:34]([C:33]1[CH:36]=[CH:37][C:30]([CH:27]([CH3:29])[CH3:28])=[CH:31][CH:32]=1)[OH:35])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Brc1ccccc1OCc1ccccc1
Reactant: CC(C)c1ccc(C=O)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1ccc(C(O)c2ccccc2OCc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
In a nitrogen stream, an n-butyllithium hexane solution (2.44 M, 5.14 mL) was added dropwise to a solution of 1-benzyloxy-2-bromobenzene (3.0 g, 11.4 mmol) in THF (114 mL) at −78° C. and the reaction mixture was stirred at the same temperature for 30 minutes. To this solution, a solution of 4-isopropylbenzaldehyde (1.41 g, 9.49 mmol) in THF (38 mL) was added dropwise at −78° C. The reaction mixture was stirred at the same temperature for one hour and furthermore at 0° C. for one hour. Water was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:5)] to obtain the title compound (2.63 g, 84%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=O)[N:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:27][C@H:28]1[CH2:33][CH2:32][C@H:31]([NH2:34])[CH2:30][CH2:29]1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH3:27][C@H:28]1[CH2:33][CH2:32][C@H:31]([NH:34][C:11]([C:3]2[N:2]=[CH:1][C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)=[O:13])[CH2:30][CH2:29]1
Reactant: C[C@H]1CC[C@H](N)CC1
Reactant: O=C(O)c1cc2ccccc2cn1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CC[C@H](NC(=O)c2cc3ccccc3cn2)CC1
Temperature: 50 °C

Procedure:
A solution of isoquinoline-3-carboxylic acid (346 mg, 2 mmol), and 1,1′-carbonyldiimidazole (325 mg, 2 mmol) in dimethylformamide (4 mL) was heated at 50° C. for 1 hour. After this time, trans-4-methylcyclohexylamine hydrochloride (300 mg, 2 mmol), and N,N-diisopropylethylamine (0.523 mL, 3 mmol) were added and the mixture heated at 50° C. for 16 hours. The reaction mixture was cooled, and diluted with ethyl acetate (20 mL). The organic solution was washed with water (3×15 mL), brine (20 mL), dried over anhydrous MgSO4, filtered and concentrated to afford 377 mg (70%) of 406:
Reaction SMILES: [CH2:1]([C:8](=[CH2:25])[C:9]([NH:11][N:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(Cl)Cl>[CH2:25]=[C:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]([NH:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:10]
Reactant: C=C(Cc1ccccc1)C(=O)NN1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=C(Cc1ccccc1)C(=O)NN1CCNCC1
Reaction time: 2 h
Yield: 68.5 %

Procedure:
Under an inert atmosphere, 7.4 g of the product of Step A were cooled to -15° C. in 20 ml of methylene chloride and then 13 ml of trifluoroacetic acid were added dropwise. After allowing to return to ambient temperature and stirring for 2 hours, neutralizing with a saturated aqueous solution of sodium bicarbonate, extractin was done with ethyl acetate. The extracts were washed with salted water, dried and the solvents were eliminated under reduced pressure to obtain 3.6 g of the expected product melting at 78° C.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=2[C:9]=1/[CH:10]=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]>CCOC(C)=O.[Pd]>[CH2:1]([C:5]1[O:6][C:7]2[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=2[C:9]=1[CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1oc2ccccc2c1/C=C\c1ccc(OC)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCc1oc2ccccc2c1CCc1ccc(OC)cc1

Procedure:
At ambient temperature, a solution containing cis-2-butyl-3-[2-(4-methoxy-phenyl)-vinyl]-benzofuran (0.400 g, 1.31 mmol) in EtOAc (5 mL) and 10% palladium on carbon (200 mg) was stirred under H2 (atmospheric conditions). The reaction was filtered and the filtrate concentrated to the title compound as a clear oil. 1H NMR (DMSO-d6) δ0.83 (t, 3H), 1.20 (sextet, 2H), 1.37 (quintet, 2H), 2.49-2.52 (m, 2H, with DMSO), 2.78-2.85 (m, 4H), 3.68 (s, 3H), 6.78 (d, 2H), 7.03 (d, 2H), 7.17-7.21 (m, 2H), 7.41-7.43 (m, 1H), 7.54-7.56 (m, 1H). IR (KBr) 2950, 1610, 1510, 1450 and 1250 cm−1. mass spectrum (EI) m/z 308 (M+). Anal. Calcd. for C21H24O2: C, 81.78; H, 7.84; N, 0.00. Found: C, 81.55; H, 7.57; N, 0.10.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][C@H:11]3[C@@H:15]([CH3:16])[CH2:14][N:13](C(OCC4C=CC=CC=4)=O)[CH2:12]3)=[C:8]([C:27](=[O:29])[NH2:28])[CH:7]=[N:6][N:5]2[CH:30]=1.I[Si](C)(C)C.CO>C(#N)C>[Br:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][C@H:11]3[C@@H:15]([CH3:16])[CH2:14][NH:13][CH2:12]3)=[C:8]([C:27]([NH2:28])=[O:29])[CH:7]=[N:6][N:5]2[CH:30]=1.[BrH:1]
Reactant: C[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)nc12
Agent: C[Si](C)(C)I
Solvent: CC#N
Solvent: CO
Product: Br
Product: C[C@H]1CNC[C@H]1Nc1c(C(N)=O)cnn2cc(Br)nc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 197 %

Procedure:
To a suspension of (3S,4S)-benzyl 3-((2-bromo-7-carbamoylimidazo[1,2-b]pyridazin-8-yl)amino)-4-methylpyrrolidine-1-carboxylate (3.78 g, 7.98 mmol) in acetonitrile (53 ml) at 0° C. was added iodotrimethylsilane (3.26 ml, 23.96 mmol) dropwise. The reaction solution was stirred at room temperature for 1.5 h. The reaction was cooled to 0° C. and quenched with methanol (3.23 ml, 80 mmol). The resulting suspension was stirred at 0° C. for 30 min, filtered, washed with diethyl ether, and dried under vacuum to afford 2-bromo-8-(((3S,4S)-4-methylpyrrolidin-3-yl)amino)imidazo[1,2-b]pyridazine-7-carboxamide, 2 hydrobromide (3.94 g, 7.86 mmol, 98% yield) as a light yellow solid. ESI-MS (analytical LCMS Method B): m/z 341.1 ([M+H]+). HPLC (analytical HPLC Method B) Rt: 1.503 min.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][C:3]=1[NH2:4].Cl[CH2:12][CH:13]=[O:14].C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][C:2]1[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][C:3]=1[NH:4][CH2:12][CH:13]=[O:14]
Reactant: Cc1ccc(C#N)cc1N
Reactant: O=CCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccc(C#N)cc1NCC=O
Temperature: 150 °C

Procedure:
2-Methyl-5-cyanoaniline (0.3 mole), the dimethyl acetal of 2-chloroacetaldehyde (0.3 mole) and sodium carbonate (20 grams) are charged into a glass reaction flask equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated to about 150° C. for a period of about 8 hours. After this time the mixture is filtered and the filtrate is distilled to yield the desired product the dimethyl acetal of 2-(2-methyl-5-cyanoanilino)acetaldehyde.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[CH:4][C:3]=1[Cl:9].[CH2:10]([S-:12])[CH3:11].[Na+]>CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:12][CH2:10][CH3:11])=[CH:4][C:3]=1[Cl:9]
Reactant: Fc1ccc(Br)c(Cl)c1
Reactant: CC[S-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCSc1ccc(Br)c(Cl)c1
Temperature: 100 °C
Yield: 70 %

Procedure:
To a room temperature solution of 1-bromo-4-fluoro-2-chlorobenzene (1.9 g, 0.97 mmol) in DMSO (10 mL) was added sodium ethanethiolate (0.84 g, 1 mmol) and the resulting reaction mixture was heated to 100° C. for 18 hours. The reaction mixture was partitioned between water (20 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer was further extracted with EtOAc (3×50 mL). The organic layers were combined and washed with saturated brine solution (20 mL) then dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography eluting with heptane to afford the title compound as a colourless liquid in 70% yield, 1.6 g.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][C:10]([OH:12])=O.C([Cl:16])(=O)C.P(Cl)(Cl)(Cl)(Cl)Cl>>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][C:10]([Cl:16])=[O:12]
Reactant: CC(=O)Cl
Reactant: O=C(O)COc1ccccn1
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: O=C(Cl)COc1ccccn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 2-(2-pyridyloxy)acetic acid hydrochloride (1.5 g) and acetyl chloride (8 ml) was added at -30° C. phosphorus pentachloride (3.3 g), and the mixture was stirred at room temperature for 18 hours. Precipitated crystals were collected by filtration and washed with a small amount of acetyl chloride and diethyl ether and dried to give 2-(2-pyridyloxy)acetyl chloride (1.3 g). A mixture of 7-(D-2-phenylglycinamido)-3-methyl-3-cephem-4-carboxylic acid (2.5 g) and trimethylsilylacetamide (0.0288 mole) in methylene chloride (70 ml) was stirred for 1.5 hours. The solution was cooled to 3° C. and the above obtained 2-(2-Pyridyloxy)acetyl chloride was added thereto. The resultant mixture was stirred under ice-cooling for 2 hours and concentrated. To the residue was added ice-water and the resultant powder was filtrated and washed with acetone containing water and acetone in turn to give powder (1.4 g). The filtrate and washings were collected together and extracted with ethyl acetate four times. The ethyl acetate extracts were washed with water, dried and concentrated to give powder (0.4 g). Thus obtained powders (1.4 g) and (0.4 g) were combined together and recrystallized from methanol to give crystals (0.9 g) of 7-{D-2-[2-(2-pyridyloxy)acetamido]-2-phenylacetamido}-3-methyl-3-cephem-4-carboxylic acid, mp 209° to 211° C. (dec).