Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[NH:9][C:8]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:18][C:19]1([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH2:21][O:20]1>CN(C=O)C>[Cl:1][C:2]1[C:10]2[N:9]([CH2:18][C:19]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)([OH:20])[CH3:21])[C:8]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC1(c2ccncc2)CO1
Reactant: CN1CCc2[nH]c3c(Cl)cccc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCc2c(c3cccc(Cl)c3n2CC(C)(O)c2ccncc2)C1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A flask was charged with 6-chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1.0 g, 4.5 mmol) in DMF (10 mL) and stirred for 5 min. To this was added NaH (60% in hexane) (220 mg, 6.8 mmol) and stirred at RT for 10 min, followed by 4-(2-methyloxiran-2-yl)pyridine (1.08 g, 9 mmol) and stirred at RT for 16 h. The progress of reaction was monitored by TLC. The mixture was poured into ice water and filtered. The filtrate was washed with water and concentrated. The residue was recrystallized from ether to get pure product. 1HNMR (DMSO, HCl salt) d (ppm): 8.70 (d, 2H), 7.90 (d, 2H), 7.40 (m, 1H), 7.0 (m, 2H), 6.0 (m, 1H), 4.80 (m, 1H), 4.60 (m, 2H), 4.25 (m, 2H), 3.80 (m, 2H), 2.90 (s, 3H), 1.60 (s, 3H).
Reaction SMILES: [CH:1]([C:3]1[N:7]([CH:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)[CH2:9][C:10]([O:12]C)=O)[CH:6]=[N:5][CH:4]=1)=O.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:22]([N:29]1[C:10](=[O:12])[CH2:9][CH:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)[N:7]2[CH:6]=[N:5][CH:4]=[C:3]2[CH2:1]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCc1ccccc1
Reactant: COC(=O)CC(c1ccc(C#N)cc1)n1cncc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: N#Cc1ccc(C2CC(=O)N(Cc3ccccc3)Cc3cncn32)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the title C compound, methyl 3-[5-formyl-imidazol-1-yl]-3-(4-cyano-phenyl)-propionate (0.22 g, 0.78 mmol) in DCE (5 mL) is added benzylamine (0.100 mL, 0.92 mmol) followed by sodium triacetoxyborohydride (0.49 g, 2.3 mmol). The reaction mixture is stirred at RT for 16 h, then partitioned between EtOAc and saturated aqueous sodium bicarbonate, and the organic solution is washed with brine, dried (anhydrous sodium sulfate) and concentrated. The residue is subjected to flash chromatography (silica) eluting with EtOAc:MeOH:NH4OH (90:10:1) to give 4-(8-benzyl-7-oxo-6,7,8,9-tetrahydro-5H-imidazo[1,5-a][1,4]diazepin-5-yl)-benzonitrile: m.p. 65° C.; e/z (ES) 343 (M+1, 100%).
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[CH3:21][N:22]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:23][CH2:24][CH2:25][NH2:26].C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15](=[O:17])[NH:26][CH2:25][CH2:24][CH2:23][N:22]([CH3:21])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: CN(CCCN)c1ccccc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCC(=O)NCCCN(C)c2ccccc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and N1-methyl-N1-phenyl-propane-1,3-diamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C22H28N2O5 [M+H]+: 401.
Reaction SMILES: Cl.C(OC([N:9]1[C:13]2=[C:14]([NH:29][S:30]([C:33]3([CH2:36][CH:37]([OH:40])[CH2:38][OH:39])[CH2:35][CH2:34]3)(=[O:32])=[O:31])[C:15]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=3[F:28])=[C:16]([CH3:19])[C:17](=[O:18])[N:12]2[CH2:11][CH2:10]1)=O)(C)(C)C.CO>C1COCC1.C(Cl)(Cl)Cl>[F:28][C:22]1[CH:23]=[C:24]([I:27])[CH:25]=[CH:26][C:21]=1[NH:20][C:15]1[C:14]([NH:29][S:30]([C:33]2([CH2:36][CH:37]([OH:40])[CH2:38][OH:39])[CH2:34][CH2:35]2)(=[O:31])=[O:32])=[C:13]2[NH:9][CH2:10][CH2:11][N:12]2[C:17](=[O:18])[C:16]=1[CH3:19]
Reactant: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2(CC(O)CO)CC2)c2n(c1=O)CCN2C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2(CC(O)CO)CC2)c2n(c1=O)CCN2
Temperature: 40 °C
Reaction time: 2 h
Yield: 14.7 %

Procedure:
Concentrated HCl (3 mL) was added to a stirred solution of 8-[1-(2,3-dihydroxy-propyl)-cyclopropanesulfonylamino]-7-(2-fluoro-4-iodo-phenylamino)-6-methyl-5-oxo-2,3-dihydro-5H-imidazo[1,2-a]pyridine-1-carboxylic acid tert-butyl ester (80 mg) in THF (5 mL). The resulting mixture was stirred at 40° C. for 2 hours. The reaction was monitored by TLC (15% MeOH in CHCl3). The reaction mixture was concentrated and partitioned between ethylacetate and water. The organic layer was washed with saturated NaHCO3 solution and concentrated to afford the crude product. Purification by column chromatography on silica gel (5% methanol in CHCl3), followed by preparative HPLC afforded 10 mg of the product (14.7% yield)
Reaction SMILES: [F:1][C:2]1[C:3](I)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:17][CH:16]=[N:15][C:14]=1[CH3:18].C([O-])([O-])=O.[Na+].[Na+].[NH2:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1.CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[NH2:26][C:27]1[CH:32]=[C:31]([C:3]2[C:2]([F:1])=[CH:10][CH:9]=[C:8]3[C:4]=2/[C:5](=[CH:12]/[C:13]2[NH:17][CH:16]=[N:15][C:14]=2[CH3:18])/[C:6](=[O:11])[NH:7]3)[CH:30]=[CH:29][CH:28]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COCCOC
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(-c3cccc(N)c3)c21

Procedure:
A solution of (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (50 mg, 0.135 mmol) (Starting Material 11), 2M aqueous Na2CO3 solution (0.14 mL), (Ph3P)2PdCl2 (11 mg, 0.0135 mmol) and 3-aminobenzeneboronic acid (52.5 mg, 0.339 mmol) (Lancaster) in a 1:4 mixture of DMF:1,2-dimethoxyethane (5 mL) was heated at 104° C. for 4 days. The reaction mixture was concentrated and the crude material was purified by C18 reverse phase chromatography to give (Z)-4-(3-Aminophenyl)-1,3-dihydro-5-fluoro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one. (Yield 18 mg, 40%).
Reaction SMILES: [As:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH2:12]SCCC(N[C@H](C(O)=O)CCC(O)=O)=O)=[O:11])=[CH:5][CH:4]=1)=[O:2].[SH:28][CH2:29][CH2:30][C:31]([NH:33][C@@H:34]1[C@@H:40]([OH:41])[C@H:39]([OH:42])[C@@H:38]([CH2:43][OH:44])[O:37][CH:35]1[OH:36])=[O:32].[Na].[Na].C(=O)(O)[O-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CS(C)=O>[As:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([CH2:12][S:28][CH2:29][CH2:30][C:31]([NH:33][C@@H:34]2[C@@H:40]([OH:41])[C@H:39]([OH:42])[C@@H:38]([CH2:43][OH:44])[O:37][CH:35]2[OH:36])=[O:32])=[O:11])=[CH:7][CH:8]=1)=[O:2]
Reactant: O=C(CCS)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: O=[As]c1ccc(NC(=O)CSCCC(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Product: O=[As]c1ccc(NC(=O)CSCCC(=O)N[C@H]2C(O)O[C@H](CO)[C@@H](O)[C@@H]2O)cc1

Procedure:
The procedure used was the same as for N-(3-(4-arsenosophenylcarbamoylmethylthio)propanoyl)-L-glutamic acid, using 3.00 mL (210 μmol) of 70.0 mM BRAO in DMSO, the disulfide of disodium N-(3-mercaptopropanoyl)-D-glucosamine (0.67 g), 0.5 M bicarbonate buffer, pH 9 (11.96 mL, 600 mmol), and 0.69 M triphenylphosphine in DMSO (1.9 mL, 1.3 mmol). The active concentration of trivalent arsenic was found to be 13.5 mM (11.0 mL of solution).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([N:8]2[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([O:24]CC)=[O:23])=[CH:16][CH:15]=3)[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([N:8]2[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([OH:24])=[O:23])=[CH:16][CH:15]=3)[CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C=C/c1ccc(N[C@@H]2CCN(C(=O)c3ccc(Cl)cc3)C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)/C=C/c1ccc(N[C@@H]2CCN(C(=O)c3ccc(Cl)cc3)C2)cc1
Temperature: 70 °C
Yield: 37.3 %

Procedure:
To a solution of ethyl (2E)-3-(4-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}phenyl)acrylate (297 mg) in dioxane (3 mL) was added 1N NaOH aq solution (2.23 mL), and the mixture was heated at 70° C. for 18 hours. Resulting mixture was diluted with water and washed with ether. The pH value of aqueous phase was adjusted to 5, and the precipitate was collected by filtration and dried in vacuo to give (2E)-3-(4-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}phenyl)acrylic acid (103 mg) as pale yellow powder.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][O:7][CH3:8])=[O:3].[O:9]1[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]1[C:18]1[C:19]([NH2:35])=[N:20][CH:21]=[C:22]([C:24]2[CH:25]=[N:26][N:27]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[CH:28]=2)[CH:23]=1>N1C=CC=CC=1>[NH2:35][C:19]1[N:20]=[CH:21][C:22]([C:24]2[CH:25]=[N:26][N:27]([CH:29]3[CH2:34][CH2:33][N:32]([C:2]([O:4][CH2:5][CH2:6][O:7][CH3:8])=[O:3])[CH2:31][CH2:30]3)[CH:28]=2)=[CH:23][C:18]=1[C:10]1[O:9][C:17]2[C:12]([N:11]=1)=[N:13][CH:14]=[CH:15][CH:16]=2
Reactant: COCCOC(=O)Cl
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ncccc2o1
Solvent: c1ccncc1
Product: COCCOC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4nc5ncccc5o4)c3)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-methoxyethyl chloroformate (0.035 ml) at 25° C. was added over a period of 5 minutes under argon to a stirred mixture of 3-oxazolo[4,5-b]pyridin-2-yl-5-[1-(4-piperidyl)pyrazol-4-yl]pyridin-2-amine (90 mg) and pyridine (5 ml). The resulting suspension was stirred at 25° C. for 2 hours. The solvent was evaporated. A solution of ammonia in methanol 7N (1 ml) was added and the mixture was adsorbed on silica gel. The crude product was purified by flash chromatography on silica gel eluting with 1 to 5% methanolic ammonia (7 N) in dichloromethane. The solvent was evaporated to dryness to afford 2-methoxyethyl 4-[4-(6-amino-5-oxazolo[4,5-b]pyridin-2-yl-3-pyridyl)pyrazol-1-yl]piperidine-1-carboxylate (75 mg) as a solid. NMR Spectrum: (CDCl3): 1.95-2.07 (m, 2H), 2.17-2.26 (m, 2H), 3.01 (bs, 2H), 3.40 (s, 3H), 3.63 (t, 2H), 4.28 (bs, 2H), 4.29-4.44 (m, 3H), 7.02 (bs, 2H), 7.35 (dd, 1H), 7.69 (s, 1H), 7.79 (s, 1H), 7.90 (dd, 1H), 8.41 (d, 1H), 8.42 (d, 1H), 8.59 (dd, 1H); Mass spectrum: M+H+ 464.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([C:10]([F:13])([F:12])[F:11])=[CH2:9])[CH:5]=[C:4]([Cl:14])[CH:3]=1.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N+:23]#[C-:24])=[CH:18][C:17]=1[CH3:25]>C1(C)C=CC=CC=1.[Cu-]=O>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:9][C:8]([C:6]3[CH:5]=[C:4]([Cl:14])[CH:3]=[C:2]([Cl:1])[CH:7]=3)([C:10]([F:11])([F:13])[F:12])[CH:24]=[N:23]2)=[CH:18][C:17]=1[CH3:25]
Reactant: [C-]#[N+]Cc1ccc(Br)c(C)c1
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: O=[Cu-]
Solvent: Cc1ccccc1
Product: Cc1cc(C2CC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C=N2)ccc1Br
Temperature: 110 °C
Reaction time: 16 h
Yield: 26.8 %

Procedure:
A mixture of 1,3-dichloro-5-(1-trifluoromethyl-vinyl)-benzene (preparation described in, for example, EP 1,731,512) (8.03 g), 1-bromo-4-isocyanomethyl-2-methyl-benzene (Example 10.3) (4.16 g) and copper(I) oxide (0.13 g) in toluene (50 ml) was stirred at 110° C. for 16 hours. The reaction mixture was concentrated and the residue purified by chromatography on silica gel (eluent: ethyl acetate/heptane) to give 2-(4-bromo-3-methyl-phenyl)-4-(3,5-dichloro-phenyl)-4-trifluoromethyl-3,4-dihydro-2H-pyrrole (2.39 g). 1H-NMR (400 MHz, CDCl3): 7.39-6.86 (m, 7H), 5.39-4.98 (m, 1H), 3.24-2.77 (m, 1H), 2.35 (m, 3H), 2.32-2.09 (m, 1H) ppm.
Reaction SMILES: C=O.[F:3][C:4]1[CH:12]=[CH:11][C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=1.[C:13]1(C)C=CC=CC=1.[ClH:20]>C(OCC)(=O)C.[Cl-].[Cl-].[Zn+2]>[Cl:20][CH2:13][C:10]1[C:6]2[CH:5]=[C:4]([F:3])[CH:12]=[CH:11][C:7]=2[S:8][CH:9]=1
Reactant: Cl
Reactant: Cc1ccccc1
Reactant: Fc1ccc2sccc2c1
Agent: C=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: Fc1ccc2scc(CCl)c2c1
Temperature: -10 °C
Yield: 82.6 %

Procedure:
A mixture of formol (37%; 31 g) and ZnCl2 (10 g) in ethyl acetate (90 ml) and HCl (12 N; 190 ml) was stirred at −10° C. HCl (gas) was allowed to bubble through the mixture until saturation (at −10° C.). 5-Fluoro-benzo[b]thiophene (0.35 mol) was added dropwise at <0° C. The reaction mixture was stirred overnight at room temperature. Toluene (200 ml) was added and the mixture was stirred vigorously. The organic layer was separated, washed with an aqueous NaHCO3 solution and with water, dried, filtered and the solvent was evaporated. The residue was triturated under hexane, filtered off and dried, yielding 58 g (82.6%) of 3-(chloromethyl)-5-fluorobenzo[b]-thiophene (interm 11).
Reaction SMILES: [Li+].[OH-].[C:3]([O:7][C:8]([NH:10][C@H:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]([O:22]C)=[O:21])[CH:18]=2)[CH2:13][CH2:12]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>O.CO.C1COCC1>[C:3]([O:7][C:8]([NH:10][C@H:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]([OH:22])=[O:21])[CH:18]=2)[CH2:13][CH2:12]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)c1ccc2c(c1)[C@H](NC(=O)OC(C)(C)C)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1CCc2ccc(C(=O)O)cc21
Temperature: 0 °C
Reaction time: 6 h
Yield: 70 %

Procedure:
LiOH (647 mg, 15.42 mmol, 3 eq), dissolved in water (8 ml), was added dropwise to an ice-cooled (0° C.) solution of (R)-methyl 3-(tert-butoxycarbonylamino)-2,3-dihydro-1H-indene-5-carboxylate (stage (ii) product of A-07) (1.5 g, 5.15 mmol, 1 eq) in MeOH:THF (1:1, 16 ml), and stirring was carried out for 6 h at RT. After monitoring by thin-layer chromatography, the reaction solution was concentrated and the residue was taken up in water (20 ml) and adjusted to pH 3 with NaHSO3. The acidic, aqueous phase was extracted with ethyl acetate (2×150 ml), washed with sat. NaCl solution (2×50 ml), dried over sodium sulfate and concentrated under reduced pressure. Yield: 70% (1.0 g, 3.61 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11]([C:13]2[N:14]=[C:15]([CH2:18][N:19]3C(=O)C4C(=CC=CC=4)C3=O)[O:16][CH:17]=2)=[O:12])[CH:5]=[CH:6][CH:7]=1.O.NN>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11]([C:13]2[N:14]=[C:15]([CH2:18][NH2:19])[O:16][CH:17]=2)=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCCc1cccc(Cl)c1)c1coc(CN2C(=O)c3ccccc3C2=O)n1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCc1nc(C(=O)NCCc2cccc(Cl)c2)co1
Reaction time: 12 h

Procedure:
2-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-oxazole-4-carboxylic acid [2-(3-chloro-phenyl)-ethyl]-amide (0.75 g, 1.8 mmol) was dissolved in ethanol (5 mL). Hydrazine monohydrate (0.44 mL, 9.2 mmol) was added. The mixture was stirred for 12 hours. A white precipitate formed during the course of the reaction. The mixture was filtered and the solid was washed with methanol. The filtrate was reduced in vacuo to afford the title compound: 1H NMR (400 MHz, d6-DMSO): 8.46 (s, 1H), 8.27 (t, 1H), 7.27 (m, 3H), 7.16 (m, 1H), 3.78 (s, 2H), 3.45 (m, 2H), 2.82 (t, 2H); MS (ESI-LCMS) for C13H14ClN3O2: 280 (MH+).
Reaction SMILES: [NH2:1][C@@H:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9]OC(=O)CC(=O)C)[CH2:7][S:8][C@H:3]12.C(=O)([O-])O.[Na+].[SH:27][C:28]1[S:29][C:30]([CH3:33])=[N:31][N:32]=1>O>[NH2:1][C@@H:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][S:27][C:28]3[S:29][C:30]([CH3:33])=[N:31][N:32]=3)[CH2:7][S:8][C@H:3]12
Reactant: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Cc1nnc(S)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)[C@@H](N)[C@H]3SC2)s1
Temperature: 60 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
In water (30 ml) was dissolved 7β-amino-3-(3-oxobutyryloxy)methyl-3-cephem-4-carboxylic acid (3.14 g) together with sodium hydrogen carbonate (1.84 g) and 2-mercapto-5-methyl-1,3,4-thiadiazole(1.6 g) and the resultant solution was adjusted its pH to 6.4, followed by stirring for one hour at 60° C. After cooling, the reaction solution was washed with dichloromethane and pH of the aqueous layer was adjusted to 3.5 under ice-cooling, followed by stirring for one hour. The precipitated materials were collected by filtration and washed with water, methanol and acetone in this order, followed by drying to give 7β-amino-3-(2-methyl-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (2.9 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[CH:10][CH:11]=[CH:12][C:13](Cl)=[O:14].CCN(CC)CC.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]=[CH:31][CH2:32][NH2:33])=[CH:26][CH:25]=1.CO>C(Cl)Cl.CN(C1C=CN=CC=1)C.C([O-])(O)=O.[Na+]>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([CH:30]=[CH:31][CH2:32][NH:33][C:13](=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])=[CH:28][CH:29]=1
Reactant: O=C(Cl)C=CC=Cc1ccc(Cl)cc1Cl
Reactant: NCC=Cc1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(C=CC=Cc1ccc(Cl)cc1Cl)NCC=Cc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
To a solution of 5-(2,4-dichloro-phenyl)-penta-2,4-dienoyl chloride (62.5 mmol) in 300 mL CH2Cl2 at 0° C. was added Et3N (13.0 mL) followed by DMAP (i.e., 4-diaminomethylpyridine) (760 mg). To this was added a solution of 3-(4-chloro-phenyl)-allylamine (10.5 g) in 30 mL CH2Cl2. The mixture was stirred at 0° C. for 1 hr. Then 2 mL of MeOH was added, and the solution was stirred for 10 min. The solution was then diluted with aq. NaHCO3 and extracted with EtOAc. Filtration of solids and concentration of EtOAc layers provided a combined yield of 24.6 g of 5-(2,4-dichloro-phenyl)-penta-2,4-dienoic acid [3-(4-chloro-phenyl)-allyl]-amide. MS: m/e 392.2 (MH+)
Reaction SMILES: C(=O)(O)[O-].[Na+].[NH2:6][C@@H:7]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:8]([OH:10])=[O:9].[CH3:19][O:20][C:21]1[CH:26]=[C:25]([CH3:27])[C:24]([S:28](Cl)(=[O:30])=[O:29])=[C:23]([CH3:32])[CH:22]=1>O1CCOCC1.O.O1CCOCC1>[C:15]([O:14][C:12](=[O:13])[CH2:11][C@H:7]([NH:6][S:28]([C:24]1[C:25]([CH3:27])=[CH:26][C:21]([O:20][CH3:19])=[CH:22][C:23]=1[CH3:32])(=[O:30])=[O:29])[C:8]([OH:10])=[O:9])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)C[C@H](N)C(=O)O
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(C)c(S(=O)(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)O)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
Sodium bicarbonate (1.5 eq) was added to a suspension of (S)-2-amino-4-tert-butoxy-4-oxobutanoic acid (5.1 mmol, 1.2 eq) in dioxane/water (1:1, 20 ml) and the mixture was stirred for 30 min at room temperature. A solution of 4-methoxy-2,6-dimethylbenzenesulfonic acid chloride (4.3 mmol, 1.0 eq) in dioxane (10 ml) was added and the reaction mixture stirred for 16 h at room temperature. On completion of the reaction the organic solvent was removed under vacuum and the aqueous phase acidified with 10% HCl (eq). Extraction was then performed with DCM and the organic phase was washed with saturated sodium chloride solution, dried (Na2SO4) and concentrated to small volume under vacuum. Yield: 45%.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:3]=1[CH2:4]P(=O)(OCC)OCC.[Br:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23]([CH:26]=1)[CH:24]=O.CC(C)([O-])C.[K+].CCCCCC>O1CCCC1.CCOCC>[Br:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23](/[CH:24]=[CH:4]/[C:3]2[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:2]=2[F:1])[CH:26]=1
Reactant: CCOP(=O)(Cc1cc(F)ccc1F)OCC
Reactant: O=Cc1cncc(Br)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOCC
Product: Fc1ccc(F)c(/C=C/c2cncc(Br)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.1 %

Procedure:
To a stirred solution of diethyl 2,5-difluorobenzylphosphonate (63.5 g, 240 mmol) and 5-bromonicotinaldehyde (50.7 g, 264 mmol) in tetrahydrofuran (1923 ml) was added potassium tert-butoxide in tetrahydrofuran (312 ml, 312 mmol) at −10° C. After three hours, the reaction mixture was allowed to warm to ambient temperature and stirring was continued for another 16 hours at which time the reaction mixture was diluted with ether (800 mL) and washed with H2O. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to provide a yellow wax to which was added 300 mL of hexane and after sonication filtered to provide (E)-3-bromo-5-(2,5-difluorostyryl)pyridine (54 g, 173 mmol, 72.1%) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 8.78 (d, J=1.8 Hz, 1H), 8.63 (d, J=2.1 Hz, 1H), 8.44 (t, J=2.0 Hz, 1H), 7.67 (ddd, J=9.4, 6.0, 3.2 Hz, 1H), 7.56-7.48 (m, 1H), 7.46-7.40 (m, 1H), 7.34 (td, J=9.6, 4.6 Hz, 1H), 7.24 (tt, J=8.3, 3.6 Hz, 1H). MS Anal. Calcd. for [M+H]+ C13H9BrF2N: 296.0. found 298.1.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([NH2:12])=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:13][C:14]1[N:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[N:16]=[CH:17][CH:18]=1)[CH3:2]>C1(C)C=CC=CC=1.COC(O)C>[CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([N:12]3[CH:1]=[N:3][CH:4]=[N:5]3)=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:13][C:14]1[N:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[N:16]=[CH:17][CH:18]=1)[CH3:2]
Reactant: CCn1c(Cc2ccnn2-c2cccc(F)c2)nc2cc(N)ccc21
Agent: COC(C)O
Solvent: Cc1ccccc1
Product: CCn1c(Cc2ccnn2-c2cccc(F)c2)nc2cc(-n3cncn3)ccc21

Procedure:
1-Ethyl-2-{[2-(3-fluorophenyl)-pyrazol-3-yl]methyl}-5-amino-1H-benzimidazole (274 mg) is treated with N,N-dimethylformamide azine hydrochloride (1 eq) in toluene (10 mL) and methoxyethanol (10 mL) and refluxed for 6 h. After cooling and concentrating, the residue is treated with water and extracted with dichloromethane (2×). The aqueous layer is adjusted to pH 8 with aqueous sodium bicarbonate and extracted with dichloromethane (2×). The combined organic extracts are washed with saturated aqueous sodium chloride, dried (MgSO4), concentrated, purified by preparative silica gel chromatography, and triturated with ether to afford 1-Ethyl-2-{[2-(3-fluorophenyl)-pyrazol-3-yl]methyl}-5-(1,2,4-triazol-1-yl)-1H-benzimidazole, which is converted to the hydrochloride salt in ethyl acetate. LCMS MH+406.2.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:10]3=[N:11][CH:12]=[C:13]([NH:15][NH:16]C(OC(C)(C)C)=O)[N:14]=[C:9]3[CH:8]=2)[CH:4]=[N:3]1.Cl.O1CCOCC1>CCOC(C)=O>[NH:15]([C:13]1[N:14]=[C:9]2[CH:8]=[C:7]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:10]2=[N:11][CH:12]=1)[NH2:16]
Reactant: Cn1cc(-c2cc3nc(NNC(=O)OC(C)(C)C)cnc3n2COCC[Si](C)(C)C)cn1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cn1cc(-c2cc3nc(NN)cnc3n2COCC[Si](C)(C)C)cn1
Temperature: 60 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a flask was added tert-butyl 2-(6-(1-methyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate (0.152 g, 0.331 mmol, Preparation #O.1), HCl (4.0 M in 1,4-dioxane, 0.827 mL, 3.31 mmol) and 1,4-dioxane (5 mL). The mixture was heated to about 60° C. for about 1 h then stirred at rt overnight. The mixture was diluted with EtOAc (10 mL), washed with aqueous saturated NaHCO3, dried over anhydrous MgSO4 and concentrated in vacuo to give 2-hydrazinyl-6-(1-methyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (0.100 g, 84%): LC/MS (Table 2, Method c) Rt=1.43 min; MS m/z 360 (M+H)+.